Conditions: Cardiac Failure Aggravated
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 32
Healthy volunteers: no

Brief summary:
Primary Objectives:

* Assess the safety and tolerability of sotagliflozin in hemodynamically stable participants with worsening of heart failure, compared to placebo.
* Estimate the effects of sotagliflozin on plasma volume changes in hemodynamically stable participants with worsening of heart failure, compared to placebo.

Secondary Objectives:

* Explore the effect of sotagliflozin on erythropoiesis, as assessed by changes in plasma erythropoietin levels, in hemodynamically stable participants with worsening of heart failure, compared to placebo.
* Explore the effect of sotagliflozin on changes in plasma N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels, in hemodynamically stable participants with worsening of heart failure, compared to placebo.

Detailed description:
The total study duration will be approximately 27-40 days, including a screening period of 1-10 days, a treatment period of 14 days, and a follow-up period of 14±2 days.

Arms:
arm 1: Participants were randomized to matching placebo to sotagliflozin administered as two tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days. arm 2: Participants were randomized to Sotagliflozin 200 mg administered as 1 sotagliflozin tablet and 1 matching placebo tablet, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days. arm 3: Participants were randomized to Sotagliflozin 400 mg administered as two 200 mg sotagliflozin tablets, once daily, before the first meal of the day in the double-blind treatment period for up to 14 days.

Interventions: intervention 1: Sotagliflozin intervention 2: Placebo
Intervention descriptions: intervention 1: Pharmaceutical form: Tablet; Route of administration: Oral intervention 2: Pharmaceutical form: Tablet; Route of administration: Oral

Protocol document:
Prot_000.pdf: 
Official Title: 
An exploratory, randomized, double-blind, placebo-controlled, 
parallel arm trial of the safety and pharmacodynamic activity of 
sotagliflozin in hemodynamically stable patients with worsening 
heart failure  
NCT Number: 
NCT03292653 
Document Date(s): 
Protocol Version 2: 02 August 2019 


 
 
 
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 
 
 
Page 1 
 
AMENDED CLINICAL TRIAL PROTOCOL 03 
  
 
COMPOUND: Sotagliflozin / SAR439954 
An exploratory, randomized, double-blind, placebo-controlled, parallel arm trial of 
the safety and pharmacodynamic activity of sotagliflozin in hemodynamically 
stable patients with worsening heart failure 
STUDY NUMBER: PDY15079 
 
VERSION DATE / STATUS: 01-Aug-2019 / Approved 
 
 
 
 
 
 
 
 
 
 
 
 
Version Number: 
2   
EudraCT  
2017-002774-39 
IND Number(s) 
IND 
 
WHO universal trial number: 
U1111-1190-7962 
Date: 
01-Aug-2019  
Total number of pages: 
124 
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CLINICAL TRIAL SUMMARY 
COMPOUND: SAR439954 
STUDY No : PDY15079 
TITLE 
An exp oratory, random zed, doub e-b nd, p acebo-contro ed, 
para e  arm tr a  of the safety and pharmacodynam c act v ty of 
sotag f oz n n hemodynam ca y stab e pat ents w th worsen ng 
heart fa ure. 
INVESTIGATOR/TRIAL LOCATION 
Pr nc pa  Invest gator; Dr. 
. 
Mu t nat ona , mu t center, Up to 15 s tes for cohort 1 and 2. 
US on y, m ted number of centers 1-3 for cohort 3 
STUDY OBJECTIVE(S) 
Primary objectives:  
The pr mary object ve of th s study s the assessment of safety 
and to erab ty of sotag f oz n, added to the standard of care 
treatment, n hemodynam ca y stab e pat ents w th worsen ng of 
heart fa ure, compared to p acebo. 
A co-pr mary object ve of th s tr a  s the est mat on of the effect 
of sotag f oz n, when added to the standard of care treatment, on 
changes n p asma vo ume, as assessed by d rect ( nd cator 
d ut on) and/or nd rect (hemo-concentrat on) methods, n 
hemodynam ca y stab e pat ents w th worsen ng of heart fa ure, 
compared to p acebo. 
Secondary objectives: 
Exp ore the effect of sotag f oz n, added to standard of care 
treatment, on erythropo es s, as assessed by changes n p asma 
erythropo et n eve s, n hemodynam ca y stab e pat ents w th 
worsen ng of heart fa ure, compared to p acebo. 
Exp ore the effect of sotag f oz n, added to standard of care 
treatment, on changes n p asma NT-proBNP eve s, n 
hemodynam ca y stab e pat ents w th worsen ng of heart fa ure, 
compared to p acebo. 
Other objectives: 
Exp ore the effect of sotag f oz n compared to p acebo treatment, 
n hemodynam ca y stab e pat ents w th worsen ng of heart 
fa ure, on the fo ow ng endpo nts: 
Change n tota  body water from base ne to 14 days  
Change n ur c ac d from base ne to 14 days 
Change n beta-hydroxybutyrate from base ne to 14 days 
Change n tota  b ood vo ume from base ne to 14 days 
Change n red ce  mass from base ne to 14 days 
Percentage of pat ents w th n 15% of dea  b ood vo ume on 
study day 14 
B ood pressure, s tt ng (SBP and DBP) at day 14 compared to 
base ne 
STUDY DESIGN 
A random zed, doub e-b nd, p acebo-contro ed, para e  arm tr a  
of the safety, to erab ty and pharmacodynam c act v ty of 
sotag f oz n n hemodynam ca y stab e pat ents w th worsen ng 
heart fa ure. Study drug w  be n t ated (e ther n the hosp ta  or 
outpat ent fac ty) w th n 7 days fo ow ng comp et on of 
ntravenous d uret c therapy, and cont nued n an outpat ent 
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sett ng for a tota  of 14 days.  
An n t a  cohort of pat ents (Cohort 1) w  rece ve sotag f oz n 
200 mg (approx mate n=10) or p acebo (approx mate n=5) ora y 
for 14 days. Fo ow ng safety mon tor ng and rev ew of Cohort 1 
by the data mon tor ng comm ttee (DMC), Cohort 2 w  rece ve 
sotag f oz n 400 mg (approx mate n=10) or p acebo 
(approx mate n=5) ora y for 14 days. Fo ow ng safety mon tor ng 
and rev ew of Cohort 2 by the DMC, conduct of cohort 3 w  
commence where pat ents  w  be a ocated to two arms, 
sotag f oz n  400 mg (approx mate n=17)  or p acebo 
(approx mate n=17)  ora y for 14 days. 
 
STUDY POPULATION 
Ma e and fema e pat ents, 18 years and o der w th worsen ng of 
heart fa ure requ r ng adm n strat on of ntravenous d uret cs. 
Main selection criteria: 
Inclusion criteria: 
Inclusion criteria at screening 
I 01. 
Wr tten nformed consent; 
I 02. 
18 years of age or o der 
I 03. 
Pat ent adm tted to the hosp ta  or had urgent v s t to 
emergency department or heart fa ure un t/c n c or 
nfus on center for Congest ve Heart Fa ure (CHF), 
def ned by: 
- Presence of ≥2 of the fo ow ng c n ca  s gns and 
symptoms of congest on: jugu ar ve n d stens on, p tt ng 
edema n ower extrem t es greater than trace , 
dyspnea, ra es heard on auscu tat on, rad ograph c 
pu monary congest on, we ght ga n above h stor ca  dry 
we ght of at east 5 bs. (2.27 kg) 
AND 
- Requ r ng treatment w th IV d uret cs  
  
I 04. 
Est mated g omeru ar f trat on rate (eGFR) ≥30 
m /m n/1.73m2 at the screen ng or random zat on v s t by 
the 4 var ab e Mod f cat on of D et n Rena  D sease 
(MDRD) equat on   
I 05. 
Fema e subject must use a doub e contracept on 
method dur ng the study nc ud ng a h gh y effect ve 
method of b rth contro , except f she has undergone 
ster zat on at east 3 months ear er or s 
postmenopausa .  
I 06. 
Ma e part c pants, un ess vasectom zed and conf rmed 
ster e by sperm ana ys s, must use condoms dur ng the 
study and refra n from donat ng sperm up to 90 days 
after the day of ast dose. If the pat ent has a fema e 
partner of ch dbear ng potent a , the pat ent must wear 
a condom and fema e partner must use at east 1 h gh y 
effect ve method of b rth contro  dur ng the study 
treatment per od and the Fo ow-up per od. 
Inclusion criteria at randomization 
I 07. 
Trans t on ng from ntravenous (IV) to ora  d uret cs and 
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ora  d uret c treatment has been prescr bed or 
adm n stered 
I 08. 
 Hemodynam ca y stab e, def ned as: 
-SBP ≥100 mmHg w th no requ rement for IV notropes 
or IV vasod ators 
 
Exclusion criteria 
E01. H story of Type 1 d abetes me tus 
E02. Appears un ke y or unab e to part c pate n the 
requ red study procedures, as assessed by the study 
Invest gator, study coord nator, or des gnee (ex: 
c n ca y-s gn f cant psych atr c, add ct ve, or 
neuro og ca  d sease) or sect oned due to an off c a  or 
court order 
E03. Tachyarrhythm a w th ventr cu ar rate> 130 bpm at the 
t me of screen ng, un ess determ ned to be c n ca y 
stab e by the nvest gator; or current adm ss on for 
worsen ng heart fa ure that s c ear y and pr mar y 
tr ggered by causes such as acute coronary syndrome, 
pu monary embo sm, cerebrovascu ar acc dent, heart 
va ve d sorders (such as severe aort c stenos s), as 
determ ned by the Invest gator  
E04. C n ca y s gn f cant myocard a  nfarct on (MI) w th n 
past 1 month as determ ned by Invest gator and w th 
object ve ev dence from ECG, and/or card ac mag ng 
and/or coronary ang ography. Sma  so ated e evat ons 
n tropon n that often accompany HF hosp ta zat on 
are not an exc us on, nor are c n ca y s gn f cant MIs 
that have been re-vascu ar zed w thout comp cat ons 
E05. Pat ents who recent y had or schedu ed to have 
card ac ntervent ons may be e g b e f: 
-Stab e 48 hours post procedure AND 
-Have d uret c treatment p anned for the durat on of 
treatment n th s study   
E06. Current use of or recent suspens on of d gox n therapy 
w th h gh eve s of d gox n ( eve  shou d be obta ned 
and must be <1.2 ng/mL) at screen ng.       
E07. H story of heart or k dney transp ant 
E08. D agnos s of hypertroph c obstruct ve card omyopathy   
E09. End-stage HF def ned as requ r ng eft ventr cu ar 
ass st dev ce nsert on, ntra-aort c ba oon p acement 
(IABP), or any type of mechan ca  support dur ng the 
study per od 
E10. Pregnancy (demonstrated by serum pregnancy test at 
screen ng), breast-feed ng, or nab ty or refusa  to 
undergo pregnancy test ng 
E11. Use of any nvest gat ona  drug(s) or proh b ted therapy 
or sod um-g ucose co-transporter 2 (SGLT2) nh b tor 5 
ha f- ves pr or to screen ng  
E12. Pat ents w th moderate or severe resp ratory, hepat c, 
neuro og ca , psych atr c, act ve ma gnant tumor or 
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other major system c d sease ( nc ud ng any d seases 
w th ev dence of ma absorpt on), mak ng 
mp ementat on of the protoco  and/or the nterpretat on 
of the study resu ts d ff cu t 
E13. Known a erg es, hypersens t v ty, or nto erance to 
sotag f oz n or any nact ve component of sotag f oz n 
or p acebo ( .e.,, m crocrysta ne ce u ose, 
croscarme ose sod um [d s ntegrant], ta c, s con 
d ox de, and magnes um stearate [non-bov ne]), un ess 
the react on s deemed rre evant to the study by the PI 
E14. Laboratory f nd ngs at the Screen ng V s t: 
a. 
A an ne am notransferase (ALT) or aspartate 
am notransferase (AST) >3 t mes the upper 
m t of the norma  aboratory range (ULN) (1 
repeat ab a owed) 
b. 
Tota  b rub n >1.7 t mes the ULN (except n 
case of G bert’s syndrome) (1 repeat ab 
a owed) 
c. 
Amy ase and/or pase > 3 t mes the ULN (1 
repeat ab a owed) 
E15. Pat ents w th a severe or pers stent n sp te of opt ma  
treatment gen tour nary tract nfect on at t me of 
random zat on.  
E16. Pat ent s the Invest gator or any Sub- nvest gator, 
research ass stant, pharmac st, study coord nator, 
other staff or re at ve thereof d rect y nvo ved n the 
conduct of the protoco  
Additional exclusion criteria for patients with diabetes 
E17. H story of d abet c ketoac dos s or non-ketot c 
hyperosmo ar coma w th n 3 months pr or to the 
screen ng v s t 
E18. Lower extrem ty d abet c comp cat ons (such as sk n 
u cers, nfect on, osteomye t s and gangrene) dent f ed 
dur ng the Screen ng per od, and st  requ r ng 
treatment at Random zat on 
Total expected number of patients: 
Approx mate y 64 pat ents comp et ng treatment w  be enro ed. 
Expected number of sites: 
Up to 15 s tes 
STUDY TREATMENT(s) 
Investigational medicinal product(s) 
 
 
 
 
 
 
 
 
 
 
Sotag f oz n 200 mg (on y cohort 1): 
 
200 mg tab ets  
 
Ora  
 
200 mg, adm n stered as one (1) 200-mg tab et p us 
one (1) p acebo tab et ( dent ca  to sotag f oz n 200 mg 
n appearance), once da y pr or to the f rst mea  of the 
day for 14 days. 
Sotag f oz n 400 mg (cohorts 2 and 3): 
 
200 mg tab ets 
 
Ora  
 
400 mg, adm n stered as two (2) 200-mg tab ets, once 
da y pr or to the f rst mea  of the day for 14 days. 
P acebo (a  cohorts): 
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Non investigational medicinal product(s) 
(NIMP) 
 
 
 
 
 
 
 
 
Tab ets dent ca  n appearance to sotag f oz n 200 mg 
 
Ora  
 
P acebo adm n stered as two (2) p acebo tab ets, 
( dent ca  to sotag f oz n 200 mg n appearance), once 
da y pr or to the f rst mea  of the day for 14 days. 
131I-albumin: 
Supp ed as ≤25µC  n 1m  at date of ca brat on.   
Each m  conta ns: 
10mg human a bum n (non-react ve to HBsAg) 
16mg sod um d bas c phosphate 
1.6mg sod um monobas c phosphate 
0.4mg guan d ne hydroch or de 
Sod um ch or de 
9mg benzy  a coho  
Route of adm n strat on: Intravenous 
Dose reg men: 10mg (≤25 µC ) adm n stered once on study 
Days 1 and 14. 
Deuterium Oxide: 
Formu at on; deuter um ox de 10 g / 10 mL pre-ster zed v a  or 
ora  syr nge w th t p cap for entera  adm n strat on 
Route of adm n strat on: Ora  
Dose reg men: V a  or Syr nge contents d uted to a vo ume of 
100 mL n ster e water, adm n stered once on study Day 1 and 
14 
PRIMARY ENDPOINT(S) AND MAIN 
SECONDARY ENDPOINT(S) 
Primary endpoints:  
Safety and To erab ty:   
Safety assessment nc ude: 
AEs, hypog ycem a (a  Invest gator reported events, severe 
and/or documented symptomat c or asymptomat c),  
Events of Spec a  Interest (EOSIs), Adverse Events of Spec a  
Interest (AESIs), AEs ead ng to d scont nuat on from the IMP, 
ser ous AEs (SAEs), and deaths. 
C n ca  aboratory resu ts 
V ta  s gns and e ectrocard ogram (ECG) resu ts. 
 
 
Pharmacodynam c:   
Changes n hemoconcentrat on from base ne to 14 days. 
Changes n p asma vo ume from base ne to 14 days. 
Secondary endpoints: 
Change n erythropo et n from base ne to 14 days 
Change n NT-proBNP from base ne to 14 days 
Other endpoints: 
Change n tota  body water from base ne to 14 days  
Change n ur c ac d from base ne to 14 days 
Change n beta-hydroxybutyrate from base ne to 14 days 
Change n tota  b ood vo ume from base ne to 14 days 
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Change n red ce  mass from base ne to 14 days 
Percentage of pat ents w th n 15% of dea  b ood vo ume on 
study day 14 
B ood pressure, s tt ng (SBP and DBP) at day 14 compared to 
base ne 
ASSESSMENT SCHEDULE 
Screen ng w  occur when pat ents are hosp ta zed or had 
urgent v s t to emergency department or heart fa ure un t/c n c or 
nfus on center and treated w th ntravenous d uret cs for 
worsen ng heart fa ure.  Random zat on (Day1) w  take p ace 
w th n 7 days fo ow ng d scont nuat on of ntravenous treatment 
w th d uret cs. 
Base ne aboratory parameters, tota  body water and p asma 
vo ume measurements, n t at on of IMP adm n strat on occur on 
Day 1.  
The f na  assessment for hemoconcentrat on, tota  body water 
and p asma vo ume changes w  be on day 14+/-1 day. 
STATISTICAL CONSIDERATIONS 
Pharmacodynamic endpoints 
Descr pt ve stat st cs for the pharmacodynam c endpo nts, as raw 
data and change from base ne w  be prov ded by treatment. 
S m ar y t me prof e p ots of mean + SEM w  be prov ded by 
treatment for a  pharmacodynam cs endpo nts.   
Safety 
The safety ana ys s w  be based on the rev ew of descr pt ve 
stat st cs (summary tab es) and nd v dua  data for v ta  s gns, 
rena  funct on, adverse events (AEs) and other c n ca  aboratory 
va ues and ECG parameters. Adverse events w  be coded us ng 
Med ca  D ct onary for Regu atory Act v t es (MedDRA) n an 
updated vers on ava ab e at the study, and the number of 
pat ents w th Treatment-Emergent Adverse Events (TEAEs) w  
be summar zed. Potent a y c n ca y s gn f cant abnorma t es 
(PCSAs) for c n ca  aboratory, v ta  s gn, and ECG data and out-
of-norma  range va ues for c n ca  aboratory data w  be f agged 
and summar zed n frequency tab es. 
DURATION OF STUDY PERIOD 
(per subject) 
- 
Screen ng: 1-21 days 
- 
Treatment per od: 14±1 days 
- 
Fo ow-up: 14±2 days 
Tota  study durat on: 26 – 51 days 
STUDY COMMITTEES 
Steering committee: No 
Data monitoring committee: Yes  
Clinical Endpoint Committees: No 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
 
 
 
OVERALL RATIONALE FOR THE AMENDMENT 
During the conduct of the first two cohorts of this study, it was determined through data from 
concurrent studies that the 200mg dose level would not be explored further as a therapeutic dose.  
To reduce the burden on patients, the 200mg dose level is being removed from cohort 3, and the 
study is being simplified without compromising patient safety or scientific merit.  
Document 
Country/Countries 
impacted by amendement 
Date, version 
Amended C n ca  Tr a  Protoco  03  
A  
                          
01-Aug-2019, vers on 2 (e ectron c 7.0) 
 
Protoco  Amendment 03 (Canada) 
Canada 
18-Ju -2018, vers on 1 (e ectron c 1.0) 
Amended C n ca  Tr a  Protoco  02 
A  
04-Mar-2018, vers on 1 (e ectron c 1.0) 
Protoco  Amendment 02 
A  
14-Mar-2018, vers on 1 (e ectron c 1.0) 
Amended C n ca  Tr a  Protoco  01 
A  
09-Jan-2018, vers on 1 (e ectron c 1.0) 
Protoco  Amendment 01 
A  
28-Feb-2018, vers on 1 (e ectron c 1.0) 
Or g na  Protoco  
A  
05-Ju -2017, vers on 1 (e ectron c 1.0) 
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Sect on 1.1 Graph ca  des gn (th s change 
was made to the c n ca  tr a  summary 
tab e),  Sect on 6.1 Descr pt on of study 
(reca cu ated n tab e1), sect on 8.1 
Number of pat ents p anned, 10.1.3 
Assessment schedu e nc ud ng 
reca cu ated tab e 6 
The 200mg arm was removed from 
cohort 3 w thout rep ac ng subjects 
Reduce the tota  number of subjects to 64. 
the sponsor s proceed ng deve opment 
w th 400mg dose on y 
Sect on 1.4 f ow chart (cohort 3), 
sect on1.5 per od f owchart (cohort 3), 
sect on 13.1.3.4 V s t 3 and v s t 4, and 
numerous ment ons of v s t 3 and/or 4 n 
the text  
In cohort 3 forgo V s t 4  v s t 3 w  
occur between Day 6 and Day 8 v s t, 
hence obv at ng one s te v s t. In order 
to prevent confus on the or g na  v s t 
number ng w  be kept as n cohort 1 
and 2, n f owcharts and n text v s t 4 
n cohort 3 w  be devo d of any v s t 
act v ty. 
Reduce the burden off the pat ent - 
trave ng to the s te 
 
Sect on 10.3 Pharmacok net cs, nc ud ng 
reca cu at ng Tab e 9, Sect on 1.4 f ow 
chart (cohort 3), sect on1.5 per od 
f owchart (cohort 3) 
 
 
 
 
 
 
C n ca  tr a  summary, Sect on 8.3 
Exc us on cr ter a exc us on cr ter on 03 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK assessments were removed from 
cohort 3. 
 
 
 
 
 
 
 
Current y: E03.Current adm ss on 
or v s t for Worsen ng HF that s 
c ear y  and pr mar y tr ggered by 
causes such as tachyarrhythm a 
(examp e: susta ned ventr cu ar 
tachycard a,  or atr a  
f br at on/f utter w th susta ned 
ventr cu ar response > 130 beats 
per m nute), acute coronary 
syndrome, pu monary embo sm, 
cerebrovascu ar acc dent, heart 
va ve d sorders (such as severe 
aort c stenos s), as determ ned by 
the Invest gator 
Changed to: 
E03.Tachyarrhythm a w th 
ventr cu ar rate> 130 bpm at 
screen ng, un ess 
determ ned to be c n ca y 
stab e by the nvest gator;  or 
current adm ss on for 
worsen ng heart fa ure that 
s c ear y and pr mar y 
 
PK samp ng mposed a substant a  burden 
for pat ents part c pat ng n the tr a , and as 
a consequence, t was removed. PK s not 
a pr mary object ve n th s study; forgo ng 
PK samp ng s not comprom s ng ts 
sc ent f c va ue 
 
 
 
 
C ar f cat on that tachycard a >130 at 
screen ng s grounds for exc us on 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Section # and Name 
Description of Change 
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sect ons: C n ca  tr a  summary n 
stat st ca  cons derat on and n study 
des gn 
A so; Sect on 14.10 Inter m ana ys s 
 
 
 
 
 
 
 
Sect on13.1.4 Study restr ct ons 
 
 
 
 
 
 
 
 
 
 
tr ggered by causes such as 
acute coronary syndrome, 
pu monary embo sm, 
cerebrovascu ar acc dent, 
heart va ve d sorders (such 
as severe aort c stenos s), 
as determ ned by the 
Invest gator 
 
 
 
 
 
 
 
Remove reference to nter m ana ys s 
 
 
 
 
 
 
 
 
 
 
In cohort 3 remove the requ rement to 
eat 15 m nutes after IMP 
adm n strat on 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The IA was or g na y ntended to assess 
safety and to cons der whether the number 
of subjects needs to be ncreased go ng 
forward w th cohort 3. Accumu at ng 
favorab e safety data n the CHF n th s 
study and other ongo ng stud es w th arger 
number of subjects and onger exposure 
obv ated the need to study the ower dose 
of 200mg. There the number of the 
rema n ng subjects who are on 400 mg s 
too sma  for a mean ngfu  IA. Hence the IA 
was removed. 
 
 
Invest gators not ce that th s s d ff cu t for 
the subjects to comp y and record feed ng 
t mes 
 
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1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN  
DMC 
Cohort 1 
N~15 
 
 
Sota 200 mg (N ~ 10) 
 
Placebo (N~5) 
 
Treated for 2 weeks 
DMC 
Cohort 2 
N~15 
 
 
Sota 400 mg (N ~ 10) 
 
Placebo (N~ 5) 
 
Treated for 2 weeks 
Cohort 3 
N~34 
 
 
Sota 400 mg (N ~ 17) 
 
Placebo (N ~17) 
 
Treated for 2 weeks 
 
 
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k Patients will be taught how to perform the automated BP readings. Automated BP readings will be performed in triplicate, between 6 AM to 10 AM on a daily basis, starting D2 and ending at the last post-study 
follow up. 
l 
Study treatment ends on Day 14 (EOT). 
m Physical examination includes at a minimum: heart and respiratory auscultation; peripheral arterial pulse; pupil, and abdomen examination. All physical examinations in diabetic patients, including abbreviated 
physical examinations, will include examination of the lower extremities to evaluate for any evidence of foot ulcers or infection should be performed as part of the general physical examination and this examination 
should be documented on the e-CRF. 
n All body weight measurements on scale provided by site staff. 
o All patients must have a documented echocardiogram, either performed during current admission or within 12 months from the index hospitalization. 
p ECG at Visit 2, Visit 3 and EOT Visit 5 only. 
q Oral or tympanic body temperature. 
r 
Complete blood count / hematocrit / hemoglobin.  
s Creatinine, urea, electrolytes. 
t 
For Visits 2 (Day 1) and 5 (Day 14±1), those samples will be obtained as part of the Hemoconcentration sampling, thus no additional samples for Hematology or Biochemistry are required. It is indicated here as a 
reminder that baseline hematology and biochemistry is done on Visits 2 and 5. For all other Visits, Hematology and Biochemistry samples are to be obtained as indicated. 
u Beta-HCG test will be for all women of child-bearing potential as defined in the inclusion/exclusion criteria, and FSH to assess menopausal status when necessary. 
v Pharmacokinetic samples taken on Visit 3 and Visit 4 are pre-dose drug treatment samples. 
w Hemoconcentration is determined by measurement of hematocrit, hemoglobin, albumin and total protein. Baseline biochemistry (creatinine, urea and electrolytes) and hematology (CBC) is also determined from 
those samples. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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m One sample will be collected just before injection of 131I-albumin (-1H, PD00) and further sample collection will start 12 min following the injection. Samples will then be collected every 6 minutes starting – 
0H48min: -0H48min (PD01), -0H42min (PD02), -0H36min(PD03), -0H30min(PD04), -0H24min(PD05) min. For blood collection on D14 sample notation should be: -1H (PD06), -0H48min (PD07), -0H42min (PD08), 
-0H36min(PD09), -0H30min(PD10), -0H24min(PD11)  
n Following administration of deuterium oxide, blood collection on D1: At -2.5H (PY00), 1H (PY01), and on Day 14: At -2.5H (PY02), 1H (PY03) 
o All body weight measurements on scale provided by site staff 
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m Physical examination includes at a minimum: heart and respiratory auscultation; peripheral arterial pulse; pupil, and abdomen examination. All physical examinations in diabetic patients, including abbreviated 
physical examinations, will include examination of the lower extremities to evaluate for any evidence of foot ulcers or infection should be performed as part of the general physical examination and this examination 
should be documented on the e-CRF. 
n All body weight measurements on scale provided by site staff. 
o All patients must have a documented echocardiogram, either performed during current admission or within 12 months from the index hospitalization. 
p ECG at Visit 2, Visit 3 and Visit 5 (EOT) only. 
q Oral or tympanic body temperature. 
r 
Complete blood count / hematocrit / hemoglobin.  
s Creatinine, urea, electrolytes. 
t 
For Visits 2 (Day 1) and 5 (Day 14±1), those samples will be obtained as part of the Hemoconcentration sampling, thus no additional samples for Hematology or Biochemistry are required. It is indicated here as a 
reminder that baseline hematology and biochemistry is done on Visits 2 and 5. For all other Visits, Hematology and Biochemistry samples are to be obtained as indicated. 
u Beta-HCG test will be for all women of child-bearing potential as defined in the inclusion/exclusion criteria, and FSH to assess menopausal status when necessary. 
v Hemoconcentration is determined by measurement of hematocrit, hemoglobin, albumin and total protein. Baseline biochemistry (creatinine, urea and electrolytes) and hematology (CBC) is also determined from 
those samples. 
 
 
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n Following administration of deuterium oxide, blood collection on D1: At -2.5H (PY00), 1H (PY01), and on Day 14: At -2.5H (PY02), 1H (PY03) 
o All body weight measurements on scale provided by site staff 
 
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2 
TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 03 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 9 
DOCUMENT HISTORY ................................................................................................................................... 9 
OVERALL RATIONALE FOR THE AMENDMENT ........................................................................................ 9 
1 
FLOW CHARTS ............................................................................................................................. 12 
1.1 
GRAPHICAL STUDY DESIGN ...................................................................................................... 12 
1.2 
STUDY FLOW CHART FOR COHORTS 1 AND 2 ........................................................................ 17 
1.3 
PERIOD FLOW CHART (COHORT 1 AND 2) ............................................................................... 20 
1.4 
STUDY FLOW CHART COHORT 3 (FORGO VISIT 4 AND KEEP VISIT NUMBERING AS 
IN COHORT 1 AND 2) ................................................................................................................... 23 
1.5 
PERIOD FLOW CHART (COHORT 3) .......................................................................................... 26 
2 
TABLE OF CONTENTS ................................................................................................................ 29 
2.1 
LIST OF TABLES ........................................................................................................................... 36 
2.2 
LIST OF FIGURES ......................................................................................................................... 36 
3 
LIST OF ABBREVIATIONS .......................................................................................................... 37 
4 
INTRODUCTION AND RATIONALE ............................................................................................. 38 
4.1 
INTRODUCTION ............................................................................................................................ 38 
4.2 
RATIONALE ................................................................................................................................... 38 
4.2.1 
Study rationale ............................................................................................................................... 38 
4.2.2 
Design rationale and risk assessment ........................................................................................... 39 
4.2.3 
Specific parameters rationale ........................................................................................................ 40 
5 
STUDY OBJECTIVES ................................................................................................................... 42 
5.1 
PRIMARY ....................................................................................................................................... 42 
5.2 
SECONDARY ................................................................................................................................ 42 
5.3 
OTHER OBJECTIVES ................................................................................................................... 42 
6 
STUDY DESIGN ............................................................................................................................ 43 
6.1 
DESCRIPTION OF THE STUDY ................................................................................................... 43 
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6.2 
DURATION OF STUDY PARTICIPATION .................................................................................... 43 
6.2.1 
Duration of study participation for each subject ............................................................................. 43 
6.2.2 
Determination of end of clinical trial (all patients) .......................................................................... 44 
7 
STUDY COMMITTEES .................................................................................................................. 44 
7.1 
DATA MONITORING COMMITTEE (DMC) ................................................................................... 44 
7.2 
POTENTIAL OUTCOMES FOLLOWING DMC REVIEWS ............................................................ 44 
7.2.1 
Guidance for stopping rules ........................................................................................................... 45 
8 
SELECTION OF PATIENTS .......................................................................................................... 46 
8.1 
NUMBER OF PATIENTS PLANNED ............................................................................................. 46 
8.2 
INCLUSION CRITERIA .................................................................................................................. 46 
8.2.1 
Inclusion criteria at screening ........................................................................................................ 46 
8.2.2 
Inclusion criteria at randomization ................................................................................................. 47 
8.3 
EXCLUSION CRITERIA ................................................................................................................ 47 
8.3.1 
Additional exclusion criteria for patients with diabetes .................................................................. 49 
9 
STUDY TREATMENTS ................................................................................................................. 50 
9.1 
INVESTIGATIONAL MEDICINAL PRODUCTS (IMP) ................................................................... 50 
9.2 
NON-INVESTIGATIONAL MEDICINAL PRODUCTS .................................................................... 50 
9.3 
BLINDING PROCEDURES ............................................................................................................ 51 
9.3.1 
Methods of blinding ........................................................................................................................ 51 
9.3.2 
Randomization code breaking during the study ............................................................................. 51 
9.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP .............................................. 52 
9.5 
PACKAGING AND LABELING ...................................................................................................... 52 
9.6 
STORAGE CONDITIONS AND SHELF LIFE ................................................................................ 53 
9.7 
RESPONSIBILITIES ...................................................................................................................... 53 
9.8 
CONCOMITANT MEDICATION ..................................................................................................... 53 
9.9 
TREATMENT ACCOUNTABILITY AND COMPLIANCE ............................................................... 55 
9.10 
PATIENT DIARY ............................................................................................................................ 55 
9.11 
RETURN AND/OR DESTRUCTION OF TREATMENTS .............................................................. 55 
9.12 
POSTSTUDY TREATMENT .......................................................................................................... 56 
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10 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT .............................................. 57 
10.1 
ACTIVITY OR PHARMACODYNAMICS........................................................................................ 57 
10.1.1 
Pharmacodynamic parameters ...................................................................................................... 57 
10.1.1.1 Primary endpoints .......................................................................................................................... 57 
10.1.1.2 Secondary endpoints ..................................................................................................................... 57 
10.1.1.3 Other endpoints .............................................................................................................................. 57 
10.1.2 
Assessment methods ..................................................................................................................... 57 
10.1.2.1 Hemoconcentration and Total Body Water estimation procedure on Day 1 and Day 14: ............. 58 
10.1.2.2 Plasma volume procedures on Day 1 and Day 14: ....................................................................... 59 
10.1.3 
Assessment schedule .................................................................................................................... 60 
10.1.4 
Assay methods ............................................................................................................................... 61 
10.2 
SAFETY ......................................................................................................................................... 61 
10.2.1 
Safety assessment at baseline and during the study .................................................................... 62 
10.3 
PHARMACOKINETICS .................................................................................................................. 63 
10.3.1 
Sampling times ............................................................................................................................... 63 
10.3.2 
Number of pharmacokinetic samples ............................................................................................. 63 
10.3.3 
Sample handling procedure ........................................................................................................... 63 
10.3.4 
Bioanalytical methods .................................................................................................................... 64 
10.3.5 
Pharmacokinetic parameters ......................................................................................................... 64 
 
 .............................................................................................................................. 64 
 
 ................................................................................... 64 
10.5 
SAMPLED BLOOD VOLUME ........................................................................................................ 65 
 
...................................................................................................... 65 
10.7 
MEASURES TO PROTECT BLINDING OF THE TRIAL ............................................................... 66 
11 
SUBJECT SAFETY ....................................................................................................................... 67 
11.1 
ADVERSE EVENT MONITORING ................................................................................................ 67 
11.2 
DEFINITIONS OF ADVERSE EVENTS......................................................................................... 67 
11.2.1 
Adverse event ................................................................................................................................ 67 
11.2.2 
Serious adverse event ................................................................................................................... 68 
11.2.3 
Adverse event of special interest ................................................................................................... 68 
11.2.4 
Events of Special Interest (EOSIs) ................................................................................................ 69 
11.3 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING .......................... 70 
11.3.1 
General guidelines for reporting adverse events ........................................................................... 70 
11.3.2 
Guidelines for reporting serious adverse events ........................................................................... 71 
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11.3.3 
Guidelines for reporting adverse events of special interest ........................................................... 71 
11.3.4 
Guidelines for reporting events of special interest ......................................................................... 72 
11.3.5 
Guidelines for management of specific laboratory abnormalities .................................................. 72 
11.4 
OBLIGATIONS OF THE SPONSOR ............................................................................................. 72 
11.5 
SAFETY INSTRUCTIONS FOR DIABETIC COMPLICATIONS .................................................... 73 
11.5.1 
Hypoglycemia ................................................................................................................................. 73 
11.5.1.1 Severe hypoglycemia ..................................................................................................................... 73 
11.5.1.2 Documented symptomatic hypoglycemia ...................................................................................... 73 
11.5.1.3 Asymptomatic hypoglycemia ......................................................................................................... 73 
11.5.1.4 Probable symptomatic hypoglycemia ............................................................................................ 74 
11.5.1.5 Relative hypoglycemia ................................................................................................................... 74 
11.5.2 
Instructions for the management of DKA in diabetic patients ........................................................ 74 
12 
HANDLING OF SUBJECT WITHDRAWAL .................................................................................. 75 
12.1 
LIST OF TREATMENT WITHDRAWAL CRITERIA ....................................................................... 75 
12.2 
REASONS FOR TREATMENT WITHDRAWAL ............................................................................ 75 
12.3 
REPLACEMENT OF PATIENTS ................................................................................................... 75 
12.4 
TREATMENT WITHDRAWAL FOLLOW-UP PROCEDURE ......................................................... 75 
13 
STUDY PROCEDURES ................................................................................................................ 77 
13.1 
VISIT SCHEDULE .......................................................................................................................... 77 
13.1.1 
Screening procedures .................................................................................................................... 77 
13.1.2 
Inclusion procedures ...................................................................................................................... 77 
13.1.3 
Description by type of visit ............................................................................................................. 78 
13.1.3.1 Visit 2 (Day 1) (Inpatients or Outpatients returning for Day 1 procedures).................................... 78 
13.1.3.2 Discharge procedures .................................................................................................................... 79 
13.1.3.3 Ambulatory period(s) ...................................................................................................................... 79 
13.1.3.4 Visit 3 (Between Day 3 and Day 6) and Visit 4 (Between Day 8 and Day 11) in cohort 1 and 
2; in cohort 3 visit 3 (Between Day 6 and Day 8) and visit 4 removed .......................................... 80 
13.1.3.5 Visit 5 (Day 14±1)/ .......................................................................................................................... 81 
13.1.3.6 Visit 6 (Day 26-30) ......................................................................................................................... 81 
13.1.4 
Study restriction(s) ......................................................................................................................... 82 
13.2 
DEFINITION OF SOURCE DATA .................................................................................................. 82 
14 
STATISTICAL CONSIDERATIONS .............................................................................................. 83 
14.1 
DETERMINATION OF SAMPLE SIZE ........................................................................................... 83 
14.2 
PATIENT DESCRIPTION .............................................................................................................. 83 
14.2.1 
Disposition of patients .................................................................................................................... 83 
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14.2.2 
Protocol deviations ......................................................................................................................... 83 
14.3 
ANALYSIS POPULATION ............................................................................................................. 84 
14.3.1 
Safety population ........................................................................................................................... 84 
14.3.2 
Pharmacokinetic population ........................................................................................................... 84 
14.3.3 
Pharmacodynamic (PD) population ............................................................................................... 84 
14.3.4 
Pharmacokinetic/Pharmacodynamic population ............................................................................ 84 
14.4 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ............................................................. 84 
14.4.1 
Subject demographic characteristics, medical history and diagnoses .......................................... 84 
14.4.2 
Baseline pharmacodynamic parameters........................................................................................ 85 
14.4.3 
Baseline safety parameters ........................................................................................................... 85 
14.5 
EXTENT OF STUDY TREATMENT EXPOSURE AND COMPLIANCE ........................................ 85 
14.6 
PRIOR/CONCOMITANT MEDICATION/THERAPY ...................................................................... 85 
14.7 
ANALYSIS OF PHARMACODYNAMIC VARIABLES .................................................................... 86 
14.7.1 
Description of pharmacodynamic variable(s) ................................................................................. 86 
14.7.2 
Primary analysis ............................................................................................................................. 86 
14.7.3 
Secondary analysis/analysis of secondary variables ..................................................................... 87 
14.8 
ANALYSIS OF SAFETY DATA ...................................................................................................... 87 
14.8.1 
Adverse events .............................................................................................................................. 88 
14.8.1.1 Definitions ...................................................................................................................................... 88 
14.8.1.2 Treatment-emergent adverse events ............................................................................................. 88 
14.8.1.3 Deaths, serious, and other significant adverse events .................................................................. 89 
14.8.1.4 Adverse events leading to treatment discontinuation .................................................................... 89 
14.8.1.5 Adverse events of special interest ................................................................................................. 89 
14.8.2 
Clinical laboratory evaluations ....................................................................................................... 89 
14.8.3 
Vital signs ....................................................................................................................................... 90 
14.8.4 
Electrocardiogram .......................................................................................................................... 90 
14.9 
ANALYSIS OF PHARMACOKINETIC DATA FROM COHORT 1 AND 2 ...................................... 91 
14.9.1 
Pharmacokinetic parameters ......................................................................................................... 91 
14.10 
INTERIM ANALYSIS ...................................................................................................................... 91 
15 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................... 92 
15.1 
ETHICAL AND REGULATORY STANDARDS .............................................................................. 92 
15.2 
INFORMED CONSENT ................................................................................................................. 92 
15.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC) ................................................................................................... 93 
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16 
STUDY MONITORING................................................................................................................... 94 
16.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) ....................................................................... 94 
16.2 
RESPONSIBILITIES OF THE SPONSOR ..................................................................................... 94 
16.3 
SOURCE DOCUMENT REQUIREMENTS .................................................................................... 94 
16.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST ...................................................................................................................................... 95 
16.5 
USE OF COMPUTERIZED SYSTEMS .......................................................................................... 95 
17 
ADDITIONAL REQUIREMENTS ................................................................................................... 96 
17.1 
CURRICULUM VITAE.................................................................................................................... 96 
17.2 
RECORD RETENTION IN STUDY SITE(S) .................................................................................. 96 
17.3 
CONFIDENTIALITY ....................................................................................................................... 96 
17.4 
PROPERTY RIGHTS ..................................................................................................................... 97 
17.5 
DATA PROTECTION ..................................................................................................................... 97 
17.6 
INSURANCE COMPENSATION .................................................................................................... 97 
17.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ................................. 98 
17.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE ............................................................................................................................................ 98 
17.8.1 
By the Sponsor ............................................................................................................................... 98 
17.8.2 
By the Investigator ......................................................................................................................... 99 
17.9 
CLINICAL TRIAL RESULTS .......................................................................................................... 99 
17.10 
PUBLICATIONS AND COMMUNICATIONS ................................................................................. 99 
18 
CLINICAL TRIAL PROTOCOL AMENDMENTS ........................................................................ 100 
19 
BIBLIOGRAPHIC REFERENCES ............................................................................................... 101 
20 
APPENDICES .............................................................................................................................. 104 
APPENDIX A 
CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION ............................................................................................................................ 105 
APPENDIX B 
DECISION CHARTS .......................................................................................................... 113 
APPENDIX C 
BLOOD PRESSURE AND PULSE RATE MONITORING ................................................ 117 
APPENDIX D 
DIABETIC KETOACIDOSIS .............................................................................................. 119 
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APPENDIX E 
COUNTRY SPECIFIC CHANGES .................................................................................... 121 
APPENDIX F 
PROTOCOL AMENDMENT HISTORY ............................................................................. 122 
20.1.1 
Amended Protocol 1 based on Amendment 1: 09-Jan-2018 ....................................................... 122 
20.1.2 
Amended Protocol 2 based on Amendment 2: 14-Mar-2018 ...................................................... 124 
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2.1 
LIST OF TABLES 
Table 1 - Cohort randomization and allocation scheme ................................................................................ 43 
Table 2 - Summary of investigational medicinal products ............................................................................. 50 
Table 3 - List of schedule of events for the hemoconcentration and total body water assessment procedure
 ....................................................................................................................................................................... 58 
Table 4 - List of schedule of events for the plasma and total body water volumes assessment procedures
 ....................................................................................................................................................................... 59 
Table 5 - Summary of handling procedures for 131I-albumin measurement samples samples ..................... 60 
Table 6 - Number of samples ........................................................................................................................ 60 
Table 7 - Summary of assay method for 131I-albumin ................................................................................... 61 
Table 8 - Summary of assay method for deuterium oxide ............................................................................ 61 
Table 9 - Number of plasma samples ........................................................................................................... 63 
Table 10 - Summary of handling procedures ................................................................................................ 64 
Table 11 - Summary of bioanalytical method ................................................................................................ 64 
Table 12 - Sampled blood volume ................................................................................................................. 65 
Table 13 - Highly Effective Contraceptive Methods .................................................................................... 106 
 
2.2 
LIST OF FIGURES 
Figure 1 - Hypoglycemia classification in Study PDY15079 ......................................................................... 74 
 
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3 
LIST OF ABBREVIATIONS  
 
AESI: 
adverse event of special interest 
CHF: 
congestive heart failure 
CV: 
cardiovascular 
DBP: 
diastolic blood pressure 
DMC: 
Data Monitoring Committee 
eGFR: 
estimated glomerular filtration rate 
EMPA-REG: 
EMPAgliflozin-Remove Excess Glucose 
EOSI: 
event of special interest 
GFR: 
glomerular filtration rate 
GI: 
gastrointestinal 
IB: 
Investigator's Brochure 
IMP: 
investigational medicinal product 
IRT: 
interactive response technology 
MedDRA: 
Medical Dictionary for Regulatory Activities  
MI: 
myocardial infarction 
PD: 
pharmacodynamic(s) 
PK: 
pharmacokinetic(s) 
SAE: 
serious adverse event 
SBP: 
systolic blood pressure 
SGLT1: 
sodium-glucose cotransporter type 1 
SGLT2: 
sodium-glucose cotransporter type 2 
SUSAR: 
suspected unexpected serious adverse reaction  
T1DM: 
type 1 diabetes mellitus 
T2DM: 
type 2 diabetes mellitus 
ULN: 
upper limit of normal, upper limit of normal 
 
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4 
INTRODUCTION AND RATIONALE 
4.1 
INTRODUCTION 
Sotagliflozin (Sanofi code SAR439954, Lexicon code LX4211) is an orally administered small 
molecule, the first dual inhibitor of sodium-glucose co-transporter 1 and 2 (SGLT1 and SGLT2), 
formulated as 75 mg and 200 mg coated tablets. The compound, a member of the pharmaceutical 
class of SGLT-inhibitors known as gliflozins, lowers blood glucose by decreasing and delaying 
SGLT1-mediated glucose absorption in the gastrointestinal (GI) tract as well as enhancing glucose 
excretion in the urine by reducing renal glucose re-absorption via action of SGLT2 in the kidney. 
Sotagliflozin is being investigated as a therapy to improve glycemic control in adults with 
diabetes. In type 2 diabetes (T2DM) it is being developed as monotherapy or in combination with 
other classes of anti-diabetic agents. For type 1 diabetes (T1DM) it is being developed for 
adjunctive use with insulin.  
More detailed information is provided in the Investigator’s Brochure. 
4.2 
RATIONALE 
4.2.1 Study rationale 
Recent clinical trial data support that SGLT2 inhibitors may reduce heart failure morbidity and 
mortality. The effects of the SGLT2 inhibitor empagliflozin on cardiovascular risk were studied in 
the EMPAgliflozin Remove Excess Glucose (EMPA-REG) trial (1).  In EMPA-REG, patients 
with type 2 diabetes and established cardiovascular (CV) disease were randomized to placebo or 
empagliflozin with median treatment duration of 2.6 years. The primary outcome, a composite of 
death from CV causes, non-fatal myocardial infarction (MI) and non-fatal stroke, occurred in 
12.1% of the placebo group and in 10.5% of the empagliflozin group for a hazard ratio of 0.86.  
The hazard ratio for cardiovascular death alone was 0.62, and this improvement in CV mortality 
was not a result of reduced MI or stroke, but rather was mediated by a reduction in heart failure 
hospitalization and death (hazard ratio for heart failure hospitalization was 0.65).   
In EMPA-REG, empagliflozin was well-tolerated in patients with chronic heart failure. Patients 
who are hospitalized with worsening of heart failure are more susceptible to fluctuation in their 
hemodynamic state and their renal function and the safety and tolerability of SGLT inhibition in 
this setting is unknown.  The mechanism of empagliflozin-mediated heart failure benefit is also 
unknown. One proposed mechanism is reduction in plasma volume (2). Patients with heart failure 
typically have increased total body water with the increase localized to the interstitial space and 
the vascular space. Acute and chronic therapy with diuretics can reduce plasma volume via 
natriuresis.  Diuretics in current use block sodium absorption in the kidney leading to natriuresis, 
but also activate the counter-regulatory renin-angiotensin system which ultimately limits the 
degree of diuresis and reduction in plasma volume.  In comparison, the SGLT2 inhibitor 
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dapagliflozin causes diuresis and compared to a thiazide diuretic, results in less activation of renin 
and greater volume reduction (3)(4).  Sotagliflozin, by its inhibition of both SLGT1 and SGLT2, 
may reduce volume via both renal and GI mechanisms.  The main objective of this study is to test 
the effects of combined SGLT1 and SGLT2 inhibition with sotagliflozin on hemoconcentration 
and plasma volume in patients with heart failure. Whereas empagliflozin has shown benefit in 
diabetic heart failure patients /non-diabetic patients with heart failure patients may also have 
favorable volume changes and may also benefit from SGLT inhibition, and thus both diabetic and 
non-diabetic heart failure patients will be enrolled.    
4.2.2 Design rationale and risk assessment 
Design: A parallel arm design was chosen for the comparison between sotagliflozin and placebo. 
A cross-over design was not considered feasible due to the physiologic changes typical of patients 
recently hospitalized with heart failure that would result in substantial period effect. A treatment 
duration of 14 days was selected as both the time required for maximum treatment effect on 
urinary sodium excretion and a feasible follow-up period for the selected heart failure patient 
population. The urinary sodium excretion is expected to be one of the determinants of plasma 
volume and thus the 14 day time-point should also reflect maximum plasma volume changes.  
Sodium excretion in the gastrointestinal tract may also impact plasma volume, although the 
magnitude and time-course are unknown.  
Population: The population will include patients with pre-existing heart failure who have been 
hospitalized with worsening of their heart failure, and have been stabilized sufficiently to be 
switched from IV to oral diuretic therapy (post-worsening heart failure).  Patients who present 
with worsening of heart failure are treated initially with IV diuretics due to reduced absorption of 
oral diuretics in the acute heart failure state (5).  Once the signs and symptoms of worsening heart 
failure have improved, therapy is switched from IV to oral diuretic therapy in preparation for 
chronic outpatient treatment. The switch from IV to oral diuretic therapy represents a point in the 
clinical course when the signs and symptoms of volume overload have improved although the 
plasma volume remains increased and further reduction is achieved with oral diuretic therapy. 
This post-worsening population is more clinically stable and whereas volume overload persists, is 
suitable for assessing safety and pharmacodynamics (PD) efficacy of SGLT inhibition in heart 
failure.  The limitations of this population include ongoing fluctuations of renal function and the 
limited published data on plasma volume change and hemoconcentration in this setting (6)(7)(8).  
Hemodynamic perturbations and pharmacotherapy during acute heart failure impact renal function 
and this period of flux makes renal function both vulnerable to toxic insults and difficult to assess 
for trends. Chronic kidney disease (CKD) is common in the heart failure population. It is 
anticipated that approximately 50% of patients with post-worsening heart failure may have an 
eGFR of <60mL/min/1.73m2 (9). Sotagliflozin (400 mg) was well-tolerated in patients with stage 
3 CKD for a period of 7 days.  Patients with an eGFR of <30mL/min/1.73m2 will be excluded 
from the study.  
Dose: There are no published data to support the safety and tolerability of SGLT inhibition in 
patients who are hospitalized with worsening of heart failure.  SGLT inhibition is known to 
reduce blood pressure and glomerular filtration rate (GFR) in healthy subjects and in patients with 
diabetes.  Sotagliflozin causes a dose-dependent reduction in blood pressure.  
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It is not known whether or how GFR relates to the response to sotagliflozin. A recent meta-
analysis of 11 phase 3 dapagliflozin studies suggests that its effects on BP, body weight, 
hematocrit, albuminuria, bicarbonate, pulse pressure, and uric acid are independent of eGFR 
levels (10). This post hoc analysis also showed that there is a poor relationship, which weakens 
further at lower eGFRs, between the change in HbA1c and the change with any of those 
parameters. To establish safety and tolerability, a submaximal dose of 200mg or placebo will be 
administered to the first 15 randomized post-worsening heart failure patients (randomized 2:1 
sotagliflozin: placebo).  Safety and tolerability, including effects on blood pressure and renal 
function, will be assessed by an independent data monitoring committee. Following safety review 
for the first cohort by Sponsor and DMC, the subsequent 15 patients will be randomized (2:1 
ratio) to 400 mg sotagliflozin or placebo, with ongoing safety monitoring. Upon completion of 
cohort 2, and further safety review by the DMC and Sponsor, the remainder of patients will be 
randomized 1:1 to placebo or 400mg sotagliflozin.     
4.2.3 Specific parameters rationale 
Plasma volume and hemoconcentration: Pharmacodynamic endpoints that are likely to reflect 
heart failure benefit include those that are related to improvement in the volume overload that 
typically causes acute exacerbations. Vascular and extravascular volumes can be assessed in 
humans using the indicator dilution method. A known quantity and concentration of an indicator 
is administered, and subsequent plasma samples are taken. The dilution of the indicator is directly 
proportional to the volume of distribution. The standard approach to measurement of plasma 
volume is labelled human albumin, an indicator that remains primarily localized to the 
intravascular space (11)(12). The indicator dilution method using radiolabeled ( 25I or 3 I) human 
albumin is the most accurate method for plasma volume measurement, and is commonly 
performed in hospitals or outpatient clinics (4).  Changes in plasma volume can occur as a result 
of postural changes or alterations in sympathetic tone, necessitating a controlled testing 
environment. As plasma volume falls, stable intravascular constituents become more 
concentrated. This hemoconcentration has been used as an indirect assessment of plasma volume 
changes. Examples of intravascular components whose concentrations increase with reductions in 
plasma volume include hemoglobin, hematocrit, albumin and total protein (2)(3)(13).  These 
biomarkers of plasma volume are easier to measure, require the same controlled testing 
environment used for plasma volume measurement, but may be more variable than plasma 
volume as a result of blood sampling and other interventions in the hospital setting.  
Plasma volume may decline by as much as 25% with standard diuretic therapy in patients 
hospitalized with worsening heart failure (11). Plasma volume was measured after 12 weeks of 
treatment with the SGLT2 inhibitor dapagliflozin, the diuretic hydrochlorothiazide (HCTZ) or 
placebo in diabetic patients without heart failure. Whereas placebo-treated patients had a 5.2% 
increase and HCTZ-treated patients had a 2.8% increase, dapagliflozin-treated patients had a 7.3% 
reduction in plasma volume corresponding to a 10.1% further decrease compared to diuretic 
treatment (3). The intrasubject variability for plasma volume measurements using the radiolabeled 
albumin indicator dilution technique is low (14), but little is known about such measurements in 
patients hospitalized with post-worsening heart failure (11).  Hospitalized post-worsening heart 
failure patients may have more variability in plasma volume than stable patients due to ongoing 
fluid shifts between the interstitial and intravascular spaces. Furthermore, as diuresis occurs and 
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plasma volume declines, the intravascular space may re-accumulate volume from the interstitial 
space. To investigate these potential sources of variability and capture such volume shifts 
participants will undergo measurement of total body water concurrently with plasma volume. The 
assessment for total body water also employs an indicator dilution method using deuterium oxide 
(D2O) which is distributed within total body water. Deuterium is administered orally, its 
distribution time is approximately 2.5 hours, and is measured in plasma by nuclear magnetic 
resonance spectroscopy. The intrasubject variability for the method is low (15). 
Heart failure is associated with anemia, and anemia has a negative impact on the prognosis of 
heart failure patients (16). Clinical trials are ongoing to determine whether anemia treatment 
improves outcome in heart failure patients. SGLT2 inhibition has been shown to augment release 
of erythropoietin, suggesting that hematocrit after SGLT2 inhibition may increase due to two 
distinct mechanisms; hemoconcentration and increased erythropoiesis (17). These different effects 
on hematocrit occur over different time-courses. The hemoconcentration effect may be detectable 
within several days, whereas erythropoiesis may require 4-8 weeks to detect (4)(18). Increased 
concentration of erythropoietin in plasma can be detected within hours following an hypoxic 
stimulus (19), and in diabetic patients erythropoietin concentrations increase within approximately 
2 weeks of starting treatment with an SGLT2 inhibitor (3). Additional objectives of the study will 
be to determine whether sotagliflozin increases plasma concentrations of erythropoietin in heart 
failure patients, and explore the relationship with ketone body production as assessed by beta-
hydroxybutyrate plasma levels. 
 
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY 
The primary objective of this study is the assessment of safety and tolerability of sotagliflozin, 
added to the standard of care treatment, in hemodynamically stable patients with worsening of 
heart failure, compared to placebo. 
A co-primary objective of this trial is the estimation of the effect of sotagliflozin, when added to 
the standard of care treatment, on changes in plasma volume, as assessed by direct (indicator 
dilution) and/or indirect (hemoconcentration) methods, in hemodynamically stable patients with 
worsening of heart failure, compared to placebo. 
5.2 
SECONDARY 
Secondary objectives for this study are:  
Explore the effect of sotagliflozin, added to standard of care treatment, on erythropoiesis, as 
assessed by changes in plasma erythropoietin levels, in hemodynamically stable patients with 
worsening of heart failure, compared to placebo. 
Explore the effect of sotagliflozin, added to standard of care treatment, on changes in plasma NT-
proBNP levels, in hemodynamically stable patients with worsening of heart failure, compared to 
placebo. 
5.3 
OTHER OBJECTIVES 
A further objective for this study is to explore the effect of sotagliflozin compared to placebo 
treatment, in hemodynamically stable patients with worsening of heart failure, on the following 
endpoints: 
 
Change in total body water from baseline to 14 days  
 
Change in uric acid from baseline to 14 days 
 
Change in beta-hydroxybutyrate from baseline to 14 days 
 
Change in total blood volume from baseline to 14 days 
 
Change in red cell mass from baseline to 14 days 
 
Percentage of patients within 15% of ideal blood volume on study day 14 
 
Blood pressure, sitting (SBP and DBP), at day 14 compared to baseline 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE STUDY 
This is a phase 2, multi-center, multinational, randomized, double-blind, placebo-controlled, 
parallel arm trial of the safety, tolerability and pharmacodynamic activity of sotagliflozin in 
hemodynamically stable patients with worsening heart failure. Study drug will be initiated in the 
hospital or other appropriate setting such as heart failure or infusion unit, after completion of 
intravenous diuretic therapy, and continued in an outpatient setting for a total of fourteen days. 
The main pharmacodynamic endpoints studied are changes in plasma volume and total body 
water as measured by indicator dilution methods using 131-I-albumin and deuterium oxide, and 
hemoconcentration as measured by changes in hematocrit, hemoglobin, plasma total protein and 
plasma albumin levels.  
An initial cohort of patients (Cohort 1) will receive sotagliflozin 200mg (n approximately10) or 
placebo (n  approximately 5) for fourteen days. Following safety monitoring and review by the 
DMC, Cohort 2 will receive sotagliflozin 400mg (n  approximately 10) or placebo (n  
approximately 5) orally for fourteen days. Following completion of Cohort 2 and review of safety 
and tolerability by the DMC,  conduct of cohort 3 will commence where patients will be allocated 
to sotagliflozin  400 mg (n  approximately 17) or placebo (n  approximately 17) orally for 
fourteen days. This is summarized in Table 1.  
Table 1 - Cohort randomization and allocation scheme 
Cohort 
Randomization 
Sotagliflozin 200 
mg 
Sotagliflozin 
400 mg 
Placebo 
Total N 
1 
2:1 
10 
0 
5 
15 
2 
2:1 
0 
10 
5 
15 
3 
1:1 
0 
17 
17 
34 
Tota  N 
 
10 
27 
27 
64 
 
 
 
 
The graphical study design/flow charts are in Section 1. 
6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each subject 
 
Screening period will be up to 21 days 
 
Treatment period is 14 1 days 
 
Follow up period will be 14 2 days 
 
Total study duration will approximately be 26-51 days 
However, subject participation could be prolonged in case of safety concerns (see 
Section 11.3.1). 
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6.2.2 Determination of end of clinical trial (all patients) 
The end of the clinical trial is defined as the day of the last follow up contact for the last patient, 
including cases where the patient could not be contacted following recurrent attempts and within a 
reasonable amount of time since last visit/contact. In such cases, the patient will be considered a 
dropout, and the end of clinical trial will be the date of the last documented contact. 
The Sponsor can terminate the trial prematurely based on the advice of the independent Data 
Monitoring Committee (DMC) or other unforeseen developments. 
 
7 
STUDY COMMITTEES 
7.1 
DATA MONITORING COMMITTEE (DMC) 
A DMC with members who are independent from the Sponsor and the Investigators will meet on 
a regular basis, and will be responsible for: 
 
Review of accumulating clinical study safety data, and 
 
Making a recommendation to the Sponsor regarding the study and dose escalation from 
Cohort 1 to Cohort 2 and dose selection from Cohort 1 and 2 to Cohort 3 following the 
scheduled end of Cohort 1 and Cohort 2 meetings,  or unscheduled meetings as triggered 
by safety signals. 
Safety data to be reviewed will include all safety data considered relevant. Details describing the 
DMC processes and procedures are outlined in a separate DMC Charter. To maintain continuous 
blinding and study integrity, the analysis will be conducted by an independent statistician, and 
measures will be taken to ensure the validity of the data. 
An expert review committee will also review all potential cases of DILIs in a treatment blinded 
manner to evaluate causality. 
7.2 
POTENTIAL OUTCOMES FOLLOWING DMC REVIEWS 
Depending on the safety profile observed in Cohort 1, one of the following decisions will be taken 
for Cohort 2 and subsequently cohort 3: 
 
Dose administration  may continue as scheduled in Section 9.4. 
 
OR a selected dose of 200, 400mg or both may be administered in - cohort 3 subsequent to 
DMC review, in balanced or unbalanced design 
 
Study may be stopped and Cohort 2 and 3 will not proceed. 
Other safety parameters will be considered as well for decision making. 
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For safety purposes, the treatment of a specific patient may be unblinded before the next dose 
level is administered, after mutual agreement between the Sponsor and Investigator. 
Similar outcomes and considerations as described above for the Cohort 1 review and its outcome, 
will also apply for the outcomes following review of Cohort 2. 
7.2.1 Guidance for stopping rules 
Discontinuation of IMP administration will be decided by the Investigator and/or the DMC. 
Patients re-hospitalized will discontinue IMP administration. In addition, IMP administration 
should be discontinued if in the opinion of the Investigator, and where appropriate following 
discussion with the Sponsor or urgent review by the DMC, IMP administration is associated with 
a serious AE or complications, or patient status deteriorates. Such cases might include a persistent 
decline of more than 50% in eGFR in the absence of any clinical improvement or development of 
new lower extremity complications (such as skin ulcers, infection, osteomyelitis, and gangrene) in 
a diabetic patient requiring treatment.  
 
 
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8 
SELECTION OF PATIENTS 
8.1 
 NUMBER OF PATIENTS PLANNED 
The study population will consist of male and female patients, 18 years and older, admitted to the 
hospital or heart failure unit or infusion center with worsening of heart failure requiring 
administration of intravenous diuretics, as per inclusion and exclusion criteria detailed below.  
A subject who received treatment and prematurely ends his/her treatment will be replaced in order 
to have approximately 64 evaluable observations.  
A patient should not be randomized more than once.  
Re-screening is allowed once during the current hospitalization, if in the opinion of the 
investigator, the change in the clinical status of the patient allows inclusion in the trial. Patients 
that failed screening during the first encounter for this trial can be rescreened during subsequent 
hospitalizations or visits to the infusion or heart failure units.  
A patient that requires re-hospitalization will be discontinued from IMP administration. Every 
effort will be made to follow up the progress of the patient and continue collection of relevant 
safety data, as appropriate and when applicable, and as judged by the Investigator with potential 
input from the DMC and Sponsor, as appropriate for each case, for the same follow up period 
(approximately 2 weeks) as for all other patients participating in the trial. In those cases, the 
follow up procedures and/or visit to clinical site should be followed as per study flow chart in 
Section 1.2. Only if judged appropriate by the Investigator and Sponsor, and in the absence of 
safety signals, the patient will be allowed to participate in some or all of the EOT study 
procedures. 
For all patients, GFR will be calculated from the serum creatinine (sCr; mg/dL) and age (years) 
via the abbreviated Modification of Diet in Renal Disease (MDRD) equation (20):  
GFR  186  (sCr)−
54  (age)−0 203  (1.212 if black)  (0.742 if female) 
8.2 
INCLUSION CRITERIA 
8.2.1 Inclusion criteria at screening 
I 01. Written informed consent; 
I 02. 18 years of age or older 
I 03. Patient admitted to the hospital or had urgent visit to emergency department or heart 
failure unit/clinic or infusion center for Congestive Heart Failure (CHF), defined by: 
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- 
Presence of ≥2 of the following clinical signs and symptoms of congestion: jugular 
vein distension, pitting edema in lower extremities greater than trace , dyspnea, rales 
heard on auscultation, radiographic pulmonary congestion, weight gain above 
historical dry weight of at least 5 lbs (2.27 kg) 
AND 
- 
Requiring treatment with IV diuretics  
  
I 04. Estimated glomerular filtration rate (eGFR) ≥30 ml/min/1.73m2 at the screening or 
randomization visit by the 4 variable Modification of Diet in Renal Disease (MDRD) 
equation   
I 05. Female subject must use a double contraception method during the study including a 
highly effective method of birth control, except if she has undergone sterilization at least 3 
months earlier or is postmenopausal. 
I 06. Male participants, unless vasectomized and confirmed sterile by sperm analysis, must use 
condoms during the study and refrain from donating sperm up to 90 days after the day of 
last dose. If the patient has a female partner of childbearing potential, the patient must 
wear a condom and female partner must use at least 1 highly effective method of birth 
control 
8.2.2 Inclusion criteria at randomization  
I 07. Transitioning from intravenous (IV) to oral diuretics and oral diuretic treatment has been 
prescribed or administered 
I 08.  Hemodynamically stable, defined as: 
- 
SBP ≥100 mmHg with no requirement for IV inotropes or IV vasodilators 
8.3 
EXCLUSION CRITERIA 
E 01. History of Type 1 diabetes mellitus 
E 02. Appears unlikely or unable to participate in the required study procedures, as assessed by 
the study Investigator, study coordinator, or designee (ex: clinically-significant psychiatric, 
addictive, or neurological disease), or sectioned due to an official or court order 
E 03. Tachyarrhythmia with ventricular rate >130 bpm at screening, unless determined to be 
clinically stable by the investigator current admission for worsening heart failure primarily 
triggered by causes such as acute coronary syndrome, pulmonary embolism, 
cerebrovascular accident, heart valve disorders (such as severe aortic stenosis), as 
determined by the Investigator  
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E 04. Clinically significant myocardial infarction (MI) within past 1 month as determined by 
Investigator and with objective evidence from ECG, and/or cardiac imaging and/or 
coronary angiography. Small isolated elevations in troponin that often accompany HF 
hospitalization are not an exclusion, nor are clinically significant MIs that have been re-
vascularized without complications 
E 05. Patients who recently had or scheduled to have cardiac interventions may be eligible if: 
- 
Stable 48 hours post procedure AND 
- 
Have diuretic treatment planned for the duration of treatment in this study   
E 06. Current use of or recent suspension of digoxin therapy with high levels of digoxin (level 
should be obtained and must be <1.2 ng/mL) at screening.       
E 07. History of heart or kidney transplant 
E 08. Diagnosis of hypertrophic obstructive cardiomyopathy   
E 09. End-stage HF defined as requiring left ventricular assist device insertion, intra-aortic 
balloon placement (IABP), or any type of mechanical support during the study period 
E 10. Pregnancy (demonstrated by serum pregnancy test at screening), breast-feeding, or 
inability or refusal to undergo pregnancy testing 
E 11. Use of any investigational drug(s) or prohibited therapy or sodium-glucose co-transporter 2 
(SGLT2) inhibitor 5 half-lives prior to screening  
E 12. Patients with moderate or severe respiratory, hepatic, neurological, psychiatric, active 
malignant tumor or other major systemic disease (including any diseases with evidence of 
malabsorption), making implementation of the protocol and/or the interpretation of the 
study results difficult 
E 13. Known allergies, hypersensitivity, or intolerance to sotagliflozin or any inactive 
component of sotagliflozin or placebo (i.e., microcrystalline cellulose, croscarmellose 
sodium [disintegrant], talc, silicon dioxide, and magnesium stearate [non-bovine]), unless 
the reaction is deemed irrelevant to the study by the PI 
E 14. Laboratory findings at the Screening Visit: 
a) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 times the 
upper limit of the normal laboratory range (ULN) (1 repeat lab allowed) 
b) Total bilirubin >1.7 times the ULN (except in case of Gilbert’s syndrome) (1 repeat lab 
allowed) 
c) Amylase and/or lipase > 3 times the ULN (1 repeat lab allowed) 
E 15. Patients with a severe or persistent in spite of optimal treatment genitourinary tract 
infection at time of randomization. 
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E 16. 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 
8.3.1 Additional exclusion criteria for patients with diabetes 
E 17. History of diabetic ketoacidosis or non-ketotic hyperosmolar coma within 3 months prior 
to the screening visit 
E 18. Lower extremity diabetic complications (such as skin ulcers, infection, osteomyelitis and 
gangrene) identified during the Screening period, and still requiring treatment at 
Randomization 
 
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9 
STUDY TREATMENTS 
9.1 
INVESTIGATIONAL MEDICINAL PRODUCTS (IMP) 
The IMPs are sotagliflozin 400 mg, sotagliflozin 200 mg, and matching placebo. Patients will be 
provided with treatment kit according to the cohort number and the arm allocation in the cohort 
for the Double -Blind Treatment Period: 
 
Placebo kit: containing placebo tablets  
 
Or Sotagliflozin 200 mg kits: containing placebo tablets and Sotagliflozin 200 mg tablets 
 
Or Sotagliflozin 400 mg tablets: containing Sotagliflozin 200 mg tablets. 
Table 2 - Summary of investigational medicinal products 
IMP: 
Sotagliflozin 200 mg  
Sotagliflozin 400 mg 
Placebo group 
Name of IMP 
Sotag f oz n (SAR439954) 
Sotag f oz n (SAR439954) 
P acebo 
Pharmaceutical Form 
Sotag f oz n (SAR439954) 
w  be supp ed as 200 mg 
tab ets 
Sotag f oz n (SAR439954) 
w  be supp ed as 200 mg 
tab ets 
P acebo w  be supp ed 
as tab ets ( dent ca  to 
sotag f oz n n 
appearance) 
Dose, timing, and route of 
administration 
Sotagliflozin 200 mg 
group:  
One 200 mg tab et, taken 
ora y once da y, before the 
f rst mea  of the day and 
One p acebo tab et, taken 
ora y once da y, before f rst 
mea  of the day 
Sotagliflozin 400 mg 
group:   
Two 200 mg tab ets, taken 
ora y once da y, before f rst 
mea  of the day  
 
Placebo group: 
Two p acebo tab ets, 
taken ora y once da y, 
before f rst mea  of the day  
 
Duration of treatment 
14 days doub e-b nd 
Treatment Per od fo ow ng 
Random zat on 
 
14 days doub e-b nd 
Treatment Per od fo ow ng 
Random zat on 
 
14 days doub e-b nd 
Treatment Per od 
fo ow ng Random zat on 
 
Storage conditions 
Store between +15 C and +30 C (59 F and 86 F) 
9.2 
NON-INVESTIGATIONAL MEDICINAL PRODUCTS  
131I-albumin: 
Supplied as ≤25µCi in 1mL, at date of calibration.  Each mL contains: 
 
10mg human albumin (non-reactive to HBsAg) 
 
16mg sodium dibasic phosphate 
 
1.6mg sodium monobasic phosphate 
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 
0.4mg guanidine hydrochloride 
 
Sodium chloride 
 
9mg benzyl alcohol 
Route of administration: IV, see Laboratory manual for detailed instructions. 
Dose: 10mg (≤25 µCi) 
Deuterium Oxide:  
Formulation; deuterium oxide 10 g / 10 mL presterilized vial or oral syringe with tip cap for 
enteral administration 
Dose and Administration: The vial or syringe volume (10 mL) will be diluted to a final volume of 
100 mL with sterile water. Patients will be asked to drink it all, under direct supervision. Details 
of the procedure for diluting the contents of the syringe and administration method are provided in 
the laboratory manual. 
9.3 
BLINDING PROCEDURES 
9.3.1 Methods of blinding 
To maintain blinding, sotagliflozin and the matching placebo tablets and packaging will be 
blinded and indistinguishable.  During the double-blind Treatment Period for each cohort, each 
treatment package will be labeled with a number, which is generated by a computer program from 
Sanofi. Investigators will not have access to the randomization (treatment) code except under 
circumstances described in Section 9.3.2. 
The randomization and the treatment allocation will be performed centrally by an IRT. The study 
biostatistician provides the randomization scheme to the IRT. Then, the IRT generates the subject 
randomization list from which it allocates treatment arms to the subject. 
Details for the circumstances under which unblinded reports or data will be provided to DMC are 
provided in the DMC Charter. 
9.3.2 Randomization code breaking during the study 
In case of an AE, the code should only be broken in circumstances when knowledge of the IMP is 
required for treating the subject. 
Code breaking can be performed at any time by using the proper module of the IRT and/or by 
calling any other phone number provided by the Sponsor for that purpose. If the blind is broken, 
the Investigator should document the date, time of day, and reason for code breaking in source 
data. The identity of the unblinded personnel, how the code was broken, and the treatment kit 
number should also be recorded. The Sponsor should also be informed. If the code is broken by 
the Investigator (or other medical doctor in emergency situation), the patient must be withdrawn 
from IMP administration. 
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9.6 
STORAGE CONDITIONS AND SHELF LIFE 
Investigators or other authorized persons (eg, pharmacists) are responsible for storing the 
IMP/NIMP in a secure and safe place in accordance with local regulations, labeling specifications, 
policies, and procedures. 
Control of IMP/NIMP storage conditions, especially control of temperature (e.g., refrigerated 
storage) and instructions for handling the Sanofi compound should be managed according to the 
rules provided by the Sponsor. 
The expiry date and storage conditions are written on the IMP/NIMP labels.  
The IMP Sotagliflozin 400 mg or sotagliflozin 200 mg or placebo treatment kit should be stored 
between 15°C and 30°C (59°F and 86°F). 
9.7 
RESPONSIBILITIES 
The Investigator, the clinical site pharmacist, or other personnel allowed to store and dispense 
IMP/NIMP will be responsible for ensuring that the IMP/NIMP used in the clinical trial is 
securely maintained as specified by the Sponsor and in accordance with the applicable regulatory 
requirements. 
All IMP/NIMP shall be dispensed in accordance with the Investigator’s prescription and it is the 
Investigator’s responsibility to ensure that an accurate record of IMP/NIMP issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP/NIMP provided by the Sponsor 
(deficiency in condition, packaging, 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/NIMP provided by the Sponsor may be subject to 
initiation of a recall procedure by the Sponsor. In this case, the Investigator will be responsible for 
promptly addressing any request made by the Sponsor or delegate, in order to recall IMP and 
eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP/NIMP provided by the Sponsor to a 
third party, allow the IMP provided by the Sponsor to be used other than as directed by this 
clinical trial protocol, or dispose of IMP in any other manner. 
9.8 
CONCOMITANT MEDICATION 
A concomitant medication is any treatment received by the patient concomitantly to any 
IMP(s).The IMP includes placebo and sotagliflozin 200 mg and 400 mg. 
All concomitant medications should be documented on the concomitant medications and herbal 
therapies page of the e-CRF. This includes all non IMP treatments that are taken by the patients 
at any time during the clinical study, beginning Day 1. 
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Additionally, a history of all medications in the 3 months prior to Day 1 should be taken. 
An accurate record of all concomitant medications must be entered in the eCRF, including the 
name of the medication (INN), daily dosage, and duration of use. 
Doses of chronically administered medicines should be kept fixed during the trial if at all possible. 
Special consideration should be given to the following: 
Digoxin 
A drug interaction study with digoxin, a sensitive P-glycoprotein (P-gp) substrate, indicated that 
sotagliflozin acts as a weak P-gp inhibitor. Thus, sotagliflozin increases systemic exposure of 
digoxin. As this study assesses the safety of sotagliflozin for the first time in this patient 
population, it will have patients with supra-therapeutic levels (defined for the purposes of this 
study as >/  1.2ng/ml) of digoxin at screening excluded from the trial. Patients that require 
digoxin during the study should have their plasma digoxin levels monitored. 
Non-steroidal anti-inflammatory drugs (NSAIDS) 
Concomitant use of NSAIDs increases the risk of acute renal injury and re-hospitalization in this 
patient population (21) and NSAIDs use during treatment for heart failure is contraindicated. Any 
NSAIDs use during the study would be at the discretion of the Investigator.  
Anti-hypertensives 
See also Section 9.12. Because sotagliflozin may reduce BP, adjustment of antihypertensive 
medication may be needed during the study in patients with hypertension, or following 
discontinuation of treatment with IMP. 
Anti-diabetic medications 
Sotagliflozin might reduce the need for insulin administration or other relevant medications in 
diabetic patients. Patients should monitor their blood glucose levels and adjust the dose and/or 
frequency of administration of relevant medication as required. Please refer to Section 11.5 for the 
management of hypoglycemic events. 
Diuretics 
Co-administration of IMP with loop and thiazide diuretics might lead to clinically significant 
volume depletion.   
Modifications to the dose of the loop and/or thiazide diuretic might be necessary. The Investigator 
should consult with relevant experts (e.g., nephrologists) as appropriate. For patients with a 
systolic blood pressure <110 mm Hg at Randomization, the doses of any diuretic or other 
antihypertensive medication may be decreased in order to prevent possible hypotension. 
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9.9 
TREATMENT ACCOUNTABILITY AND COMPLIANCE 
Compliance of IMP: 
On Days 1 and 14, sotagliflozin will be administered under direct medical supervision, and an 
appropriate record will be made in the source data by the Investigator or his/her delegate.  
Accounting and compliance for IMPs will be performed on, Visit 3 (between day 6 and day 8) and 
EOT Visit 5 (Day 14 1), or earlier in cases of discontinuation. The Investigator or his/her 
delegate will check the compliance to the study treatments based on the patient diary and will then 
complete the appropriate Site treatment and patient treatment log forms. Visual check on returned 
IMP will be performed by site staff. In addition the dosing information will be recorded on the 
appropriate pages of the e-CRF. 
If compliance is inadequate as determined by the Principal Investigator (PI), patients will be 
trained again and mentored. If suboptimal compliance continues after training and mentoring, 
patients may be discontinued at the discretion of the PI after discussion with the Sponsor’s 
medical monitor.   
Missed doses of study medication can be made up if taken within 12 hrs. of the regularly 
scheduled time.  Otherwise, the dose should be skipped and patients should take the next 
scheduled dose at the usual time.  Patients with emesis should not take a replacement dose. 
9.10 
PATIENT DIARY 
Paper diaries will be used for this study.  Information recorded into diary will document the 
compliance of IMP as well as other safety information (BP, Hypoglycemia, etc) and these 
recordings will be carefully reviewed also at each visit. 
Patients will enter self-reported information starting at Visit 2 into their paper diaries and they 
will bring it back to the center at each following visit during the treatment and follow-up period).  
Patients will be instructed how to fill in it every day. 
The diary includes sections for recording: 
 
Date and time of IMP dose 
 
Any change or new concomitant medication. 
 
Adverse events, including signs and symptoms suggesting occurrence of hypoglycemia 
 
Blood Pressure reading 
9.11 
RETURN AND/OR DESTRUCTION OF TREATMENTS 
Patients are to return all in use or unused IMP at Visit 5 (or final assessment on-treatment visit in 
case of permanent premature discontinuation).All partially-used or unused IMPs will be retrieved 
by the sponsor CRO or delegate. Investigational medicinal product reconciliation must be 
performed 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. 
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A written authorization for destruction will be given by the study 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.  
For NIMP not provided by the Sponsor (i.e., metformin or other oral anti-diabetic drugs), tracking 
and reconciliation is to be undertaken by the Investigator (or pharmacist if appropriate) according 
to the system proposed by the Sponsor. 
9.12 
POSTSTUDY TREATMENT 
Patients will continue monitoring and recording their BP on a daily basis following 
discontinuation of IMP. At the follow up telephone check/onsite (only if required by 
investigator’s clinical judgement) visit between day 26 and day 30, the patient will discuss entries 
in the diary, and any concerns with the investigator or his/her delegate. If, in the opinion of the 
investigator, the patient needs to attend for further examination and/or investigation, a follow up 
Visit (Visit 6) will be scheduled to meet the urgency and needs of patient treatment. If no further 
visit is scheduled, patients will be reminded to return their completed diaries. 
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10 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
10.1 
ACTIVITY OR PHARMACODYNAMICS 
10.1.1 Pharmacodynamic parameters  
10.1.1.1 Primary endpoints 
 
Change in hemoconcentration from baseline to D14 as assessed by changes in hematocrit, 
hemoglobin, albumin and total protein, based on the assumptions made by Dill and Costill 
(22) 
 
Change in plasma volume in milliliters from baseline to D14 as assessed by the indicator 
dilution method using 3 I-labelled human albumin 
10.1.1.2 Secondary endpoints 
 
Change in erythropoietin (mU/ml) from baseline to D14 measured by chemiluminescent 
enzyme-labelled immunometric assay 
 
Change in NT-proBNP (pg/mL) from baseline to D14 measured by standard 
electrochemiluminescence immunoassay  
10.1.1.3 Other endpoints 
 
Change in total body water (mL) from baseline to D14 as assessed by the indicator 
dilution method using deuterium oxide 
 
Change in uric acid (mg/dL) from baseline to D14 as measured by standard assay 
 
Change in beta-hydroxybutyrate (µM) from baseline to D14 as measured by standard 
enzymatic colorimetric assay 
 
Change in red cell mass (mL) from baseline to D14, as derived from measurements of 
plasma volume (assessed by the indicator dilution method using 3 I-labelled human 
albumin) and hematocrit  
 
Change in total blood volume (mL) from baseline to 14 days, as assessed by the indicator 
dilution method using 3 I-labelled human albumin 
 
Percentage of patients within 15% of ideal blood volume on study day 14 
 
Blood pressure (sitting, SBP and DBP) at day 14, compared to baseline 
10.1.2 Assessment methods 
All eligible patients will have hemoconcentration samples obtained and total body water 
(deuterium oxide) assessment performed as per Section 10.1.2.1 below. 
Sites that have the capacity to perform the additional plasma volume assessment by the 
3 I-albumin method will follow the procedure described in Section 10.1.2.2. 
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Patients who decline measurement of total body water or plasma volume by the indicator dilution 
methods, or in cases where in the opinion of the Investigator technical issues might prevent 
successful completion of those techniques, may still participate in the study provided they have 
measurements of plasma volume by the indirect hemoconcentration method. 
10.1.2.1 Hemoconcentration and Total Body Water estimation procedure on Day 1 and Day 
14: 
Hemoconcentration will be determined as previously described (22)(23), at all sites.  
A new 18 or 20-gauge IV will be placed in a large vein, ideally the antecubital position, on the 
morning of day 1 and 14.  Baseline urine, plasma and serum samples will first be collected.  
All patients must have completed the last planned IV bolus or infusion therapy with diuretics. 
It is recommended that procedures commence in the morning of D1. The actual start time may 
vary. The times provided below in Table 3 are indicative. 
Total body water measurement, by the deuterium oxide dilution method, will also take place at all 
sites. Intake of the deuterium oxide solution will take place immediately after completion of the 
physical exam and baseline specimens at T0 (approximately 7:30 AM). One sample for 
measurement of deuterium concentration will be collected at baseline and the second one will be 
collected approximately 3.5 ( 10 min) hours after ingestion of the deuterium oxide solution. 
At approximately 8 AM the subject will be asked to assume a semi recumbent position that will 
be comfortable to them for the next one and a half hours.  The angle of the bed or chair should be 
at approximately 45º and will be recorded.  At approximately 9:00 AM (after approximately one 
hour of recumbency) the blood samples for hematocrit, hemoglobin, albumin and total protein 
will be collected. The arm that the blood samples are being drawn from will not be in a dependent 
position and will be as close to the level of the right atrium as possible (to prevent 
hemoconcentration in the arm which can introduce substantial inaccuracy in the measurements). 
At approximately 10:00 AM the patient will receive the IMP.  At approximately 11:00 AM, a 
blood sample for deuterium oxide determination will be obtained.   
Table 3 - List of schedule of events for the hemoconcentration and total body water assessment 
procedure 
Time points 
(from IMP intake) 
Day / Time 
Procedure 
 
D1 and D14 
 
T0 (-2.5 H) 
7:30 am 
Phys ca  exam, v ta  s gns, b ood and ur ne samp es, ECG 
Deuter um ox de ntake ( mmed ate y after b ood samp e co ect on) 
T1 (- 2 H) 
8:00 am 
Pat ent assumes sem -recumbent pos t on  
T2 (-1 H) 
9:00 am 
Hemoconcentrat on samp es (Hematocr t, Hemog ob n, A bum n, and Tota  
Prote n).  
Pat ent a owed mob z ng.  
T3 (0 H) 
10:00 am 
IMP adm n stered fo owed by breakfast 
T4 (1 H) 
11:00 am 
B ood samp e for deuter um ox de 
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10.1.2.2 Plasma volume procedures on Day 1 and Day 14:  
The procedure for plasma volume determination by the 3 I-albumin method will be performed at 
all sites with the capacity to do so.  
The overall procedure and documentation are very similar to those described above, in 
Section 10.1.2.1. The schedule of events for 3 I-albumin IV administration, including the relevant 
sampling time points is as described below in Table 4. All times shown are indicative. 
Intake of deuterium oxide will take place immediately after completion of the physical exam and 
baseline specimens at T0 (approximately 7:30 AM). The post-equilibration sample should be 
collected 3.5 hrs ( 10 min) following administration of the deuterium oxide solution. 
At approximately 9:00 AM (after one hour of recumbency), and immediately after the samples for 
‘hemoconcentration’ have been obtained, the patient will receive the 3 I-albumin injection. 
Further blood samples will be collected at 9:12 AM and then every 6 minutes for a total of 6 
blood draws (including baseline). Samples should be collected as close to the specified time 
intervals as possible, however, small deviations (+/- 2 minutes) are acceptable as long as the 
actual time the sample collected is accurately recorded. A further sample for hematocrit 
determination will also be obtained at 9:36 AM, together with the final sample for 3 I-albumin 
determination. 
Table 4 - List of schedule of events for the plasma and total body water volumes assessment 
procedures 
Time points 
(from IMP intake) 
Day/Time 
Procedure 
 
D1 and D14 
 
T0 (-2.5H) 
7:30 am 
Phys ca  exam, v ta  s gns, b ood and ur ne samp es, ECG.  
Intake of Deuter um ox de. 
T1 (-2.0 H) 
8:00 am 
Pat ent assumes sem -recumbent pos t on  
T2 (-1.0 H) 
9:00 am 
 
 
9:12 
9:18 
9:24 
9:30 
9:36 
Hemoconcentrat on samp es (Hematocr t, Hemog ob n, A bum n, Tota  
Prote n) and samp e for background rad at on counts 
131I-a bum n adm n stered IV 
P asma co ect on; Record t me 
P asma co ect on; Record t me;  
P asma co ect on; Record t me 
P asma co ect on; Record t me 
P asma co ect on; record t me; CBC 
 
Pat ent a owed mob z ng 
T3 (0 H) 
10:00 am 
Sotag f oz n or p acebo adm n stered fo owed by breakfast 
T4 (1 H) 
11:00 am 
P asma samp e for deuter um ox de  
 
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Table 5 - Summary of handling procedures for 131I-albumin measurement samples samples 
131I-albumin measurement samples 
Blood sample volume 
7 mL 
Anticoagulant 
K2 EDTA 
Handling procedures 
Samp es w  be centr fuged for p asma preparat on.  Immed ate y after 
centr fugat on the resu t ng p asma w  be transferred to an appropr ate y abe ed 
tube  and be frozen mmed ate y unt  131I-a bum n measurements 
Plasma storage conditions 
-20ºC 
Plasma shipment conditions 
Samp es w  be sh pped on dry ce. 
Deuterium samples 
Blood Sample volume 
3 mL 
Anticoagulant 
K2 EDTA 
Handling procedures 
Centr fugat on at 1000g for 10m ns at 4oC 
Plasma aliquot split 
1m  cryov a  for Deuter um ox de 
Plasma storage conditions 
-20oC 
Plasma shipment conditions 
Samp es w  be sh pped on dry ce. 
 
Further details for the collection, identification, storage, and shipment of 3 I-albumin and 
deuterium oxide samples are provided in the Laboratory manual. 
10.1.3 Assessment schedule  
The assessment timing can be found in the period flow chart (Section 1.3). 
Table 6 - Number of samples 
 
131I-albumin 
Deuterium oxide 
By subject / D 1 
6 
2 
By subject / D 14 
6 
2 
Tota  by subject 
12 
4 
Tota  for study  
(approx mate y 64  pat ents) 
 
approx mate y 768 
 
 approx mate y 256 
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10.1.4 Assay methods   
A brief outline of the bioanalytical assays is provided in the summary tables below. 
Table 7 - Summary of assay method for 131I-albumin  
Analyte 
131I-albumin 
Matr x 
P asma 
Ana yt ca  techn que 
Gamma counter (BVA-100 ana yzer) 
Lower m t of quant f cat on 
 
Assay vo ume 
1 mL 
S te of b oana ys s 
 
Method reference 
Manzon  et a . J Nuc  Med Techno  2007; 35:55-63 (12) 
Table 8 - Summary of assay method for deuterium oxide 
Analyte 
Deuterium oxide 
Matr x 
P asma 
Ana yt ca  techn que 
NMR spectroscopy 
Assay vo ume 
0.2m  
S te of b oana ys s 
 
Method reference 
Kha ed et a . Am J C n Nutr 1987; 45:1-6 (24) 
 
10.2 
SAFETY 
Assessments for safety include AEs, clinical laboratory assessments, physical examination, ECG, 
weight and vital signs. An independent DMC will meet on a regular basis to review accumulating 
clinical trial safety data. Enrollment in Cohort 2 will only proceed following review of cases in 
Cohort 1 by the DMC, and similarly enrollment in Cohort 3 will only proceed following review of 
cases in Cohort 2 by the DMC. 
Serum creatinine will be assessed at Baseline (Day 1, Visit 1) and on-site Visits 2, 3 and 4 (in 
cohort 3 on-site visit 4 was eliminated precluding any serum collection). A central laboratory will 
analyze samples and estimate change from Baseline in serum creatinine and eGFR. Renal safety 
will also be assessed on a regular basis by an independent expert, who may also be a member of 
the DMC.  
The following safety endpoints will be assessed: 
 
Adverse events, AEs leading to discontinuation from the IMP, adverse events of special 
interest (AESIs), Events of Special Interest (EOSIs), SAEs and deaths 
 
Hypoglycemia (severe, documented symptomatic, or asymptomatic) 
 
Clinical laboratory results, vital signs and ECG results 
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10.2.1 Safety assessment at baseline and during the study 
The safety and tolerability investigations at baseline and during the study will consist of: 
1. Physical examination (includes at a minimum: heart and respiratory auscultation; 
peripheral arterial pulse; pupil, and abdomen examination). All physical examinations in 
diabetic patients, including abbreviated physical examinations, will include examination of 
the lower extremities to evaluate for any evidence of foot ulcers or infection should be 
performed as part of the general physical examination and this examination should be 
documented on the e-CRF. New lower extremity complications (such as skin ulcers, 
infection, osteomyelitis, and gangrene) requiring treatment should lead to permanent 
discontinuation of IMP. 
2. Body weight (kg) and height (cm). Body weight should be obtained with patients wearing 
undergarments or very light clothing and no shoes, and with an empty bladder.  The same 
scale should be used throughout the study, and calibrated on a regular basis as 
recommended by the manufacturer. 
3. Oral or tympanic body temperature; 
4. Vital signs, including heart rate, systolic and diastolic blood pressure measured after 10 
minutes in supine or sitting resting position.  
Prior to discharge on Day 1 (T6H) and on EOT Day 14( 1)(T6H), and on Visits 3 and 4 
(only Visit 3 in cohort 3), orthostatic changes in blood pressure will be assessed once for 
all patients not limited by mobility issues (assess BP when supine or sitting for 10 mins 
and after 3 mins standing). 
5. Laboratory tests (in fasting conditions for blood samples): 
 
Hematology: red blood cell count, hematocrit, hemoglobin, white blood cell count with 
differential count (neutrophils, eosinophils, basophils, monocytes, and lymphocytes), 
platelets, MCV, MCHC, RDW. 
 
Biochemistry:  
- 
Plasma/serum electrolytes: sodium, potassium, chloride, calcium. 
- 
Liver function: AST, ALT, alkaline phosphatase, gamma-glutamyl transferase, total 
and conjugated bilirubin. 
- 
Renal function: urea, creatinine. 
- 
Pancreatitis: Amylase and Lipase 
- 
Potential muscle toxicity: creatine phosphokinase  
- 
Metabolism: glucose, albumin, total proteins. 
6. Urinalysis: A urine sample will be collected and sent for quantitative measurement for 
glucose, protein, erythrocytes, and leucocytes count. Microbiological analysis will be 
requested in the presence of symptoms suggestive of urinary tract infection.  
7. If female and of child bearing potential, beta-HCG serum test. 
8. If female without a clear history of menopause, plasma follicle-stimulating hormone. 
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9. Adverse events, spontaneously reported by the subject or observed by the Investigator, 
will be monitored. 
10. The ECG assessment of “normal” or “abnormal” will be analyzed. A 12-lead ECG record 
is performed locally at Visit 2, Visit 3 and Visit 5 (EOT) in cohorts 1 and 2, and 3. The 12-
lead ECG should be performed after at least 10 minutes in supine position and, when 
possible, prior to the morning IMP administration. The Investigator should review the 
ECG and document the interpretation, sign and date it on the ECG print out and in the e-
CRF. Each ECG trace is analyzed in comparison with the screening recorded trace. All 
original traces are kept as source data. 
Any new ECG abnormality should be rechecked for confirmation and reported as 
appropriate for that finding. 
10.3 
PHARMACOKINETICS 
10.3.1 Sampling times 
Sparse pharmacokinetic (PK) samples will be collected. PK samples will be collected only from 
patients in cohort 1 and 2. The sampling times for plasma collection can be found in the study and 
period flow charts (Section 1.2 and Section 1.3). 
10.3.2 Number of pharmacokinetic samples 
Table 9 - Number of plasma samples 
 
sotagliflozin 
By subject  
7 
Tota  by subject 
7 
Tota  for cohort 1 and 2 on y (30 p anned ) 
210 
10.3.3 Sample handling procedure 
The sample handling procedure for the PK samples is summarized in Table 10 below. 
Special procedures for collection, storage, and shipment are provided in the Laboratory manual. 
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11 
SUBJECT SAFETY 
The Investigator is the primary person responsible for taking all clinically relevant decisions on 
safety issues. 
If judged necessary, the opinion of a Specialist should be envisaged in a timely manner (eg, acute 
renal failure, convulsions, skin rashes, angioedema, cardiac arrest, electrocardiographic 
modifications, etc.) 
11.1 
ADVERSE EVENT MONITORING 
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final clinical study report. 
11.2 
DEFINITIONS OF ADVERSE EVENTS 
11.2.1 Adverse event 
An adverse event (AE) is any untoward medical occurrence in a subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with 
this treatment. 
Adverse events will be graded according NCI-CTCAE v4.03 and classified by system organ class 
(SOC) / preferred term (PT) according the last available version of the Medical Dictionary for 
Regulatory Activities (MedDRA) dictionary. For AEs not included in the NCI CTCAE, the 
Investigator will be required to assess the intensity of the adverse drug/biologic experience using 
the CTCAE general guideline: 
 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (ADL). Instrumental ADL refer to 
preparing meals, shopping for groceries or clothes, using the telephone, managing money, 
etc. 
 
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL. Self-care ADL refer to bathing, dressing and undressing, feeding self, using the 
toilet, taking medications and not bedridden. 
 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
 
Grade 5: Death related to AE. 
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11.2.2 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 
subject was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
 
Requires inpatient hospitalization or prolongation of existing hospitalization, or 
 
Results in persistent or significant disability/incapacity, or 
 
Is a congenital anomaly/birth defect, or 
 
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 subject or may require medical or surgical intervention to prevent one of 
the other outcomes listed in the definition above. 
Note: Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias, convulsions, ALT > 3 x ULN + total bilirubin > 2 x 
ULN or asymptomatic ALT increase > 10 x ULN, or development of drug dependence or drug 
abuse. Unblinding of suspected unexpected serious adverse reaction (SUSAR) by the Sponsor is 
described in Section 9.3.2. 
11.2.3 Adverse event of special interest 
An adverse event of special interest (AESI) is an adverse event (serious or nonserious) of 
scientific and medical concern, specific to the IMP or program, for which ongoing monitoring and 
rapid communication by the Investigator to the Sponsor may be appropriate. 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 the study by protocol amendment. 
The AESIs for this study are: 
1. Pregnancy of a female patient entered in a study as well as pregnancy occurring in a 
female partner of a male patient entered in a study with IMP/NIMP. 
Pregnancy occurring in a female patient included 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 11.2.2), 
a) In the event of pregnancy in a female patient, IMP should be discontinued, 
b) Follow-up of the pregnancy in a female patient or in a female partner of a male patient is 
mandatory until the outcome has been determined (see Appendix A). 
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2. Symptomatic overdose (serious or nonserious) with IMP/non investigational medicinal 
product (NIMP) 
 
A symptomatic overdose (accidental or intentional) with the IMP/NIMP is an event 
suspected by the Investigator or spontaneously notified by the patient and resulting in 
clinical symptoms and/or signs accompanied by administration of more than twice the 
intended daily dose within a 24-hour period. It will be recorded in the e-CRF as an AESI 
with immediate notification “Symptomatic OVERDOSE (accidental or intentional)” in all 
cases and will be qualified as an SAE only if it fulfills the SAE criteria. 
(Please note that an Asymptomatic overdose with the IMP/NIMP, accidental or 
intentional, defined as administration of more than twice the intended daily dose within a 
24-hour period, without clinical symptoms and/or signs, either suspected by the 
Investigator or spontaneously notified by the patient, not based on accountability 
assessment. It will be recorded as an AE “Asymptomatic OVERDOSE, accidental or 
intentional.”) 
3. ALT increased ≥ 3X ULN (refer to related flowchart in Appendix B) 
11.2.4 Events of Special Interest (EOSIs) 
An EOSI is a serious or non-serious AE of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring may be appropriate. Such events 
may require further investigation in order to characterize and understand them. These events 
should be reported on the specific e-CRF page and will only qualify for expedited reporting when 
serious (fulfilling SAE criteria). 
The EOSIs for this study are: 
4. MACE (cardiovascular death, myocardial infarction, or stroke) and other specific CV 
events (eg, heart failure leading to hospitalization). 
5. Severe hypoglycemia (see Section 11.5.1.1) 
6. Venous thrombotic events (including venous thrombosis deep and pulmonary embolism) 
7. Pancreatitis 
8. Fracture bone 
9. AEs leading to amputations 
10. Diabetic Ketoacidosis (DKA) 
11. Malignancies of special interest (breast, bladder, renal cell, Leydig cell tumor of the testis, 
pancreatic, prostate, and follicular thyroid cancer) 
12. Genital mycotic infections (to include vulvovaginal candidiasis in females and candida 
balanitis in males) 
13. Urinary tract infection 
14. Diarrhea 
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15. Volume depletion with serious consequence (orthostatic hypotension, orthostatic collapse 
fall, fracture) 
16. Renal events, to include 50% decline in eGFR, end stage renal failure, renal death defined 
as eGFR < 15 ml/min/1.73m2 
11.3 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
11.3.1 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, are to be recorded 
on the corresponding page(s) or screen(s) of the case report form for included patients. Whenever 
possible, diagnosis or single syndrome should be reported instead of symptoms. The Investigator 
should specify the date of onset, intensity (see definitions in Section 11.2.1), action taken with 
respect to IMP/NIMP, corrective treatment/therapy given, additional investigations performed (eg, 
in the case of dermatologic lesions photographs are required), outcome, and Investigator’s opinion 
as to whether there is a reasonable possibility that the AE was caused by the IMP/NIMP.  
In this study, the use of concomitant medication, as well as the nature of the disease and 
comorbidities, might make it difficult to assess causal relationships, as might for example be the 
case with renal function or shifts in blood pressure. In such cases, where the nature of the 
relationship cannot be determined by the investigator, the Global Safety Officer with input from 
other appropriate study team members and/or DMC will determine if there is a causal 
relationship.   
In order to ensure the safety of the patients, 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.  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. 
When treatment is prematurely discontinued, patients are to be assessed using the procedure 
planned for the end-of-study visit, including a pharmacokinetic sample if appropriate as defined 
by the protocol. 
Laboratory, vital signs, or ECG abnormalities are to be recorded as AEs in the eCRF only if:  
 
symptomatic, and/or  
 
requiring either corrective treatment or consultation, and/or  
 
leading to IMP/NIMP discontinuation or modification of dosing, and/or  
 
fulfilling a seriousness criterion, and/or  
 
defined as an AESI. 
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11.3.2 Guidelines for reporting serious adverse events 
In the case of a SAE, the Investigator must immediately: 
 
ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the eCRF; the system will automatically send the notification to the monitoring team after 
approval by the Investigator within the eCRF or after a standard delay. 
 
SEND (preferably by fax or e-mail) the 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 e-mail address appear on the clinical trial protocol. 
Care should be taken to ensure that the subject's identity is protected and the subject's 
identifiers in the clinical trial are properly mentioned on any copy of source document 
provided to the Sponsor. For laboratory results, include the laboratory normal ranges. 
 
All further data updates should be recorded in the eCRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medication, subject status, etc.) should be sent (by fax or e-mail) to the monitoring team 
within 24 hours of knowledge. In addition, any effort should be made to further document 
within the week (7 days) following initial notification any SAE that is fatal or life 
threatening. 
 
A back-up plan is used (using paper flow) when the eCRF system does not work. 
Back-up plan 
 
SEND (within 24 hours, preferably by fax or e-mail) the signed and dated corresponding 
page(s) in the case report form to the representative of the monitoring team whose name, 
fax number, and e-mail address appear on the clinical trial protocol. 
 
ATTACH the photocopy of all examinations carried out and the dates on which these 
examinations were performed. Care should be taken to ensure that the subject’s identity is 
protected and the subject’s identifiers in the clinical trial are properly mentioned on any 
copy of source document provided to the Sponsor. For laboratory results, include the 
laboratory normal ranges. 
 
All further documentation should be sent to the monitoring team within 24 hours of 
knowledge. In addition, every effort should be made to further document within the week 
(7 days) following initial notification any SAE that is fatal or life threatening.  
Any SAE brought to the attention of the Investigator at any time after the end of the study for the 
subject and considered by the Investigator to be caused by the IMP with a reasonable possibility, 
should be reported to the monitoring team. 
11.3.3 Guidelines for reporting adverse events of special interest 
For AESI, the Sponsor is to be informed immediately (ie, within 24 hours), as per SAE 
notification guidelines described in Section 11.3.2, even if a seriousness criterion is not met, using 
the corresponding pages of the case report form (to be sent) or screens in the eCRF. 
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11.3.4 Guidelines for reporting events of special interest 
If an EOSI fulfills the criteria of an SAE, reporting should be performed according to the 
instructions for reporting of SAEs (see Section 11.3.2). Otherwise, reporting should follow the 
instructions for an AE (see Section 11.3.1). 
11.3.5 Guidelines for management of specific laboratory abnormalities 
Once the subject is included in the clinical trial, the following laboratory abnormalities must be 
monitored, documented, and managed according to the related decision charts in Appendix B.  
 
Neutropenia 
 
Thrombocytopenia 
 
ALT increase 
 
Creatine phosphokinase (CPK) increase, suspected to be on non-cardiac origin and not related 
to an intensive physical activity 
Renal function and the extent of renal injury that is commonly precipitated by intensive diuretic 
treatment in this patient population will be reviewed on a frequent basis by an independent renal 
expert, member of the Data Monitoring Committee (DMC), who shall communicate potential 
issues to the Sponsor. Overall renal safety in Cohorts 1 and 2 will be assessed by the DMC.  
11.4 
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, IRB/IECs 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. 
 
The following AESI to the Regulatory Authorities requiring such reporting: 
- 
Pregnancy 
- 
Symptomatic overdose 
- 
ALT increase >3 x ULN  
Adverse events that are considered as expected events will be specified by the reference safety 
information provided in the Investigator’s Brochure.  
If required, unblinding of SUSARs will be the responsibility of the Sponsor.  
The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report. 
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11.5 
SAFETY INSTRUCTIONS FOR DIABETIC COMPLICATIONS 
11.5.1 Hypoglycemia 
During the study, diabetic patients are instructed to document any hypoglycemic episodes in their 
study diary. The hypoglycemia will be reported in the specific e-CRF page with onset date and 
time, symptoms and/or signs, the SMBG value if available, and the treatment. Unless the event 
fulfills SAE criteria, hypoglycemia will not be reported as an AE.  
Hypoglycemia is categorized according to the ADA workgroup on hypoglycemia classification 
(25) and summarized in Figure 1. 
11.5.1.1 Severe hypoglycemia 
Severe hypoglycemia is an event requiring assistance of another person to actively administer 
carbohydrate, glucagon, intravenous glucose or other resuscitative actions. These episodes may be 
associated with sufficient neuroglycopenia to induce seizure, unconsciousness or coma. 
Self-monitored plasma glucose values may not be available, but neurological recovery attributable 
to the restoration of plasma glucose to normal is considered sufficient evidence that the event was 
induced by a low plasma glucose concentration. 
Note: “requiring assistance of another person” means that the patient could not help himself or 
herself to treat the hypoglycemia. Assisting a patient out of kindness, when assistance is not 
required, should not be considered a “requires assistance” incident. A severe hypoglycemic 
incident should be confirmed by the Investigator. 
Any hypoglycemic event which leads to unconsciousness, coma, or seizure should also be 
reported as an SAE. 
11.5.1.2 Documented symptomatic hypoglycemia 
Documented symptomatic hypoglycemia is an event during which typical symptoms of 
hypoglycemia accompanied by a measured plasma glucose concentration of ≤3.9 mmol/L (≤70 
mg/dL). 
Clinical symptoms that are considered to result from a hypoglycemic episode are eg, increased 
sweating, nervousness, asthenia/weakness, tremor, dizziness, increased appetite, palpitations, 
headache, sleep disorder, confusion, seizures, unconsciousness, or coma. 
11.5.1.3 Asymptomatic hypoglycemia 
Asymptomatic hypoglycemia is an event not accompanied by typical symptoms of hypoglycemia 
but with a measured plasma glucose concentration ≤3.9 mmol/L (≤70 mg/dL). 
Note: low plasma glucose values without symptoms or signs should not be reported more than 
once within 30 minutes. Repeated low glucose values within a short period could be due to 
malfunction of the device, error testing or following up a low glucose reading. The Investigator 
should try not to document false low SMPG values or redundant low glucose values as 
asymptomatic hypoglycemic event. Further clarification with the patients is needed. 
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11.5.1.4 Probable symptomatic hypoglycemia 
Probable symptomatic hypoglycemia is an event during which symptoms of hypoglycemia are not 
accompanied by a plasma glucose determination, (but that was presumably caused by a plasma 
glucose concentration ≤3.9 mmol/L [≤70 mg/dL]), i.e., symptoms treated with oral carbohydrate 
without a test of plasma glucose. 
11.5.1.5 Relative hypoglycemia 
Relative hypoglycemia is an event during which the patient reports typical symptoms of 
hypoglycemia, and interprets the symptoms as indicative of hypoglycemia, but with a measured 
plasma glucose concentration >3.9 mmol/L (>70 mg/dL). 
Figure 1 - Hypoglycemia classification in Study PDY15079 
 
11.5.2 Instructions for the management of DKA in diabetic patients  
Diabetic ketoacidosis, including atypical (euglycemic) DKA, is the most serious emergency in 
patients with T1D and T2D. It is possible that GI or other AEs occurring with sotagliflozin may 
mask presenting symptoms of DKA. Because sotagliflozin lowers blood glucose by insulin 
independent SGLT1 and SGLT2 inhibition, it is possible for DKA to be present with normal or 
low blood glucose. Therefore, the Investigator must still consider a DKA event even if blood 
glucose is low or normal. Please refer to Appendix D for further details regarding DKA. 
 
 
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12 
HANDLING OF SUBJECT WITHDRAWAL 
12.1 
LIST OF TREATMENT WITHDRAWAL CRITERIA 
Refer to Section 11.3.3 for cases in which AESI lead to treatment discontinuation. 
Pregnancy will lead to permanent treatment discontinuation in all cases (Refer to Section 11.3.3). 
12.2 
REASONS FOR TREATMENT WITHDRAWAL 
 
The patient may withdraw from the treatment if they decide to do so, at any time and 
irrespective of the reason, or upon the Investigator’s decision or at the specific request of 
the Sponsor.   
 
However, withdrawal of consent for treatment should be distinguished from withdrawal of 
consent for follow-up visits. Patient who withdraws should be explicitly asked about the 
contribution of possible AEs to their decision to withdraw consent, and any AE 
information elicited should be documented. Such information about the reason of patient‘s 
withdrawal will be filled in in the appropriate eCRF page. 
 
In case of withdrawal, 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. The 
informed consent for the study should note that although a patient is free to leave the study 
and stop taking study medication, the investigators hope the patient will remain for follow 
up status evaluations. 
12.3 
REPLACEMENT OF PATIENTS 
According to the study design, a patient who prematurely ends his/her study period after the start 
of the baseline period and who received treatment may be replaced in order to have 81 patients 
who have completed a minimum of 12 days treatment with IMP (sotagliflozin or placebo). 
In the case of a discontinuation related to an AE, the replacement may be discussed between the 
Investigator and the Sponsor.  
12.4 
TREATMENT WITHDRAWAL FOLLOW-UP PROCEDURE 
All study treatment withdrawals should be recorded by the Investigator on the appropriate case 
report form pages or screens for eCRF when considered as confirmed. 
If possible, patients are to be assessed using the procedure planned for the end-of-study visit, 
including a pharmacokinetic sample if appropriate. 
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For any patient who fails to return to the site at the EOT visit, unless the patient withdraws the 
consent for follow-up, the Investigator should make every effort to contact the patient (eg, contact 
the patient’s family or private physician, review available registries or health care database), and 
to determine his/her health status, including at least his/her vital status. Attempts to contact the 
patient must be documented in the patient’s records (e.g., times and dates of attempted telephone 
contact, receipt for sending a registered letter). 
Patients withdrawn from the study must not be re-included in the study. Their inclusion and 
treatment numbers must not be reused. 
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13 
STUDY PROCEDURES 
13.1 
VISIT SCHEDULE 
The visit schedule and procedures/assessments are listed in the Study Flow Chart (Section 1.2). 
The aim of this section is to provide details on how some of the procedures/assessments should be 
performed. All data obtained during the trial visits are reviewed by the Investigator and/or Sub-
Investigators who are qualified in the treatment of heart failure patients and are familiar with the 
study. 
13.1.1 Screening procedures 
Patients will undergo Screening assessments at Visit 1 (Day -21 to Day -1, and up to 
randomization on D1, to allow, for example, cases where the patient may be admitted and likely 
to be discharged on the same day) following signing of the informed consent form. The patient 
will receive information on the study objectives and procedures from the Investigator. The patient 
will have to sign the informed consent prior to any action related to the study. 
The interactive response technology system (IRT) will be contacted at Visit 1 for notification of 
Screening Visit and to obtain the patient identification number. 
Screening will include the investigations listed in the Study Flow Chart (Section 1.2) and detailed 
in Section 10.2.  
All patients must have a documented echocardiogram, either performed during Visit 1 or within 
12 months from current admission or screening. 
Rechecking of any parameters at screening is subject to the Investigator’s judgment, allowed 
once.  
Patients who meet all the inclusion criteria and none of the exclusion criteria will be eligible for 
randomization. 
13.1.2 Inclusion procedures 
Inclusion procedures will be carried out during Screening (D-21 to D-1) or D1, as appropriate for 
each patient. Those will include the investigations listed in the study flow chart (Section 1.2) and 
detailed in Section 10.2. 
Baseline parameters may be rechecked once, at the Investigator’s discretion. Results of a 
rechecked value should be known before the inclusion. The last value should be considered as the 
baseline value and reported in the case report form.  
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For patients eligible for discharge from hospital or unit: The patient diary is dispensed during day 
1 and instructions/training on its use and completion are provided: Adverse events (AE), 
Concomitant medications, IMP intake (and whether it was taken before breakfast) and BP 
measurements (and time) are recorded on a daily basis between Day 2 and last follow up. 
The automated BP monitors will also be dispensed on Day 1 and patients will be trained in their 
use. The technique employed should observe the following (described in detail in Appendix C): 
1. First time (performed on Day 1 by the Investigator or qualified site staff): Determine 
the arm with higher BP (based on SBP) and evaluate for inconsistency of BP between 
arms to exclude major vascular problems  
2. Day 2 until last follow up:  
 
Measurements should take place, to the extent possible, within the same time 
window each day and preferably in the morning between 6 AM and 10 AM. 
 
BP obtained after 5-10 minutes in the sitting resting position 
 
Measurements should be done in triplicate, not less than 1-2 minutes between 
readings, and all measurements recorded in the Diary.  
 
The same arm, as determined on Day 1 (unless it becomes uncomfortable or 
contraindicated due to a newly developed skin, musculoskeletal or other condition) 
should be used throughout the study 
Entries in the diary (such as AE and IMP intake, and if not recorded in source documents, 
concomitant medications and BP) will also be recorded for patients that have not been discharged.  
If BP monitoring is not standard, recordings using the BP monitor provided by the Sponsor or 
other appropriate monitor should be used to obtain BP readings. If the patient is discharged, they 
will be reminded to continue with diary updates as described above. 
13.1.3.2 Discharge procedures 
Inpatients eligible for discharge or patients returning to the day care unit for the procedures of 
Day 1 may be discharged the same day (Day 1), after a complete review of the available safety 
data by the Investigator, and not less than 6 hours have elapsed from administration of IMP.  
3 I-Albumin has a half-life of 7-8 days. It is safe for patients to return home, without any 
restrictions as far as use of common areas, lavatory facilities or contact with other people is 
concerned. Sites should discuss the discharge plan and any restrictions with a radiation officer or 
nuclear medicine department. 
13.1.3.3 Ambulatory period(s) 
After institutionalization, patients should immediately contact the Investigator or one of the 
clinical unit managers in the event of any unexplained symptom or any unexpected effect or event 
occurring during the study. For this reason, patients will be informed that they can contact the 
clinical unit by telephone 24 hours a day. Patients must give the Investigator a telephone number 
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where they can be contacted in an emergency. Patients must carry with them, during ambulatory 
study period(s), the patient card indicating the study number and the emergency telephone number 
provided by the study site. 
13.1.3.4 Visit 3 (Between Day 3 and Day 6) and Visit 4 (Between Day 8 and Day 11) in 
cohort 1 and 2; in cohort 3 visit 3 (Between Day 6 and Day 8) and visit 4 removed 
Patients in cohort 1 and 2 who are discharged from hospital will return to the clinical site or other 
appropriate facility on a day convenient to them between Day 3 and Day 6 (Visit 3) and on a day 
convenient to them between Day 8 and Day 11 (Visit 4). Patients in cohort 3 who are discharged 
from the hospital will return to the clinical site or other appropriate facility on a day convenient to 
them between Day 6 and Day 8 (visit 3). Patients in cohort 1 and 2 will have PK samples obtained 
in those visits  and should be instructed not to take their morning dose of IMP on those days, as it 
will be administered by site staff as per the period flow chart in Section 1.3. Inpatients will also 
have the same assessments in the hospital or other appropriate unit. PK sampling will not be 
collect from patients in cohort 3 at all, as PK studies were removed from this cohort.  
For patients discharged home or patients transferred to other units (for example rehabilitation 
wards or HF units) who may have mobility or other issues that prevent them from attending the 
site, the PI or delegate may arrange for the Visit and all relevant assessments to take place at a an 
appropriate facility and as approved by the Institution and Sponsor.  
All patients will have safety assessments, including collection of blood samples for measurement 
of creatinine, as detailed in the study flow chart, Section 1.2. 
Patients returning to the site will bring their Diaries. The information recorded in the Diaries will 
be transcribed to the eCRFs.  
The technique for measuring BP will be reviewed and further training provided as appropriate. 
The Investigator will assess compliance with IMP.   
In some countries, local guidelines and institutional policies might require patients to stay in 
hospital for prolonged periods. In those cases, administration of IMP, daily diary recording and 
assessments for Visit 3 (including patients in cohort 3) and/or Visit 4 (in 1 and 2 only) may take 
place in the hospital setting.   Note: cohort 3 will be conducted exclusively in the US.  
 
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13.1.3.5 Visit 5 (Day 14±1)/ 
Discharged Patients will return to the clinical site on day 14 1 (Visit 5;). Exceptions can be made 
for those patients who may have been transferred to a step down unit, or rehabilitation ward or a 
different hospital. In those cases, plasma volume will not be assessed by the radiolabeled albumin 
method, unless the place is authorized for administration and collection of radioactive samples 
(such as a nuclear medicine facility) and has been discussed and approved by the relevant 
authority of the Institution(s) and Sponsor.    
On days of site visits patients should be instructed not to take their dose of IMP in the morning of 
that day, as this will be administered by site staff as per the period flow chart in Section 1.3. 
The guidelines described above for Day 1 procedures and discharge, should also apply on day 14. 
Please refer to the study flow chart in Section 1.2 and the period flow chart in Section 1.3. 
A patient who had plasma volume assessment performed on Visit 2 (Day 1) by the 3 I-albumin 
method, should also have plasma volume assessment performed on Visit 5   by the 3 I-albumin 
method (Day 14 1).  
A patient who did not have plasma volume assessment performed on Visit 2 (Day 1) by the 3 I-
albumin method, need not have plasma volume assessment performed on Visit 5(Day 14 1).   
Patients should bring their Diaries, and relevant information will be transcribed to the eCRFs. 
New diaries will be dispensed.  
The technique for measuring BP will be reviewed and further training provided as appropriate. 
The Investigator will assess compliance with IMP.   
IRT will be notified for end of treatment (EOT).  
13.1.3.6 Visit 6 (Day 26-30) 
All patients enrolled in the study will be followed up with a telephone interview during that period 
(between day 26 and day 30). Safety, including adverse events and assessment of BP as recorded 
in the diary since discontinuation of IMP will be reviewed during the telephone interview. 
A clinical site visit during that period is reserved only for those patients who, in the opinion of the 
Investigator, need followed up in clinic. The rationale and justification for the visit, as well as 
laboratory or other investigations’ results performed to address those concerns, should be clearly 
documented, and relevant records kept for review by the DMC and Sponsor.  
Diaries will be retrieved for those patients returning to the site. The  patients who did not return to 
the site will return their diaries by courier, using a pre-paid service.  
IRT will be notified for end of study (EOS). 
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13.1.4 Study restriction(s) 
Throughout the treatment period, patients will be asked to take their breakfast within 
approximately15 minutes after administration of study drug. Meal times will not be collected in 
the eCRF anymore in cohort 3.  
In cohorts 1 and 2 on study days during Visit 2 and Visit 5 a meal will be provided within 
approximately 15 minutes after administration of study drug. Patients should fast (water allowed) 
for 6 hours prior to the administration of IMP.  
Similarly in cohort 1 and 2 for Visits 3 and 4, patients should also fast for 6 hours (water allowed) 
prior to IMP administration. A snack or meal should be taken within 15 min of IMP 
administration. Note: Visit 4 was eliminated from cohort 3. 
During the study, patients will be advised by their physicians on water intake, salt intake and other 
relevant dietary restrictions which might constitute part of their treatment. On treatment day 1 
(Visit 2) and day 14 1 (Visit 5), water and salt intake during the study procedures will be adjusted 
as per treatment plan. 
13.2 
DEFINITION OF SOURCE DATA 
All evaluations that are reported in the case report form must be supported by appropriately 
identified source documentation. 
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14 
STATISTICAL CONSIDERATIONS 
14.1 
DETERMINATION OF SAMPLE SIZE 
Sample size is based on empirical consideration. No formal sample size calculation has been 
performed.  
14.2 
PATIENT DESCRIPTION 
14.2.1 Disposition of patients 
Screened patients are defined as any patient who meets the inclusion criteria and signed the 
informed consent.  
Randomized and treated patients consist of all patients with a treatment kit number assigned and 
recorded and received at least one administration of IMP. Patients treated without being 
randomized will not be considered as randomized and will not be included in any analysis 
population for which being randomized is required.   
The safety data of patients treated but not randomized will be reported separately, and these 
patients will not be in the safety population. 
A detailed description of subject accountability including count of patients screened, randomized 
and treated, patients who did not complete the study along with the main reason for treatment 
discontinuation will be provided. 
All patients discontinuation from the study, taking place on or after study drug intake, will be 
fully documented in the body of the clinical study report (CSR).  
14.2.2 Protocol deviations 
During the blinded review of the database, compliance with the protocol will be examined with 
regard to inclusion and exclusion criteria, treatment or dosing compliance, prohibited therapies, 
and timing and availability of planned assessments. Protocol deviations will be identified by the 
study team before database lock and listed in the Data Review and Surveillance Report, including 
missing data and study drug discontinuations, and classified as critical, major or minor deviations. 
Individual deviations to inclusion and exclusion criteria as reported by the Investigator will be 
listed. 
If any, major and critical deviations other than those involving inclusion/exclusion will be listed 
by subject and/or described in the body of the clinical study report. 
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14.3 
ANALYSIS POPULATION  
14.3.1 Safety population 
All randomized patients who are exposed to IMP (regardless of the amount of treatment 
administered) will be included in the safety population. For safety analyses, patients will be 
included in the treatment group as actually received. Non-randomized and treated patients will not 
be part of the safety population, but their safety data will be summarized separately. 
14.3.2 Pharmacokinetic population  
The PK population will consist of all patients in the safety population from cohort 1 and 2 who 
have at least one non-missing and eligible plasma concentration data.  
Only patients with no major or critical deviations related to IMP (eg, vomiting just after drug 
administration), and for whom PK data are considered sufficient and interpretable, will be 
included in the pharmacokinetic population.  
Patients will be analyzed according to the treatment actually received. Patients having received 
only placebo will not be included in the pharmacokinetic population. 
14.3.3 Pharmacodynamic (PD) population  
For the main PD endpoints of plasma volume and hemoconcentration, the PD population will 
consist of all randomized and treated patients who have valid values of the main PD parameters 
both at baseline and at Day 14/EOT.  
14.3.4 Pharmacokinetic/Pharmacodynamic population  
All patients being included in both the pharmacokinetic and the pharmacodynamic populations 
will be included in the pharmacokinetic/pharmacodynamic population. In addition, patients being 
included in the pharmacodynamic population and having received only placebo will also be 
included in the pharmacokinetic/pharmacodynamic population. 
14.4 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
14.4.1 Subject demographic characteristics, medical history and diagnoses 
The response to IMP might be affected by several variables, including continuous variables (e.g., 
age, height, weight, body mass index (BMI) and qualitative variables (gender, race and/or 
ethnicity). BMI can be described both quantitatively and qualitatively (Underweight: BMI is less 
than 18.5; Normal weight: BMI is 18.5 to 24.9; Overweight: BMI is 25 to 29.9; Obese: BMI is 30 
or more). The following variables will be summarized by descriptive statistics for the safety 
population and for additional population if relevant (eg, if many patients from the safety 
population are not part of the PK population): 
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1. Age (years) 
2. Height (cm) 
3. Body mass index (Kg/m²) 
4. Race and/or ethnicity  
5. Gender 
14.4.2 Baseline pharmacodynamic parameters  
Baseline values of PD parameters are defined to be those taken or measured approximately one to 
three (3) hours prior to the first dosing of study treatment on Day 1.  
All baseline PD parameters will be summarized and presented by treatment group as with all other 
baseline patient characteristics. In addition, for the main PD parameters such as plasma volume 
and hemoconcentration, the mean baseline values of the PD parameters will also be summarized 
along with the mean Day 14/EOT values and mean change from baseline values. 
14.4.3 Baseline safety parameters 
Baseline for safety parameters will be defined as the last available and evaluable parameter value 
before and closest to the first IMP dosing for laboratory data, vital sign parameters, and for 
12-lead ECG parameters. 
Baseline definitions specific to each type of safety parameter will be detailed in corresponding 
sections (Section 14.8.2 to Section 14.8.4). 
Baseline safety values will be presented along with subsequent safety values assessed during or 
after dosing. 
14.5 
EXTENT OF STUDY TREATMENT EXPOSURE AND COMPLIANCE 
A summary table presenting the exposure of treatment (ie, the number of days of administration 
and number of tablets taken, etc) will be provided by treatment group for the safety population. 
The following listings will be provided: 
 
Patients receiving IMP from specified batch 
 
Randomization scheme. 
14.6 
PRIOR/CONCOMITANT MEDICATION/THERAPY 
Medications will be coded according to the World Health Organization Drug Dictionary (Drug 
Dictionary (WHO-DD), last available version before database lock). Medications that were 
stopped before the first IMP dosing and concomitant medications with the IMP will be listed 
separately by subject. 
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14.7 
ANALYSIS OF PHARMACODYNAMIC VARIABLES 
14.7.1 Description of pharmacodynamic variable(s) 
See Section 10.1.1. 
Primary PD variables  
 
Change in hemoconcentration from baseline to D14/EOT as assessed by changes in 
hematocrit, hemoglobin, albumin and total protein. 
 
Change in plasma volume in milliliters from baseline to D14/EOT as assessed by the 
indicator dilution method using 3 I-labelled human albumin.  
Secondary PD variables: 
 
Change in erythropoietin (mU/ml) from baseline to D14 measured by chemiluminescent 
enzyme-labelled immunometric assay 
 
Change in NT-proBNP (pg/mL) from baseline to D14 measured by standard 
electrochemiluminescence immunoassay  
Other Exploratory PD endpoints 
 
Change in total body water (mL) from baseline to D14 as assessed by the indicator 
dilution method using deuterium oxide 
 
Change in uric acid (mg/dL) from baseline to 14 days as measured by standard assay 
 
Change in beta-hydroxybutyrate (µM) from baseline to 14 days as measured by standard 
enzymatic colorimetric assay 
 
Change in red cell mass (mL) from baseline to D14, as derived from measurements of 
plasma volume (assessed by the indicator dilution method using 3 I-labelled human 
albumin) and hematocrit  
 
Change in total blood volume (mL) from baseline to 14 days, as assessed by the indicator 
dilution method using 3 I-labelled human albumin 
 
Percentage of patients within 15% of ideal blood volume on study day 14 
 
Blood pressure (sitting, SBP and DBP) at day 14, compared to baseline 
14.7.2 Primary analysis 
Descriptive statistics for the primary pharmacodynamic endpoints, as raw data and change from 
baseline will be provided by treatment. Similarly time profile plots of mean +- SEM will be 
provided by treatment for the main pharmacodynamics endpoints.  
 
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14.7.3 Secondary analysis/analysis of secondary variables 
Descriptive statistics for all secondary and other pharmacodynamic endpoints, as raw data and 
change from baseline will be provided by treatment. Similarly time profile plots of mean +- SEM 
will be provided by treatment for all secondary and other pharmacodynamics endpoints. 
For exploratory purposes, the main pharmacodynamic variables, change from baseline to Day 14 
in hemoconcentration and plasma volume, will be analyzed using an analysis of covariance 
(ANCOVA) model with fixed terms for treatment and stratification factor of baseline patient 
status (diabetic, non-diabetic, ejection fraction status (reduced-preserved), and with baseline 
plasma volume as covariate. An estimate for the between-group difference in treatment mean 
changes and corresponding 2-sided 90% confidence interval (CI) will be calculated from the 
model. The main treatment comparison will be between the pooled treatment (200 mg and 400 
mg) group and placebo which will be made at 1-sided α 0.05 (or equivalently, 2-sided α 0.10).  
Similar ANCOVA models will be fitted for the secondary and other pharmacodynamic variables 
or endpoints. 
14.8 
ANALYSIS OF SAFETY DATA 
See also Section 10.2. The summary of safety results will be presented by treatment group. 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 the first dose of 
IMP. 
 
Treatment emergent period for safety population is defined as the time from the first 
administration of study medication to the end of the Post-treatment Period. 
The safety analysis will be based on the review of descriptive statistics (summary tables) and 
individual data for vital signs, renal function, adverse events (AEs) and other clinical laboratory 
values and ECG parameters.  
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA), and 
the number of patients with Treatment-Emergent Adverse Events (TEAEs) will be summarized by 
treatment group. Potentially clinically significant abnormalities (PCSAs) for clinical laboratory, 
vital sign, and ECG data and out-of-normal range values for clinical laboratory data will be 
flagged and summarized in frequency tables. The PCSA values are defined as abnormal values 
considered medically important by the Sponsor according to predefined criteria/thresholds based 
on literature review for clinical laboratory tests, vital signs and ECG parameters. 
For all safety data, the observation period will be divided into three segments: 
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 
the pretreatment period is defined as the time between informed consent signature and 
the first IMP administration; 
 
the TEAE (treatment emergent AE) period is defined as the time from the first IMP 
administration up to  approximately 5 days after the last IMP administration 
(approximately 5 times the half-life of sotagliflozin);  
 
the post-TEAE period is defined as the time starting after the TEAE period up to the final 
study follow up telephone check. 
14.8.1 Adverse events 
14.8.1.1 Definitions 
Adverse events will be coded to a “Preferred Term (PT)” and High Level Group Term (HLGT)”, 
“High Level Term (HLT)” and primary “System Organ Class (SOC)” using the Medical 
Dictionary for Regulatory Activities (MedDRA, version currently in use by the sponsor at the 
time of database lock). Their severity will be graded according NCI-CTCAE v4.03. 
They will be classified into predefined standard categories according to chronological criteria: 
 
Pretreatment AEs: AEs that occurred, worsened or became serious during the 
pretreatment period; 
 
Treatment emergent AEs (TEAEs): AEs that occurred, worsened or became serious 
during the TEAE period; 
 
Post-TEAEs: AEs that occurred, worsened or became serious during the post-TEAE 
period. 
TEAEs will be assigned to the treatment received at the time of the AE onset.  
If the onset date (or time) of an AE (occurrence, worsening or becoming serious) is incomplete or 
missing, then the AE will be considered as a TEAE unless a partial date (or time) shows it as a 
pre- or post-treatment event. 
All AEs reported in the study will be listed, sorted by subject, onset date and time. 
14.8.1.2 Treatment-emergent adverse events 
The following TEAEs summaries will be provided by treatment for the safety population: 
 
Overview of TEAEs: number and percentage of patients with any TEAE, any serious 
TEAE, any TEAE leading to death (if any occurred), and any TEAE leading to permanent 
treatment discontinuation. 
 
Summary of TEAEs by primary SOC and PT: 
- 
number and percentage of patients with at least one TEAE; 
- 
number of occurrences of TEAEs. 
Patients presenting TEAEs will be listed sorted by primary SOC and PT. 
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14.8.1.3 Deaths, serious, and other significant adverse events 
Any deaths, serious and other significant AEs will be listed. 
14.8.1.4 Adverse events leading to treatment discontinuation 
Any AEs leading to permanent treatment discontinuation will be listed. 
14.8.1.5 Adverse events of special interest 
Number (%) of patients experiencing treatment emergent AESI will be presented by AESI 
category and PT, sorted by decreasing incidence of PT within each AESI category. 
14.8.2 Clinical laboratory evaluations  
Baseline definition 
The values to be used as the baselines will be the Day 1 predose assessment values. If any of the 
scheduled baseline tests are repeated for any subject, the last rechecked values will be considered 
as baselines, provided they were done before the first IMP administration. 
Abnormalities analyses 
For parameters with laboratory ranges and/or abnormality criteria (PCSA), analysis will be 
performed using all post-baseline assessments done during the TEAE period, including all 
unplanned and rechecked values. Counts of patients with PCSAs according to baseline status will 
be presented by treatment. The same type of summary tables will be provided for out-of-normal 
laboratory range values.  
Descriptive statistics and plots 
Raw data and changes from baseline will be summarized in descriptive statistics for all endpoint 
parameters, by treatment and scheduled time of measurement. 
Additionally, graphs over time for these parameters will be presented plotting mean +/- SD by 
treatment. 
PCSA Listings 
A listing of individual data from patients with post-baseline PCSAs will be provided; values will 
be flagged when outside the laboratory limits and/or when reaching the PCSA criteria. 
A listing of liver function data for patients experiencing at least one of the following situations 
will be provided: 
 
ALT > 3ULN and total bilirubin > 2ULN during the study, with at least one of them being 
post first dose, irrespective of the definition of the TEAE period; 
 
Conjugated bilirubin>35% of Total bilirubin and Total bilirubin>1.7 ULN, on the same 
sample post first dose, irrespective of the definition for the TEAE period. 
Out-of-normal range definitions will be listed. 
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14.8.3 Vital signs  
Heart rate (HR), systolic and diastolic blood pressures (SBP and DBP) will be analyzed as raw 
parameter value (for supine/sitting and standing positions), change from baseline (for supine or 
sitting position only) and as orthostatism parameter (standing-sitting/supine parameter values). 
Body weight will be analyzed as raw parameter value and percent change from baseline and BMI 
will be analyzed as raw parameter value. 
Baseline definition 
The values to be used as baselines will be the Day 1 pre-dose assessment values. If any of the 
scheduled baseline tests are repeated for any subject, the last rechecked values will be considered 
as baselines, provided they were done before the IMP administration of the respective treatment 
phase, and in the same condition.  
Abnormalities analyses 
For all parameters, analysis will be performed using all post-baseline assessments done during the 
TEAE period, including all unplanned and rechecked values. Counts of patients with PCSAs will 
be presented by treatment, regardless of the baseline status. 
Descriptive statistics and plots 
For heart rate and blood pressures, raw data (supine/sitting and standing positions) and changes 
from baseline (supine/sitting position only) will be summarized in descriptive statistics by 
treatment and scheduled time of measurement.  
For body weight, raw data and percent change from baseline will be summarized in descriptive 
statistics by treatment and scheduled time of measurement. 
Additionally, graphs over time will be presented plotting mean +/- SD by treatment. 
PCSA Listings 
A listing of individual data from patients with post-baseline PCSAs will be provided; values will 
be flagged when reaching the PCSA criteria. 
14.8.4 Electrocardiogram  
ECG parameters (HR in bpm, QTc, QT, QRS and PR in msec) will be derived from the ECG 
obtained in hospital or during Visit days as per schedule of events. All parameters will be 
analyzed as raw data and absolute change from baseline. In addition, for the abnormalities 
analysis, PR and QRS will be also analyzed as percent change from baseline. 
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Baseline definition 
The values to be used as baselines will be the Day 1 predose assessment values. If any of the 
scheduled baseline tests are repeated for any subject, the last rechecked values will be considered 
as baselines, provided they were done before the IMP administration of the respective treatment 
phase, and in the same condition.  
Abnormalities analyses 
For all parameters, analysis will be performed, using all post-baseline assessments done during 
the TEAE period, including all unplanned and rechecked values. Counts of patients with PCSAs 
will be presented by treatment, regardless of the baseline status. 
Descriptive statistics and plots 
ECG parameters (raw data and absolute change from baseline) will be summarized in descriptive 
statistics by treatment and scheduled time of measurement. 
Additionally, graphs over time will be presented plotting mean +/- SD by treatment. 
14.9 
ANALYSIS OF PHARMACOKINETIC DATA FROM COHORT 1 AND 2 
See also Section 10.3. 
14.9.1 Pharmacokinetic parameters  
No formal analysis of PK parameters will be performed. Single concentration-time-points will be 
subject to descriptive statistical analysis. 
14.10  INTERIM ANALYSIS 
Except DMC safety review planned after cohort 1 and cohort 2, there are no planned interim 
analysis. 
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15 
ETHICAL AND REGULATORY CONSIDERATIONS 
15.1 
ETHICAL AND REGULATORY STANDARDS 
This clinical trial will be conducted by the Sponsor, the Investigator, delegated Investigator staff 
and Sub-investigator, in accordance with consensus ethics principles derived from international 
ethics guidelines, including the Declaration of Helsinki on Ethical Principles for Medical 
Research Involving Human Subjects, adopted by the General Assembly of the World Medical 
Association (1996), 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 subject/patient enrollment, in compliance with applicable regulatory 
requirements and with Sanofi public disclosure commitments. 
15.2 
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 subject. 
The informed consent form used by the Investigator for obtaining the patient’s informed consent 
must be reviewed and approved by the Sponsor prior to submission to the appropriate ethics 
committee (IRB/IEC) for approval/favorable opinion. 
The written informed consent form and any other written information to be provided to patient 
should be revised whenever important new information becomes available that may be relevant to 
the subject’s consent. Any revised written informed consent form, and written information should 
receive the IRB/IEC’s approval/favorable opinion in advance of use. The patient should be 
informed in a timely manner if new information becomes available that may be relevant to the 
patient’s willingness to continue participation in the trial. The communication of this information 
should be documented. In case of study suspension due to safety concerns, study patients will be 
informed of this study suspension and the reason for it. Once it is confirmed that it is safe for the 
study to continue, study patients will be asked to confirm their agreement to continue the study. 
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15.3 
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. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, informed consent form, Investigator’s Brochure with any 
addenda, Investigator’s curriculum vitae, etc.) and the date of the review should be clearly stated 
on the written IRB/IEC approval/favorable opinion. 
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 at least annually and a summary of the trial’s outcome at 
the end of the clinical trial. 
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16 
STUDY MONITORING 
16.1 
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 case report form, discrepancy resolution form , or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents to 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 Sub-
investigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Sub-investigators shall be appointed and listed in a timely manner. The Sub-
investigators 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. 
16.2 
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 case report forms. 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. 
16.3 
SOURCE DOCUMENT REQUIREMENTS 
According to the ICH GCP, the monitoring team must check the case report form entries against 
the source documents, except for the pre-identified source data directly recorded in the case report 
form. The informed consent form will include a statement by which the patient allows the 
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Sponsor’s duly authorized personnel, the IRB/IEC, and the regulatory authorities to have direct 
access to original medical records which support the data on the case report forms (eg, patient’s 
medical file, appointment books, original laboratory records, etc.). These personnel, bound by 
professional secrecy, must maintained confidentiality of all personal identity or personal medical 
information (according to confidentiality and personal data protection rules). 
16.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST 
It is the responsibility of the Investigator to maintain adequate and accurate case report forms 
(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 case report forms should be completed in their entirety in a neat, legible manner to 
ensure accurate interpretation of data. 
Should a correction be made, the corrected information will be entered in the eCRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Data are available within the system to the Sponsor as soon as they are entered in the eCRF. 
The computerized handling of the data by the Sponsor may generate additional requests 
(discrepancy resolution forms) to which the Investigator is obliged to respond by confirming or 
modifying the data questioned. The requests with their responses will be managed through the 
eCRF. 
16.5 
USE OF COMPUTERIZED SYSTEMS 
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor and Investigator study files. 
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17 
ADDITIONAL REQUIREMENTS 
17.1 
CURRICULUM VITAE 
A current copy of the curriculum vitae describing the experience, qualification and training of 
each Investigator and Sub-investigator will be signed, dated and provided to the Sponsor prior to 
the beginning of the clinical trial. 
17.2 
RECORD RETENTION IN STUDY SITE(S) 
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. 
17.3 
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 case report forms, 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 
IRB/IEC is expressly permitted, the IRB/IEC members having the same obligation of 
confidentiality. 
The Sub-investigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Sub-investigators of the confidential nature of the clinical trial. 
The Investigator and the Sub-investigators 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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17.4 
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 /Sub-investigator 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 sub-investigators shall provide all assistance 
required by the Sponsor, at the Sponsor’s expense, for obtaining and defending any patent, 
including signature of legal documents. 
17.5 
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. 
The data collected in this study will only be used for the purpose(s) of the study. They may be 
further processed if they have been pseudonymized. 
17.6 
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 IEC/IRB or regulatory authorities in countries requiring this document. 
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17.7 
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. 
17.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE 
17.8.1 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; 
 
Non-compliance of the Investigator or Sub-investigator, 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 is included earlier than expected. 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
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17.8.2 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.  
17.9 
CLINICAL TRIAL RESULTS 
The Sponsor will be responsible for preparing a clinical study report and to provide a summary of 
the study results to the Investigator. 
17.10 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 of 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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18 
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 of the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC of an amendment, 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 some instances, an amendment may require a change to the informed consent form. The 
Investigator must receive an IRB/IEC written 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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19 
BIBLIOGRAPHIC REFERENCES 
1. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al.  Empagliflozin, 
Cardiovascular Outcomes and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 
26;373(22):2117-28. 
2. Abdul-Ghani M, Del Prato S, Chilton R, DeFronzo RA. SGLT2 inhibitors and Cardiovascular 
Risk; Lessons Learned from the EMPA-REG Outcome Study. Diabetes Care. 2016 
May;39(5):717-25. 
3. Lambers Heerspink HJ, de Zeeuw D, Wie L, Leslie B, List J. Dapagliflozin a glucose-
regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab. 
2013 Sep;15(9):853-62. 
4. Cherney DZI, Perkins BA, Soleymanlau N,  Maione M, Lai V, Lee A, et al. Renal 
hemodynamic effect of sodium glucose cotransporter 2 inhibition in patients with type 1 
diabetes. Circulation. 2014 Feb 4;129(5):587-97. 
5. Vasko MR, Brown-Cartwright D, Knochel JP, Nixon JV, Brater DC. Furosemide absorption 
altered in decompensated congestive heart failure. Ann Intern Med. 1985 Mar;102(3):314-8. 
6. Miller WL, Mullan BP. Understanding the heterogeneity in volume overload and fluid 
distribution in decompensated heart failure is key to optimal volume management: role for 
blood volume quantitation. JACC Heart Fail. 2014 Jun;2(3):298-305. 
7. Testani JM, Chen J, McCauley BD, Kimmel SE, Shannon RP. Potential effects of aggressive 
decongestion during the treatment of decompensated heart failure on renal function and 
survival. Circulation. 2010 Jul 20;122(3):265-72. 
8. Testani JM, Brisco MA, Chen J,  MCauley BD, Parikh CR, Tang WH. Timing of 
hemoconcentration during treatment of acute decompensated heart failure and subsequent 
survival: importance of sustained decongestion. J Am Coll Cardiol. 2013 Aug 6;62(6):516-24. 
9. Lofman I, Szummer K, Hagerman I, Dahlström U, Lund LH, Jernberg T. Prevalence and 
prognostic impact of kidney disease on heart failure patients. Open Heart. 2016 Jan 
18;3(1):e000324. 
10. Petrykiv S, Sjostrom CD, Greasley PJ, Xu J, Persson F, Heerspink HJL. Differential Effects of 
Dapagliflozin on Cardiovascular Risk Factors at Varying Degrees of Renal Function. Clin J 
Am Soc Nephrol. 2017;12 doi: 10.2215/CJN.10180916 
11. Kalra PR, Anagnostapoulos C, Bolger AP, Coats AJ, Anker SD. The regulation and 
measurement of plasma volume in heart failure. J Am Coll Cardiol. 2002 Jun 19;39(12):1901-
8. 
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12. Manzone TA, Dam HQ, Soltis D, Sagar VV. Blood volume analysis: a new technique and new 
clinical interest reinvigorate a classic study. J Nucl Med Technol. 2007 Jun;35(2):55-63. 
13. van der Meer P, Postmus D, Ponikowski P, Cleland JG, O'Connor CM, Cotter G, et al. The 
predictive value of short-term changes in hemoglobin concentration in patients presenting with 
acute decompensated heart failure. J Am Coll Cardiol. 2013 May 14;61(19):1973-81. 
14. Fairbanks VF, Klee GG, Wiseman GA, Hoyer JD, Tefferi A, Petitt RM, Silverstein MN. 
Measurement of Blood Volume and Red Cell Mass: Re-examination of 51Cr and 125I 
Methods. Blood Cells Mol. Dis. 1996; 22: 169-186 
15. Van Kreel BK, Van der Vegt F, Meers M, Wagenmakers T, Westerterp K, Coward A. 
Determination of total body water by a simple and rapid mass spectroscopic method. J Mass 
Spectrosc, 1996; 31:108-111 
16. Tang, YD, Katz SD. Anemia in chronic heart failure: prevalence, etiology, clinical correlates, 
and treatment options. Circulation. 2006 May 23;113(20):2454-61. 
17. Sano M, Takei M, Shiraishi Y, Suzuki Y. Increased hematocrit during sodium-glucose 
cotransporter-2 inhibitor therapy indicates recovery of tubulointerstitial function in diabetic 
kidneys. J Clin Med Res. 2016 Dec;8(12): 844-7. 
18. Heyman SN, Khamaisi M, Rosenberger C, Szalat A, Abassi Z. Increased hematocrit during 
sodium-glucose cotransporter-2 inhibitor therapy. J Clin Med Res. 2017 Feb; 9(2): 176-7. 
19. Turner G, Gibson OR, Watt PW, Pringle JS, Richardson AJ, Maxwell NS. The time course of 
endogenous erythropoietin, IL-6, and TNFα in response to acute hypoxic exposures. Scand J 
Med Sci Sports. 2016 May 17. doi: 10.1111/sms.12700 
20. Levey AS, Greene T, Kusek JW, Beck GJ. A simplified equation to predict glomerular 
filtration rate from serum creatinine [Abstract]. J Am Soc Nephrol 2000;11:155A 
21. Arfè A, Scotti L, Varas-Lorenzo C, Nicotra F, Zambon A, Kollhorst B, et al.; Safety of Non-
steroidal Anti-inflammatory Drugs (SOS) Project Consortium. Non-steroidal anti-
inflammatory drugs and risk of heart failure in four European countries: nested case-control 
study. BMJ. 2016 Sep 28;354:i4857. doi: 10.1136/bmj.i4857 
22. Dill DB, Costill DL. Calculation of percentage changes in volumes of blood, plasma, and red 
cells in dehydration. J Appl Physiol.1974;37(2):247 8. 
23. Ling HZ, Flint J, Damgaard M, Bonfils PK, Cheng AS, Aggarwal S, et al. Calculated plasma 
volume status and prognosis in chronic heart failure. Eur J Heart Fail. 2015 Jan;17(1):35-43 
24. Khaled MA, Lukaski HC, Watkins CL. Determination of total body water by deuterium NMR. 
Am J Clin Nutr. 1987 Jan;45(1):1-6 
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25. Workgroup on Hypoglycemia, American Diabetes Association. Defining and reporting 
hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on 
Hypoglycemia. Diabetes Care. 2005 May;28(5):1245-9 
 
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20 
APPENDICES 
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Appendix A 
Contraceptive guidance and collection of pregnancy information 
DEFINITIONS 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP 
1. Pre-menarchal 
2. Premenopausal female with 1 of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy. 
3. Postmenopausal 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient.  
- 
Females on hormone replacement therapy (HRT) and whose menopausal status is in 
doubt will be required to use one of the non-hormonal highly effective contraception 
methods if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrolment. 
CONTRACEPTION GUIDANCE 
Male participants 
 
Male participants with female partners of childbearing potential are eligible to participate 
if they agree to ONE of the following (during the protocol-defined time frame in 
Section 8.2): 
- 
Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
- 
Agree to use a male condom plus partner use of a contraceptive method with a failure 
rate of <1% per year as described in Table 13 when having penile-vaginal intercourse 
with a woman of childbearing potential who is not currently pregnant 
 
Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-
vaginal intercourse or use a male condom during each episode of penile penetration 
(during the protocol-defined time frame) 
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 
Refrain from donating sperm for the duration of the study and for Table 13 after [study 
completion or the last dose of study treatment] 
Female participants 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 13. 
Table 13 - Highly Effective Contraceptive Methods  
Highly Effective Contraceptive Methods That Are User Dependenta 
Failure rate of <1% per year when used consistently and correctly 
 Combined (estrogen- and progestogen-containing ) hormonal contraception associated with 
inhibition of ovulationb 
 oral 
 intravaginal 
 transdermal 
 Progestogen-only hormone contraception associated with inhibition of ovulation 
 oral 
 injectable 
Highly Effective Methods That Are User Independenta 
 Implantable progestogen-only hormonal contraception associated with inhibition of ovulationb  
- 
Intrauterine device (IUD) 
- 
Intrauterine hormone-releasing system (IUS) 
 Bilateral tubal occlusion 
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Vasectomized partner 
Vasectomized partner is a highly effective contraceptive method provided that the partner is the 
sole sexual partner of the woman of childbearing potential and the absence of sperm has been 
confirmed. If not and less than 1 year after vasectomy, additional highly effective method of 
contraception should be used. Spermatogenesis cycle is approximately 90 days. 
 Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant. 
NOTES: 
Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for participants 
participating in clinical studies. 
 
 
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See guidance below 
Are women of childbearing potential (WOCBP) included?
No measures
Other factors to consider:
Absence or reduction of measures below can be justified by the sponsor on case by case basis
Does the IMP have a marketing authorization?
SmPC/label
No specific recommendations
What is the outcome of the assessment of available non clinical and clinical data?
Unlikely risk of human
teratogenicity/fetotoxicity
Possible human
teratogenicity/fetotoxicity
Demonstrated or suspected
human teratogenicity/fetotoxicity
•
Inclusion after a negative highly 
sensitive pregnancy test  
•
Highly effective method of 
contraception preferably with low 
user dependency 
•
Contraception during treatment and 
until the end of relevant          
systemic exposure. This period  
should be extended by 30 days in 
case of genotoxicity
•
Inclusion after a negative highly 
sensitive pregnancy test  
•
Highly effective method of 
contraception  
•
Contraception during treatment and 
until the end of relevant systemic 
exposure 
•
Inclusion after a negative highly 
sensitive pregnancy test is 
recommended  
•
An acceptable effective method of 
contraception unless an absence of 
risk of human teratogenicity/ 
fetotoxicity in early pregnancy can 
be justified 
•
As a minimum, contraception until 
treatment discontinuation 
Women of Childbearing Potential (WOCBP)
Decision Trees - Recommendations Related to Contraception and Pregnancy Testing in Clinical Trials
•
Monthly pregnancy testing  
•
Pregnancy testing during treatment 
and until the end of relevant 
systemic exposure. In case of 
genotoxicity, this period  should  be  
extended  by  30 days 
•
Additional  pregnancy testing  to  be 
considered  
•
As a minimum,  at  the end of 
relevant systemic exposure 
•
Additional  pregnancy  testing 
generally not necessary 
NO
NO
YES
YES
 
 
 
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Are males with WOCBP partners included?
No measures
Does the IMP have a marketing authorization?
SmPC/label
No specific recommendations
What is the outcome of the assessment of available non clinical and clinical data?
No genotoxicity or demonstrated
or suspected human teratogenicity/ 
fetotoxicity at subtherapeutic systemic
exposure levels
No genotoxicity, but demonstrated or 
suspected human teratogenicity/ 
fetotoxicity at subtherapeutic systemic
exposure level s if relevant systemic
exposure may be achieved in the 
WOCBP partner
Genotoxicity
Males with WOCBP Partners
Decision Trees - Recommendations Related to Contraception and Pregnancy Testing in Clinical Trials
•
Condom 
•
Consider contraception for  non-
pregnant WOCBP partner 
•
Contraception during treatment and 
until the end of relevant systemic 
exposure in the male subject plus a 
90-day period 
•
Condom 
•
Contraception during treatment and 
until the end of relevant systemic 
exposure in WOCBP 
•
No measures
NO
NO
YES
YES
 
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Are women of childbearing potential (WOCBP) included?
No measures
Other factors to consider:
Absence or reduction of measures below can be justified by the sponsor on case by case basis
Does the IMP have a marketing authorization?
SmPC/label
No specific recommendations
What is the outcome of the assessment of available non clinical and clinical data?
Unlikely risk of human
teratogenicity/fetotoxicity
Possible human
teratogenicity/fetotoxicity
Demonstrated or suspected
human teratogenicity/fetotoxicity
•
Inclusion after a negative highly 
sensitive pregnancy test  
•
Highly effective method of 
contraception preferably with low 
user dependency 
•
Contraception during treatment and 
until the end of relevant          
systemic exposure. This period  
should be extended by 30 days in 
case of genotoxicity
•
Inclusion after a negative highly 
sensitive pregnancy test  
•
Highly effective method of 
contraception  
•
Contraception during treatment and 
until the end of relevant systemic 
exposure 
•
Inclusion after a negative highly 
sensitive pregnancy test is 
recommended  
•
An acceptable effective method of 
contraception unless an absence of 
risk of human teratogenicity/ 
fetotoxicity in early pregnancy can 
be justified 
•
As a minimum, contraception until 
treatment discontinuation 
Women of Childbearing Potential (WOCBP)
Decision Trees - Recommendations Related to Contraception and Pregnancy Testing in Clinical Trials
•
Monthly pregnancy testing  
•
Pregnancy testing during treatment 
and until the end of relevant 
systemic exposure. In case of 
genotoxicity, this period  should  be  
extended  by  30 days 
•
Additional  pregnancy testing  to  be 
considered  
•
As a minimum,  at  the end of 
relevant systemic exposure 
•
Additional  pregnancy  testing 
generally not necessary 
NO
NO
YES
YES
 
 
 
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Are males with WOCBP partners included?
No measures
Does the IMP have a marketing authorization?
SmPC/label
No specific recommendations
What is the outcome of the assessment of available non clinical and clinical data?
No genotoxicity or demonstrated
or suspected human teratogenicity/ 
fetotoxicity at subtherapeutic systemic
exposure levels
No genotoxicity, but demonstrated or 
suspected human teratogenicity/ 
fetotoxicity at subtherapeutic systemic
exposure level s if relevant systemic
exposure may be achieved in the 
WOCBP partner
Genotoxicity
Males with WOCBP Partners
Decision Trees - Recommendations Related to Contraception and Pregnancy Testing in Clinical Trials
•
Condom 
•
Consider contraception for  non-
pregnant WOCBP partner 
•
Contraception during treatment and 
until the end of relevant systemic 
exposure in the male subject plus a 
90-day period 
•
Condom 
•
Contraception during treatment and 
until the end of relevant systemic 
exposure in WOCBP 
•
No measures
NO
NO
YES
YES
 
Clinical Facilitation Group (September 2014) - Recommendations related to contraception and 
pregnancy testing in clinical trials 
 
 
COLLECTION OF PREGNANCY INFORMATION 
Male participants with partners who become pregnant  
 
The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study treatment. 
 
After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy  
 
The female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor.  
 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for procedure  
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Female participants who become pregnant  
 
The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study  
 
Information will be recorded on the appropriate form and submitted to the Sponsor within 
24 hours of learning of a participant's pregnancy.  
 
The participant will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the participant and the neonate, and the 
information will be forwarded to the Sponsor. Generally, follow-up will not be required 
for longer than 6 to 8 weeks beyond the estimated delivery date.  
 
Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.  
 
Any pregnancy complication or elective termination of a pregnancy will be reported as an 
AE or SAE.  
 
A spontaneous abortion is always considered to be an SAE and will be reported as such. 
 
Any post-study pregnancy-related SAE considered reasonably related to the study 
treatment by the Investigator will be reported to the Sponsor.  While the Investigator is not 
obligated to actively seek this information in former study participants, he or she may 
learn of an SAE through spontaneous reporting. 
 
Any female participant who becomes pregnant while participating in the study will 
[discontinue study treatment or be withdrawn from the study or may request continuation 
of study treatment] 
 
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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
 
 
 
 
Suspicion of rhabdomyolysis is to be recorded as AE only if at least one of the criteria listed in 
Section 11.3.1 is met. 
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Appendix C 
Blood Pressure and Pulse Rate monitoring 
Equipment 
1. Blood pressure measurements will be taken by an automated blood pressure monitor. Same 
equipment should be used throughout the study and should be calibrated as per manufacturer 
recommendation. 
2. Bladder Length  Should nearly or completely encircle the patient’s arm. For many adults, the 
standard “adult” size bladder is not long enough and the “large” size bladder is recommended. 
3. Bladder Width  Should be at least 40% of the bladder length. 
Patient Factors 
Extraneous variables associated with the measurement of blood pressure (BP) should be 
minimized. These include: 
 
Food intake, caffeine-containing beverages, cigarette smoking, or strenuous exercise 
within 2 hours prior to measurement. 
 
Full urinary bladder. 
 
The patient should not talk while BP is being measured. 
The proper sized cuff should fit snugly with the lower edge 2 to 3 cm above the antecubital fossa. 
The patient should be allowed to sit quietly in a comfortably warm place (temperature around 
25°C or 77°F) for 5-10 minutes with the arm supported at heart level, preferably with the cuff in 
place and with no restrictive clothing on the arm. The patient should be encouraged not to tense 
his or her muscles. 
Determination of the arm with the highest blood pressure 
At Visit 1 or 2, seated BP should be measured in both arms after a 10 minute rest period, and then 
again after 1-2 minutes in both arms, in seated position. The arm with the highest DBP will be 
determined at this visit, and blood pressure should be measured in this arm throughout the study 
(unless a new issue develops that prohibits measurement of BP in that arm). 
Measurement Technique 
At Visit 1 or 2, immediately following arm selection, with the patient in the same position, an 
additional seated BP should be measured in the selected arm (at least 1 minute after last 
measurement). 
At all other on-site visits, or when patients monitor their BP at home, following the 5-10-minute 
rest period, 3 separate seated BPs should be measured in the arm selected at Visits 1 or 2, with at 
least 2 minute between BP measurements and with the cuff fully deflated between measurements. 
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All 3 BPs will be recorded in the patient’s diary and e-CRF. The mean of the 3 seated BPs will 
constitute the BP value for that visit. 
Three seated pulse rate measurements will also be obtained. The mean of the 3 seated pulse rate 
measurements will constitute the pulse rate value for that visit. 
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Appendix D 
Diabetic ketoacidosis 
Recognizing diabetic ketoacidosis 
Diabetic ketoacidosis, including atypical (euglycemic) DKA, is the most serious emergency in 
patients with T1D and T2D. Common precipitating factors include infections, intercurrent 
illnesses, psychological stress and noncompliance with insulin therapy. Clinical features of DKA 
at presentation can be nonspecific; however most patients complain of polydipsia and polyuria for 
several days before onset of DKA. Symptoms of DKA include rapid weight loss, nausea or 
vomiting, stomach pain, excessive thirst, fast and deep breathing, confusion, unusual sleepiness or 
tiredness, a sweet smell to the breath, a sweet or metallic taste in the mouth, or a different odor to 
urine or sweat. 
It is possible that GI or other AEs occurring with sotagliflozin may mask presenting symptoms of 
DKA. Because sotagliflozin lowers blood glucose by insulin dependent SGLT1 and SGLT2 
inhibition, it is possible for DKA to be present with normal or low blood glucose. Therefore, the 
Investigator must still consider a DKA event even if blood glucose is low or normal.  
More information can be found in the sotagliflozin IB. 
If DKA is suspected or confirmed, study treatment should be stopped immediately and should not 
be re-started unless another cause for the ketoacidosis is identified and resolved. 
Caution should be exercised in patients with risk factors for ketoacidosis and inform patients of 
the risk factors. These include low reserve of insulin-secreting cells, conditions that restrict food 
intake or can lead to severe dehydration, a sudden reduction in insulin or an increased requirement 
for insulin due to illness, surgery or alcohol abuse. 
In addition, IMP administration should be stopped in patients in hospital for major surgical 
procedures or due to serious illness. 
Whenever AE data is collected or the patient reports DKA or intercurrent illness (including 
infections), generalized weakness, increased weight loss, GI symptoms including nausea, 
vomiting, or abdominal pain or other symptoms or signs that the Investigator believes may be 
consistent with DKA, the site will determine if an assessment for DKA, such as assessing blood 
BHB, is appropriate. If BHB or other laboratory testing confirms the presence of metabolic 
acidosis, then the “Possible DKA” e-CRF will be completed. 
 Patient communication cards will be printed with the following: 
“If you have any of these symptoms on the list, then contact your study site immediately for 
assistance with managing your diabetes: 
 Inability to maintain oral intake 
 Generalized weakness 
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 Abdominal (belly) pain 
 Increased weight loss 
 Fever 
 Frequent urination, including at night 
 Fruity-scented breath 
 Confusion 
 Acute illness 
 Consistently elevated blood glucose 
 Feeling very thirsty or drinking a lot 
 Nausea or vomiting 
 Having trouble thinking clearly or feeling tired. 
It is possible to have DKA even if your blood glucose is not elevated. Regardless of your blood 
glucose level, if you have any of these symptoms on the list, then contact your study site 
regarding the need to be evaluated for possible DKA, which will include specific blood testing. If 
your study site is closed and your study doctor is not available, go to the nearest emergency room 
for evaluation. 
If you are scheduled for a procedure or surgery that requires you to not take any food or liquids, 
please contact your study doctor for instructions on continuing study drug. In such cases your 
study doctor may advise you NOT to take your study drug from the day prior to the procedure or 
surgery until after the procedure or surgery is complete, and you are taking food and liquids as 
you normally do.” 
Whenever adverse event data are collected or the patient reports DKA or intercurrent illness 
(including infections), generalized weakness, increased weight loss, GI symptoms including 
nausea, vomiting, or abdominal pain, or other symptoms or signs that the Investigator believes 
may be consistent with DKA, then the site will determine if an assessment for DKA, such as 
assessing blood beta-hydroxybutyrate level (BHB), is appropriate. If BHB or other laboratory 
testing confirms presence of metabolic acidosis, then the “Possible DKA” e-CRF will be 
completed. 
 
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Appendix E 
Country Specific Changes 
The history of Country specific amendments in Canada) for this amended protocol are irrelevant 
because the current amendment 3 will be implemented in the US only. 
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Appendix F 
Protocol Amendment History 
The summary of changes for the current amendment is located above immediately following after 
the Clinical Trial Summary. 
20.1.1 Amended Protocol 1 based on Amendment 1: 09-Jan-2018 
 
REASON FOR AMENDMENT: 
 
Change to the duration of the Screening Period from 10 days to 21 days 
In Section(s): tabulated clinical trial summary, sections 1.1., 1.2 and 1.3, and section 6.2 
Rationale: Increase flexibility for sites and patients. 
 
Change to the duration of the interval from discontinuation of intravenous diuretics 
to randomization from 4 days to 7 days 
In Section(s): tabulated clinical trial summary, sections 1.1, 1.2 and 1.3, and section 6.2 
Rationale: Increase flexibility for sites and patients. 
 
Change to Cohort sample size: Approximately 15 patients in each of Cohorts 1 and 2, 
and approximately 51 patients in Cohort 3. 
In Section(s): tabulated clinical trial summary, sections 1.2 and 1.3, section 6.2, section 7.1 
and section 13. 
Rationale: Safety for patients is assessed on an ongoing basis by the DMC, which also has 
the ultimate decision for up-titration from Cohort 1 to Cohort 2, and from Cohort 2 to 
Cohort 3. The DMC might determine that the absence of any significant adverse events in 
a sufficient number of patients on sotagliflozin might be sufficient to allow progression to 
the next Cohort, or similarly to request expansion in the number of patients exposed to 
IMP. 
 
Change to the inclusion/Exclusion criteria 
In section(s): tabulated clinical trial summary, sections 7.2 & 7.3 of the protocol 
Rationale: 
- I01. Clarified to indicate that written consent should be obtained during the screening 
period. 
- I03. Expanded to include subjects admitted to appropriate inpatient and specialized 
units where heart failure patients are often safely assessed and screened, and to add 
increase in weight as one of the qualifying criteria for congestion as this is frequently 
an indicator of worsening heart failure in chronic heart failure patients. Clarified that 
treatment with intravenous diuretics is a requirement for consideration of patients to 
randomization whereas it is not important whether they receive bolus or infusion of 
drug. 
- I04. Removed to expand eligibility to patients with new onset heart failure, as 
treatment with sotagliflozin may also have significant benefits on fluid volume 
redistribution in eligible congestive and hemodynamically stable patients. New onset 
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heart failure patients at highest risk will be excluded based on E3-5. 
- I07. Clarified birth control requirements for male participants. 
- I08. Simplified for ease of understanding to indicate requirement for intravenous 
diuretics between screening and randomization, and transition to oral diuretic 
treatment. 
- I09. Consolidated criteria for hemodynamic stability at randomization. 
- E03. Corrected to also account for patients with worsening heart failure that may be 
admitted to a heart failure unit or infusion center rather than a hospital. 
- E04. Added and clarified that patients with uncomplicated revascularization following 
a recent myocardial infarction (index MI, within 1 month) are eligible, as the risk in 
those patients is significantly less compared to those without revascularization during 
the index MI or with procedures associated with complications. 
- E05. Adapted to harmonize with E04 and to indicate that patients who had or 
scheduled to have a procedure, such as percutaneous coronary intervention or other 
cardiac intervention, may be eligible if they are stable and congested and in need of 
diuretic treatment. 
- E12. Any moderate or severe respiratory disease is an exclusion. Oxygen therapy 
requirement is redundant in this context. 
- E14. Corrected previous omission to allow one repeat lab at screening for amylase 
and/or lipase 
- E15. Removed, as each case should be individually assessed based on multiple 
cardiorenal 
variables. Added instructions in Section 8.8 (Concomitant Medication). 
- E16. Modified, as only patients with severe or persistent GU infections at 
randomization may need to be excluded. GU infections associated with SGLT2- 
inhibitors are described as mainly mild to moderate in intensity and respond to 
standard treatment. (European Medicines Agency. Jardiance (empagliflozin) public 
assessment report. March 2014; European Medicines Agency. Forxiga (dapagliflozin) 
public assessment report. September 2012; European Medicines Agency. Canagliflozin 
public assessment report. September 2013.) 
- E18. Removed, text consolidated with E11. 
- New Exclusions added in response to Health Authority/Ethics Committees’ 
feedback: 
- Exclusion of persons dependent on the sponsor, investigator or study site is added. 
- Exclusion for diabetic patients at high risk of lower limb amputations 
• Change to the classification of 131-Iodinated-Albumin and Deuterium Oxide from 
“Noninvestigational 
medicinal product” to “Non-medicinal product” 
In section(s): Tabulated summary and 8.2 
Rationale: Correction, as recommended by Health Authority reviews in European Union 
countries 
In addition, other minor changes are listed in the description of changes 
 
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20.1.2 Amended Protocol 2 based on Amendment 2: 14-Mar-2018 
 
REASON FOR AMENDMENT: 
 
Correction of nomenclature for the non-investigational medicinal products 
In section(s): tabulated clinical trial summary, sections 9.6, 9.7, 9.11, 11.2.3, 11.3.1, of the 
protocol 
Rationale: 
Correction (and reversal to the original classification) from ‘Non-medicinal product’ to 
‘Noninvestigational medicinal product’, to be consistent with generally accepted 
nomenclature, following clarification of the classification for deuterium oxide and 
radiolabeled albumin. 
 
Change to the inclusion/Exclusion criteria 
In section(s): tabulated clinical trial summary, section 8.3 of the protocol 
Rationale: 
E02. Added exclusion of persons sectioned due to an official or court order (as per section 
1.61 of the ICH/GCP Guideline E6.) 
 
Added clarification for patients who may be stable and improving but need to 
continue their treatment in hospital or transferred to a unit, center or ward, such as 
rehabilitation ward, during the study 
In section(s): Sections 1.2, 1.3, 13.1 of the protocol 
Rationale: 
Added guidance on how sites could handle the Visit schedules for those patients who may 
need to continue part or all of their treatment within a hospital or related setting 
 
Added option for exploratory analysis to be performed for safety reasons 
In section(s): 6.3 Interim analysis, 14.1 Determination of sample size, 14.10 Interim 
analysis 
Rationale: 
Ad hoc exploratory analysis may be performed for safety reasons and/or if requested by an 
institutional review board or ethics committee 
 
Removed option for a legally-acceptable representative to sign the consent form 
In section(s): 15.2 Informed Consent 
Rationale: 
Only patients themselves can provide consent to participate in this study 
In addition, other minor changes are listed in the description of changes 
 
 
 
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Signature Page for VV-CLIN-0463139 v7.0
pdy15079-16-1-1-amended-protocol03
Approve & eSign
Clinical
02-Aug-2019 01:16:41 GMT+0000
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SAP_001.pdf: 
Official Title: 
An exploratory, randomized, double-blind, placebo-controlled, 
parallel arm trial of the safety and pharmacodynamic activity of 
sotagliflozin in hemodynamically stable patients with worsening 
heart failure  
NCT Number: 
NCT03292653 
Document Date(s): 
SAP Version 1: 19 April 2018 


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 
 
Page 1 
STATISTICAL ANALYSIS PLAN 
An exploratory, randomized, double-blind, placebo-controlled, parallel arm trial of 
the safety and pharmacodynamic activity of sotagliflozin in hemodynamically 
stable patients with worsening heart failure 
SAR439954 - PDY15079 
STATISTICIAN: 
 
 – 
 
DATE OF ISSUE: 19-Apr-2018 
Total number of pages: 
40 


Statistical Analysis Plan  
19-Apr-2018 
SAR439954 - PDY15079 -  Sotaglifozin 
Version number: 1.0 
 
Property of the Sanofi Group - strictly confidential 
Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................ 6 
1.1 
STUDY DESIGN AND RANDOMIZATION ...................................................................................... 6 
1.2 
OBJECTIVES ................................................................................................................................... 7 
1.2.1 
Primary objectives ............................................................................................................................ 7 
1.2.2 
Secondary objectives ....................................................................................................................... 7 
1.2.3 
Exploratory objective ........................................................................................................................ 7 
1.3 
DETERMINATION OF SAMPLE SIZE ............................................................................................. 8 
1.4 
STUDY PLAN ................................................................................................................................... 8 
1.5 
MODIFICATIONS FROM THE STATISTICAL SECTION OF THE PROTOCOL ............................ 9 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN ....................... 9 
2 
STATISTICAL AND ANALYTICAL PROCEDURE ....................................................................... 10 
2.1 
SUBJECT DESCRIPTION ............................................................................................................. 10 
2.1.1 
Disposition of subjects ................................................................................................................... 10 
2.1.2 
Protocol deviations ......................................................................................................................... 11 
2.2 
ANALYSIS POPULATIONS ........................................................................................................... 11 
2.2.1 
Pharmacodynamic population ........................................................................................................ 11 
2.2.2 
Safety population ........................................................................................................................... 11 
2.2.3 
Pharmacokinetic population ........................................................................................................... 11 
2.2.4 
Pharmacokinetic/Pharmacodynamic population ............................................................................ 12 
2.3 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ............................................................. 12 
2.3.1 
Subject demographic characteristics, medical history, and diagnoses ......................................... 12 
2.3.2 
Baseline pharmacodynamic parameters........................................................................................ 12 
2.3.3 
Baseline safety parameters ........................................................................................................... 13 
2.4 
EXTENT OF STUDY TREATMENT EXPOSURE AND COMPLIANCE ........................................ 13 


Statistical Analysis Plan  
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Page 3 
2.5 
PRIOR/CONCOMITANT MEDICATION/THERAPY ...................................................................... 13 
2.6 
ANALYSIS OF PHARMACODYNAMIC VARIABLES .................................................................... 13 
2.6.1 
Description of pharmacodynamic variables ................................................................................... 13 
2.6.2 
Primary analysis ............................................................................................................................. 14 
2.6.3 
Secondary analysis/analysis of secondary variables ..................................................................... 14 
2.7 
ANALYSIS OF SAFETY DATA ...................................................................................................... 15 
2.7.1 
Adverse events .............................................................................................................................. 15 
2.7.1.1 
Definitions ...................................................................................................................................... 15 
2.7.1.2 
Treatment-emergent adverse events ............................................................................................. 16 
2.7.1.3 
Deaths, serious, and other significant adverse events .................................................................. 16 
2.7.1.4 
Adverse events leading to treatment discontinuation .................................................................... 16 
2.7.1.5 
Adverse events of special interest ................................................................................................. 16 
2.7.2 
Clinical laboratory evaluations ....................................................................................................... 17 
2.7.3 
Vital signs ....................................................................................................................................... 18 
2.7.4 
Electrocardiogram .......................................................................................................................... 19 
2.7.5 
Other related safety parameters .................................................................................................... 20 
2.8 
ANALYSIS OF PHARMACOKINETIC DATA ................................................................................. 20 
2.8.1 
Pharmacokinetic parameters ......................................................................................................... 20 
2.9 
DATA HANDLING CONVENTIONS .............................................................................................. 20 
3 
INTERIM ANALYSIS ..................................................................................................................... 22 
4 
SOFTWARE DOCUMENTATION ................................................................................................. 23 
5 
APPENDICES ................................................................................................................................ 24 
APPENDIX A 
STUDY FLOW CHART ........................................................................................................ 25 
APPENDIX B 
PERIOD FLOW CHART ...................................................................................................... 28 
APPENDIX C 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA ...................... 31 
APPENDIX D 
FLAGS USED IN THE SAFETY PCSA AND ABNORMALITY ANALYSIS ......................... 39 
 


Statistical Analysis Plan  
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Statistical Analysis Plan  
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Page 5 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALT: 
alanine transaminase 
BMI: 
body mass index 
CSR: 
clinical study report 
DBP: 
diastolic blood pressure 
DMC: 
data monitoring committee 
eCRF: 
electronic case report form 
eGFR: 
estimated glomerular filtration rate 
IMP: 
investigational medicinal product 
IRT: 
interactive response technology 
PCSA: 
potentially clinically significant abnormalities 
PD: 
pharmacodynamic 
PK: 
pharmacokinetic 
PV: 
plasma volume 
SAE: 
serious adverse event 
SBP: 
systolic blood pressure 
SD: 
standard deviation 
SGLT2: 
sodium-glucose cotransporter type 2 
TEAE: 
treatment-emergent adverse event 
ULN: 
upper laboratory normal 
 
 
 
 


Statistical Analysis Plan  
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Page 6 
 
1 
OVERVIEW AND INVESTIGATIONAL PLAN 
This statistical analysis plan (SAP) provides a comprehensive and detailed description of strategy 
and statistical techniques to be used to analyze data for SAR439954 study protocol PDY15079 
approved on 05 Jul 2017 amended on 14 Mar 2018. The purpose of the SAP is to ensure the 
credibility of the study findings by prespecifying the statistical approaches to the analysis of study 
data prior to database lock. 
1.1 
STUDY DESIGN AND RANDOMIZATION 
This is a phase 2, multi-center, multinational, randomized, double-blind, placebo-controlled, 
parallel arm trial of the safety, tolerability and pharmacodynamic activity of sotagliflozin in 
hemodynamically stable patients with worsening heart failure. An initial cohort of patients 
(Cohort 1) will receive sotagliflozin 200mg (n=approximately10) or placebo (n= approximately 5) 
for fourteen days. Following safety monitoring and review by thedata monitoring committee 
(DMC), Cohort 2 will receive sotagliflozin 400mg (n= approximately 10) or placebo (n= 
approximately 5) orally for fourteen days. Following completion of Cohort 2 and review of safety 
and tolerability by the DMC, patients in Cohort 3 will be allocated to sotagliflozin 200 mg, (n= 
approximately 17) 400 mg (n= approximately 17) or placebo (n= approximately 17) orally for 
fourteen days. This is summarized in Table 1.  
 
Table 1 - Cohort randomization and allocation scheme 
Cohort 
Randomization 
Sotagliflozin 200 
mg 
Sotagliflozin 
400 mg 
Placebo 
Total N 
1 
2:1 
10 
0 
5 
15 
2 
2:1 
0 
10 
5 
15 
3 
1:1:1 
17 
17 
17 
51 
Total N 
 
27 
27 
27 
81 
 
 
 
 
 
Patients are randomized to receive either sotagliflozin or placebo, according to the randomization 
scheme for each Cohort as described below:  
 Cohort 1: 
Sotagliflozin 200 mg : Placebo = 2:1 
 Cohort 2: 
Sotagliflozin 400 mg : Placebo = 2:1 
 Cohort 3: 
Sotagliflozin 200 mg : Sotagliflozin 400 mg : Placebo = 1:1:1 


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For each randomized patient, the IRT will allocate a treatment package number corresponding to 
the treatment group assigned. 
1.2 
OBJECTIVES 
1.2.1 Primary objectives 
The primary objective of this study is to assess the safety and tolerability of sotagliflozin, added to 
the standard of care treatment, in hemodynamically stable patients with worsening of heart failure, 
compared to placebo. 
A co-primary objective of this trial is the estimation of the effect of sotagliflozin, when added to 
the standard of care treatment, on changes in plasma volume, as assessed by direct (indicator 
dilution) and indirect (hemoconcentration) methods, in hemodynamically stable patients with 
worsening of heart failure, compared to placebo. 
1.2.2 Secondary objectives 
The main secondary objectives of this study are: 
 To explore the effect of sotagliflozin, added to standard of care treatment, on 
erythropoiesis, as assessed by changes in plasma erythropoietin levels, in 
hemodynamically stable patients with worsening of heart failure, compared to placebo. 
 To explore the effect of sotagliflozin, added to standard of care treatment, on changes in 
plasma NT-proBNP levels, in hemodynamically stable patients with worsening of heart 
failure, compared to placebo. 
1.2.3 Exploratory objective 
The exploratory objectives of this study are to explore the effect of sotagliflozin compared to 
placebo treatment, in hemodynamically stable patients with worsening of heart failure, on the 
following endpoints: 
 Change in total body water from baseline to 14 days 
 Change in uric acid from baseline to 14 days 
 Change in beta-hydroxybutyrate from baseline to 14 days 
 Change in total blood volume from baseline to 14 days 
 Change in red cell mass from baseline to 14 days 
 Percentage of patients within 15% of ideal blood volume on study day 14 
 Blood pressure, sitting (SBP and DBP), at day 14 compared to baseline 


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1.3 
DETERMINATION OF SAMPLE SIZE 
The sample size determination and the statistical power are estimated based on the main PD 
endpoint of plasma volume. The following assumptions are used for the estimation of the sample 
size, based on published data of the plasma volume (PV) response following 12 weeks of 
treatment with SGLT2 inhibition, relative to the placebo response, in non-HF patients: 
 
10% reduction in plasma volume from baseline, with an averaged value of 0.47 liters 
difference for the sotagliflozin group to the end of 2-week treatment between the 
sotagliflozin and placebo groups, respectively; 
 
The placebo response might be highly variable in this population. In the study by Lambers 
Heerspink et al, PV increased by approximately 2% at the end of the 12 week treatment 
period in the non-HF population. For the purpose of sample size estimation in this study, 
the assumption is that PV will be reduced by 1% in the placebo group. 
 
A common standard deviation (SD) of 0.8 liters for the reductions from baseline to the end 
of 2-week treatment in plasma volume for both groups;  
 
A t-test at 1-sided α=0.05; or equivalently, 2-sided α=0.10;  
Based on the above assumptions, it is estimated that, with a total of 81 patients with complete 
evaluations, or 27 patients per arm, the study will have a 71% power to detect an approximately 9 
percentage point difference (10% vs 1%) in the reduction from baseline in plasma volume at the 
end of 2-week treatment for the main comparison of the pooled sotagliflozin (200 mg and 400 
mg) group versus placebo. With 60 evaluable patients, or 20 patients per group, the study power is 
60%. The calculated sample size refers to the size of completers who have plasma volume values 
at both baseline and end of the 2-week treatment.  
Furthermore, interim analyses will be performed following Cohort 2 and during Cohort 3 for the 
purpose of exploratory analyses of pharmacodynamic, pharmacokinetic or safety variables, and 
sample size re-estimation, partly based on the observed variability of changes in plasma volume 
and/or hemoconcentration. Exploratory analyses may also be performed earlier for safety reasons, 
or if requested by the DMC or institutional ethics committees. In that case, the analysis will not 
result to any changes to the protocol.  
The study population will consist of at least 30% diabetic patients. 
1.4 
STUDY PLAN 
The following figure describes an overview of the design of the study: 


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Figure 1 – Study Design 
DMC 
Cohort 1 
N~15 
 
 
Sota 200 mg (N ~ 10) 
 
Placebo (N~5) 
 
Treated for 2 weeks 
DMC 
Cohort 2 
N~15 
 
 
Sota 400 mg (N ~ 10) 
 
Placebo (N~ 5) 
 
Treated for 2 weeks 
Cohort 3 
N~51 
 
 
Sota 200 mg (N ~ 17) 
 
Sota 400 mg (N ~ 17) 
 
Placebo (N ~17) 
 
Treated for 2 weeks 
 
The study consists of: 
 Screening period will be up to 21 days 
 Treatment period is 14±1 days 
 Follow up period will be 14±2 days 
 Total study duration will approximately be 26-51 days 
1.5 
MODIFICATIONS FROM THE STATISTICAL SECTION OF THE PROTOCOL 
This SAP describes updated standard analyses as planned in the new BTD-009094. 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
Not applicable 
 


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2 
STATISTICAL AND ANALYTICAL PROCEDURE 
2.1 
SUBJECT DESCRIPTION 
2.1.1 Disposition of subjects 
A detailed description of patient accountability will be generated by treatment group, including 
count of: 
 Screened patients (i.e. having signed the informed consent); 
 Screen failure patients and reason for screen failure;  
 Patients randomized and treated (i.e. randomized patients with a treatment number 
assigned and recorded and received at least one administration of IMP); 
 Patients who permanently discontinued the IMP with the main reason for permanent 
treatment discontinuation, 
 Patients who requested permanent treatment discontinuation. 
 
Patients treated without being randomized will not be considered as randomized and will not be 
included in any analysis population for which being randomized is required. The safety data of 
patients treated but not randomized will be reported separately, and these patients will not be in 
the safety population. 
Additionally a count of screened patients including number of screened patients, screen failure 
and inclusion/exclusion criteria met will be provided. 
A listing of patients with treatment discontinuation or screen failure will be provided sorted by 
treatment group and patients, including patients status at the end of the study with the date of last 
IMP administration, date of last available information and method of contact, reason for 
permanent treatment discontinuation, and whether the blind was broken on site at time of 
discontinuation. All withdrawals from the study, taking place on or after IMP administration, will 
be fully documented in the body of the clinical study report (CSR). 
In case of code broken for medical and accidental reasons on site, a listing of concerned patients 
will be provided, specifying the reason (AE/SAE or other), the date and time of code breaking, 
and the person who broke the code. 
A listing of all comments done by the Investigator on the electronic case report form (eCRF) will 
be provided by treatment group, if any. 
 


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2.1.2 Protocol deviations 
During the blinded review of the database, compliance with the protocol will be examined with 
regard to inclusion and exclusion criteria, treatment or dosing compliance, prohibited therapies, 
and timing and availability of planned assessments. Protocol deviations will be identified by the 
study team before database lock and listed in the Data Review and Surveillance Report, including 
missing data and study drug discontinuations, and classified as critical, major or minor deviations. 
Critical or major deviations resulting in exclusion for the pharmacodynamics analyses and any 
other critical or major deviations will be summarized by treatment group. 
2.2 
ANALYSIS POPULATIONS 
The number of patients included in each study population (safety population, pharmacokinetic 
population, pharmacodynamic population, pharmacokinetic/pharmacodynamic population) will be 
provided by treatment group. All exclusions from any analysis populations (pharmacodynamic, 
pharmacokinetic, and/or safety) will be fully documented in the clinical study report. 
2.2.1 Pharmacodynamic population 
For the main PD endpoints of plasma volume and hemoconcentration, the PD population will 
consist of all randomized and treated patients who have valid values of the main PD parameters 
both at baseline and at Day 14/EOT.  
2.2.2 Safety population 
All randomized patients who are exposed to IMP (regardless of the amount of treatment 
administered) will be included in the safety population. For safety analyses, patients will be 
included in the treatment group as actually received. Non-randomized and treated patients will not 
be part of the safety population, but their safety data will be summarized separately. 
2.2.3 Pharmacokinetic population 
The PK population will consist of all patients in the safety population who have at least one non-
missing and eligible plasma concentration data.  
Only patients with no major or critical deviations related to IMP (eg, vomiting just after drug 
administration), and for whom PK data are considered sufficient and interpretable, will be 
included in the pharmacokinetic population.  
Patients will be analyzed according to the treatment actually received. Patients having received 
only placebo will not be included in the pharmacokinetic population. 


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2.2.4 Pharmacokinetic/Pharmacodynamic population 
All patients being included in both the pharmacokinetic and the pharmacodynamic populations 
will be included in the pharmacokinetic/pharmacodynamic population. In addition, patients being 
included in the pharmacodynamic population and having received only placebo will also be 
included in the pharmacokinetic/pharmacodynamic population. 
2.3 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
2.3.1 Subject demographic characteristics, medical history, and diagnoses 
The response to IMP might be affected by several variables, including continuous variables (e.g., 
age, height, weight, body mass index (BMI) and qualitative variables (gender, race and/or 
ethnicity). BMI can be described both quantitatively and qualitatively (Underweight: BMI is less 
than 18.5; Normal weight: BMI is 18.5 to 24.9; Overweight: BMI is 25 to 29.9; Obese: BMI is 30 
or more). The following variables will be summarized by descriptive statistics for the safety 
population and for additional population if relevant: 
 Age (years) 
 Weight (Kg) 
 Height (cm) 
 Body mass index (Kg/m²) 
 Race and/or ethnicity 
 Gender 
 eGFR 
Medical history will be coded according to MedDRA (last version available before database lock). 
Specific medical history (Diabetes, cardiovascular events – including but not limited to stroke, 
myocardial infarction, atrial fibrillation – and previous cardiac interventions (eg angioplasty)) will 
be summarized by treatment group and overall, and presented by primary SOC and High Level 
Term (HLT) on the safety population. The events will be sorted by SOC internationally agreed 
order and decreasing frequency of HLT. 
2.3.2 Baseline pharmacodynamic parameters 
Baseline values of PD parameters are defined to be those taken or measured approximately one to 
three (3) hours prior to the first dosing of study treatment on Day 1.  
All baseline PD parameters will be summarized and presented by treatment group as with all other 
baseline patient characteristics. In addition, for the main PD parameters such as plasma volume 
and hemoconcentration, the mean baseline values of the PD parameters will also be summarized 
along with the mean Day 14/EOT values and mean change from baseline values. 


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2.3.3 Baseline safety parameters 
Baseline for safety parameters will be defined as the last available and evaluable parameter value 
before and closest to the first IMP dosing for laboratory data, vital sign parameters, and for 12 
lead ECG parameters. 
Baseline definitions specific to each type of safety parameter will be detailed in corresponding 
Section 2.7.2 to Section 2.7.5 
Baseline safety values will be presented along with subsequent safety values assessed during or 
after dosing. 
2.4 
EXTENT OF STUDY TREATMENT EXPOSURE AND COMPLIANCE 
The extent of study treatment exposure (ie, duration of IMP exposure during the study) will be 
defined as the total number of days of IMP administrations, ignoring temporary drug 
discontinuations and will be calculated as: 
(Date of the last study drug administration - date of the first study drug administration) + 1. 
The duration of IMP exposure during the study will be summarized categorically (counts and 
percentages) by treatment group, on the safety population using the following categories: between 
1 and 7 days; between 8 and 11 days; between 10 and 12 (excluded) days; between 12 and 15 
days. 
The following listings will be provided: 
 Patients receiving IMP from specified batch 
 Randomization scheme. 
2.5 
PRIOR/CONCOMITANT MEDICATION/THERAPY 
Medications will be coded according to the World Health Organization Drug Dictionary (Drug 
Dictionary (WHO-DD), last available version before database lock). Summary of concomitant 
medications with the IMP will be provided by anatomic class and therapeutic class. 
2.6 
ANALYSIS OF PHARMACODYNAMIC VARIABLES 
All the pharmacodynamic analyses will be performed using the pharmacodynamic population. 
2.6.1 Description of pharmacodynamic variables 
The following pharmacodynamic variables will be analyzed: 
Primary PD variables  


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 
Change in hemoconcentration from baseline to D14/EOT as assessed by changes in 
hematocrit, hemoglobin, albumin and total protein. 
 
Change in plasma volume in milliliters from baseline to D14/EOT as assessed by the 
indicator dilution method using 131I-labelled human albumin.  
Secondary PD variables: 
 
Change in erythropoietin (mU/ml) from baseline to D14 measured by chemiluminescent 
enzyme-labelled immunometric assay 
 
Change in NT-proBNP (pg/mL) from baseline to D14 measured by standard 
electrochemiluminescence immunoassay  
Other Exploratory PD endpoints 
 
Change in total body water (mL) from baseline to D14 as assessed by the indicator 
dilution method using deuterium oxide 
 
Change in uric acid (mg/dL) from baseline to 14 days as measured by standard assay 
 
Change in beta-hydroxybutyrate (µM) from baseline to 14 days as measured by standard 
enzymatic colorimetric assay 
 
Change in red cell mass (mL) from baseline to D14, as derived from measurements of 
plasma volume (assessed by the indicator dilution method using 131I-labelled human 
albumin) and hematocrit  
 
Change in total blood volume (mL) from baseline to 14 days, as assessed by the indicator 
dilution method using 131I-labelled human albumin 
 
Percentage of patients within 15% of ideal blood volume on study day 14 
 
Blood pressure (sitting, SBP and DBP) at day 14, compared to baseline 
2.6.2 Primary analysis 
The main pharmacodynamic variables, change from baseline to Day 14 in hemoconcentration and 
plasma volume, will be analyzed using an analysis of covariance (ANCOVA) model with fixed 
terms for treatment and stratification factor of baseline patient status (diabetic, non-diabetic, 
ejection fraction status (reduced-preserved), and with baseline plasma volume as covariate. An 
estimate for the between-group difference in treatment mean changes and corresponding 2-sided 
90% confidence interval (CI) will be calculated from the model. The main treatment comparison 
will be between the pooled treatment (200 mg and 400 mg) group and placebo which will be 
made at 1-sided α=0.05 (or equivalently, 2-sided α=0.10).  
No multiplicity procedures will be applied as the study is exploratory in nature. 
2.6.3 Secondary analysis/analysis of secondary variables 
Similar ANCOVA models as in the primary analysis will be fitted for the secondary and other 
pharmacodynamic variables or endpoints. 


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In addition, descriptive statistics for secondary and other pharmacodynamic variables in raw data 
and in change from baseline will be provided by treatment group (Sotagliflozin doses or placebo) 
for assessment from Day 1 to Day 14. Plots of the means overtime (+/-SEM) will also be 
presented.  
2.7 
ANALYSIS OF SAFETY DATA 
The summary of safety results will be presented by treatment group. All safety analyses will be 
performed on the safety population.  
The safety analysis will be based on the review of descriptive statistics (summary tables) and 
individual data for vital signs, renal function, adverse events (AEs) and other clinical laboratory 
values and ECG parameters.  
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA), and 
the number of patients with Treatment-Emergent Adverse Events (TEAEs) will be summarized by 
treatment group. Potentially clinically significant abnormalities (PCSAs) for clinical laboratory, 
vital sign, and ECG data and out-of-normal range values for clinical laboratory data will be 
flagged and summarized in frequency tables. The PCSA values are defined as abnormal values 
considered medically important by the Sponsor according to predefined criteria/thresholds based 
on literature review for clinical laboratory tests, vital signs and ECG parameters. 
For all safety data, the observation period will be divided into three segments: 
 
the pretreatment period is defined as the time between informed consent signature and 
the first IMP administration; 
 
the TEAE (treatment emergent AE) period is defined as the time from the first IMP 
administration up to  approximately 5 days after the last IMP administration 
(approximately 5 times the half-life of sotagliflozin); 
 
the post-TEAE period is defined as the time starting after the TEAE period up to the final 
study follow up telephone check. 
2.7.1 Adverse events 
2.7.1.1 Definitions 
Adverse events will be coded to a “Preferred Term (PT)” and High Level Group Term (HLGT)”, 
“High Level Term (HLT)” and primary “System Organ Class (SOC)” using the Medical 
Dictionary for Regulatory Activities (MedDRA, version currently in use by the sponsor at the 
time of database lock). Their severity will be graded according NCI-CTCAE v4.03. 
They will be classified into predefined standard categories according to chronological criteria: 
 Pretreatment AEs: AEs that occurred, worsened or became serious during the pretreatment 
period. 


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 Treatment emergent AEs (TEAEs): AEs that occurred, worsened or became serious during 
the TEAE period. 
 Post-TEAEs: AEs that occurred, worsened or became serious during the post-TEAE 
period. 
TEAEs will be assigned to the treatment received at the time of the AE onset. 
If the onset date (or time) of an AE (occurrence, worsening or becoming serious) is incomplete or 
missing, then the AE will be considered as a TEAE unless a partial date (or time) shows it as a 
pre- or post-treatment event 
All AEs reported in the study will be listed, sorted by treatment group, subject, onset date and 
time. 
2.7.1.2 Treatment-emergent adverse events 
The following TEAEs summaries will be provided by treatment for the safety population: 
 Overview of TEAEs: number and percentage of patients with any TEAE, any TEAE of 
special interest, any severe TEAEs, any serious TEAE, any TEAE leading to death (if any 
occurred), and any TEAE leading to permanent treatment discontinuation. 
 Summary of TEAEs by primary SOC and PT: 
- 
number and percentage of patients with at least one TEAE; 
- 
number of occurrences of TEAEs. 
Patients presenting TEAEs will be listed sorted by treatment group primary SOC and PT. 
2.7.1.3 Deaths, serious, and other significant adverse events 
Any deaths, serious and other significant AEs will be listed. 
2.7.1.4 Adverse events leading to treatment discontinuation 
Any AEs leading to permanent treatment discontinuation will be listed. 
2.7.1.5 Adverse events of special interest 
Adverse event of special interests (AESI) for this study are defined as follows: 
 Pregnancy occurring in a female patient included 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. 
- 
In the event of pregnancy in a female patient, IMP should be discontinued, 
- 
Follow-up of the pregnancy in a female patient or in a female partner of a male patient 
is mandatory until the outcome has been determined. 


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 Symptomatic overdose (serious or nonserious) with IMP/non investigational medicinal 
product (NIMP) 
- 
A symptomatic overdose (accidental or intentional) with the IMP/NIMP is an event 
suspected by the Investigator or spontaneously notified by the patient and resulting in 
clinical symptoms and/or signs accompanied by administration of more than twice the 
intended daily dose within a 24-hour period. It will be recorded in the e-CRF as an 
AESI with immediate notification “Symptomatic OVERDOSE (accidental or 
intentional)” in all cases and will be qualified as an SAE only if it fulfills the SAE 
criteria. 
(Please note that an Asymptomatic overdose with the IMP/NIMP, accidental or 
intentional, defined as administration of more than twice the intended daily dose 
within a 24-hour period, without clinical symptoms and/or signs, either suspected by 
the Investigator or spontaneously notified by the patient, not based on accountability 
assessment. It will be recorded as an AE “Asymptomatic OVERDOSE, accidental or 
intentional.”) 
 ALT increased > 3X ULN  
A summary of TEAEs reported as AESI (number and percentage of patients and the number of 
events) will be provided by AESI category and PT, sorted by decreasing incidence of PT within 
each AESI category. 
2.7.2 Clinical laboratory evaluations 
Baseline definition 
The values to be used as the baselines will be the Day 1 predose assessment values. If any of the 
scheduled baseline tests are repeated for any subject, the last rechecked values will be considered 
as baselines, provided they were done before the first IMP administration. 
Abnormalities analyses 
For parameters with laboratory ranges and/or abnormality criteria (PCSA), analysis will be 
performed using all post-baseline assessments done during the TEAE period, including all 
unplanned and rechecked values. Counts of patients with PCSAs according to baseline status will 
be presented by treatment. The same type of summary tables will be provided for out-of-normal 
laboratory range values.  
Descriptive statistics and plots  
Raw data and changes from baseline will be summarized in descriptive statistics for all endpoint 
parameters, by treatment and scheduled time of measurement. 
Additionally, graphs over time for these parameters will be presented plotting mean +/- SD by 
treatment. 


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PCSA Listings 
A listing of individual data from patients with post-baseline PCSAs will be provided; values will 
be flagged when outside the laboratory limits and/or when reaching the PCSA criteria. 
A listing of liver function data for subjects experiencing at least one of the following situations 
will be provided: 
 
ALT > 3ULN and total bilirubin > 2ULN during the study, with at least one of them being 
post first dose, irrespective of the definition of the TEAE period; 
 
Conjugated bilirubin>35% of Total bilirubin and Total bilirubin>1.5 ULN, on the same 
sample post first dose, irrespective of the definition for the TEAE period. 
If any, a listing related to increase in ALT ≥ 2 ULN will be provided, including notably the 
information on drug intake, medical and surgical history, alcohol habits, and trigger factors, event 
details with ALT values, associated signs and symptoms. 
Out-of-normal range definitions and unscheduled laboratory tests, if any, will be listed. 
2.7.3 Vital signs 
Heart rate (HR), systolic and diastolic blood pressures (SBP and DBP) will be analyzed as raw 
parameter value (for supine/sitting and standing positions), change from baseline (for supine or 
sitting position only) and as orthostatism parameter (standing-sitting/supine parameter values). 
Body weight will be analyzed as raw parameter value and percent change from baseline and BMI 
will be analyzed as raw parameter value. 
Baseline definition 
The values to be used as baselines will be the Day 1 pre-dose assessment values. If any of the 
scheduled baseline tests are repeated for any subject, the last rechecked values will be considered 
as baselines, provided they were done before the IMP administration of the respective treatment 
phase, and in the same condition.  
Abnormalities analyses 
For all parameters, analysis will be performed using all post-baseline assessments done during the 
TEAE period, including all unplanned and rechecked values. Counts of patients with PCSAs will 
be presented by treatment, regardless of the baseline status. 
Descriptive statistics and plots 
For heart rate and blood pressures, raw data (supine/sitting and standing positions) and changes 
from baseline (supine/sitting position only) will be summarized in descriptive statistics by 
treatment and scheduled time of measurement.  


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For body weight, raw data and percent change from baseline will be summarized in descriptive 
statistics by treatment and scheduled time of measurement. 
Additionally, graphs over time will be presented plotting mean +/- SD by treatment. 
PCSA Listings 
A listing of individual data from patients with post-baseline PCSAs will be provided; values will 
be flagged when reaching the PCSA criteria. 
2.7.4 Electrocardiogram 
ECG parameters (HR in bpm, QTc, QT, QRS and PR in msec) will be derived from the ECG 
obtained in hospital or during Visit days as per schedule of events. All parameters will be 
analyzed as raw data and absolute change from baseline. In addition, for the abnormalities 
analysis, PR and QRS will be also analyzed as percent change from baseline. 
Baseline definition 
The values to be used as baselines will be the Day 1 predose assessment values. If any of the 
scheduled baseline tests are repeated for any subject, the last rechecked values will be considered 
as baselines, provided they were done before the IMP administration of the respective treatment 
phase, and in the same condition. 
Abnormalities analyses 
For all parameters, analysis will be performed, using all post-baseline assessments done during 
the TEAE period, including all unplanned and rechecked values. Counts of patients with PCSAs 
will be presented by treatment, regardless of the baseline status. 
Descriptive statistics and plots 
ECG parameters (raw data and absolute change from baseline) will be summarized in descriptive 
statistics by treatment and scheduled time of measurement. 
Additionally, graphs over time will be presented plotting mean +/- SD by treatment. 
Listings 
Following listings will be produced, using all data, including rechecked or unplanned values. 
 A listing of individual data of subjects with any post-baseline PCSAs will be provided; 
raw data and absolute or percent change from baseline will be displayed depending on the 
parameter and values will be flagged when reaching the limits of the PCSA criteria; 
 In addition, subjects with QTc/QTcB/QTcF >480 ms and/or change from baseline in 
QTc/QTcB/QTcF >60 ms will also be listed separately, using all post-dose timepoints. 


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 A listing of subjects with at least one abnormality in qualitative assessment (ie, abnormal 
12-lead ECG) after the 1st dosing will be also provided. 
2.7.5 Other related safety parameters 
The HbA1c and eGFR parameters will be analysed descriptively by treatment group. 
2.8 
ANALYSIS OF PHARMACOKINETIC DATA 
2.8.1 Pharmacokinetic parameters 
No formal analysis of PK parameters will be performed. Single concentration-time-points will be 
subject to descriptive statistical analysis 
2.9 
DATA HANDLING CONVENTIONS 
This section describes the rules and conventions used in the presentation and analysis of data.” 
In the in-text and appendices tables, the following treatment labels will be used: 
 Placebo 
 Sotagliflozin 200mg 
 Sotagliflozin 400mg 
All individual data for all included subjects will be presented in data listings, sorted by treatment 
group, subject number, visit and time of measurement. 
For parameters with evaluations before administration and in cases of rechecked value(s) for one 
subject, only the last observation will be used as baseline in descriptive statistics and derivations 
of other parameter values. 
After baseline, only observations planned in the protocol will be used in descriptive statistics. 
 
For clinical laboratory parameters with nonnumeric values, the imputed values used for the 
descriptive statistics and/or the flags 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 + 10[-number of digits of the considered parameter in 
the database] 
 if database value is a range (eg, ‘X – Y’), the values used will be (Y + X)/2 
 
If not otherwise stated in the statistical section of the protocol: 
 Missing data other than protocol-planned baseline values will not be replaced. 


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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 (%). 
 
Handling missing data for adverse events 
 
In case of missing or inconsistent information, an adverse event (AE will be counted as a 
treatment-emergent adverse event (TEAE, unless it can clearly be ruled out that it is not a TEAE 
(eg, by partial dates or other information). 
 
If the start date (or time) of an AE is incomplete or missing, then the AE will be considered as a 
TEAE unless a partial date (or time) or comment shows it as a pre- or post-treatment event. 
 
If relationship to study drug is missing, the AE will be assessed as unrelated if it started before 
administration of study medication; in all other cases it will be assumed to be related. 


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3 
INTERIM ANALYSIS 
Interim analyses will be performed following Cohort 2 and during Cohort 3 for sample size re-
estimation or for the purpose of exploratory analyses. These planned interim analyses will focus 
on the main pharmacodynamic parameters of hemoconcentration and plasma volume. Descriptive 
statistics will be provided and ANCOVA analyses as described above will be performed for the 
interim analyses. Exploratory analyses may also be performed earlier for safety reasons, or if 
requested by the DMC or institutional ethics committees. In that case, the analysis will not result 
to any changes to the protocol. 
The Statistician and Statistical Programmer will work independently to the study team on these 
interim analyses to ensure the blinding is preserved notably toward the Investigator. These 
analyses must provide only mean and variability data and exclude all individual information like 
minimum, maximum or median values and sample size per group. A dissemination plan of the 
results should be established upfront before the interim data unblinding.  
The outcome of this interim analysis may lead to early termination of the trial, continuation 
without any changes, or continuation with changes. 


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4 
SOFTWARE DOCUMENTATION 
The analysis of clinical data will be performed, using SAS® version 9.4 or higher 
 


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5 
APPENDICES 






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i 
Meals should be taken approximately 15 min after IMP administration throughout the study. On study day Visits 2 and 5, and Visits 3 and 4, patients should fast for approximately 6 hours prior to IMP 
administration.  
j 
Diary dispensed on D1 (Visit 2). The diary will be reviewed and information recorded on eCRF. If the last follow up is by phone check, all relevant information will be captured and transcribed to the eCRF. Patients 
who may need to remain inpatients for some or all of the visits will also receive a diary. While inpatients, relevant data such as AE and IMP intake will be entered into the diary. For inpatients, BP and concomitant 
medications will be recorded in the patient source documents. Those who become eligible for discharge will also  receive BP monitors and continue with diary updates on a daily basis. 
k Patients will be taught how to perform the automated BP readings. Automated BP readings will be performed in triplicate, between 6 AM to 10 AM on a daily basis, starting D2 and ending at the last post-study 
follow up. 
l 
Study treatment ends on Day 14 (EOT). 
m Physical examination includes at a minimum: heart and respiratory auscultation; peripheral arterial pulse; pupil, and abdomen examination. All physical examinations in diabetic patients, including abbreviated 
physical examinations, will include examination of the lower extremities to evaluate for any evidence of foot ulcers or infection should be performed as part of the general physical examination and this examination 
should be documented on the e-CRF. 
n All body weight measurements on scale provided by site staff. 
o All patients must have a documented echocardiogram, either performed during current admission or within 12 months from the index hospitalization. 
p ECG at Visit 2, Visit 3 and EOT Visit 5 only. 
q Oral or tympanic body temperature. 
r 
Complete blood count / hematocrit / hemoglobin.  
s Creatinine, urea, electrolytes. 
t 
For Visits 2 (Day 1) and 5 (Day 14±1), those samples will be obtained as part of the Hemoconcentration sampling, thus no additional samples for Hematology or Biochemistry are required. It is indicated here as a 
reminder that baseline hematology and biochemistry is done on Visits 2 and 5. For all other Visits, Hematology and Biochemistry samples are to be obtained as indicated. 
u Beta-HCG test will be for all women of child-bearing potential as defined in the inclusion/exclusion criteria, and FSH to assess menopausal status when necessary. 
v Pharmacokinetic samples taken on Visit 3 and Visit 4 are pre-dose drug treatment samples. 
w Hemoconcentration is determined by measurement of hematocrit, hemoglobin, albumin and total protein. Baseline biochemistry (creatinine, urea and electrolytes) and hematology (CBC) is also determined from 
those samples. 
 
 






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l 
Hemoconcentration is determined using the following: Hematocrit, hemoglobin, total protein and albumin. Baseline biochemistry (creatinine, urea, electrolytes) and complete blood count will also be determined 
from those samples 
m One sample will be collected just before injection of 131I-albumin (-1H, PD00) and further sample collection will start 12 min following the injection. Samples will then be collected every 6 minutes starting – 
0H48min: -0H48min(PD01), -0H42min(PD02), -0H36min(PD03), -0H30min(PD04), -0H24min(PD05) min. For blood collection on D14 sample notation should be: -1H (PD06), -0H48min (PD07), -0H42min (PD08), 
-0H36min(PD09), -0H30min(PD10), -0H24min(PD11)  
n Following administration of deuterium oxide, blood collection on D1: At -2.5H (PY00), 1H (PY01), and on Day 14: At -2.5H (PY02), 1H (PY03) 
o All body weight measurements on scale provided by site staff 
 
 
 
 
 
 
 
 
 


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Appendix C 
Potentially clinically significant abnormalities criteria 
Laboratory parameter  
      PCSA criteria n/N1 (%) 
Adults 
Children 
Haemoglobin 
 
 
Low 
≤ 115 g/L (Male) 
≤ 95 g/L (Female) 
28 days/1 month to 23 months old : < 90 g/L 
24 months/2 years to <16/18 years old : < 100 g/L 
Decrease from baseline 
≥20 g/L 
≥ 20 g/L 
High (adults) 
≥ 185 g/L (Male) 
≥ 165 g/L (Female) 
 
 
 
 
Hematocrit 
 
 
Low 
≤ 0.37 v/v (Male) 
≤ 0.32 v/v (Female) 
28 days/1 month to 23 months old: < 0.29 v/v 
24 months/2 years to <16/18 years old: < 0.32 v/v 
High  
≥ 0.55 v/v (Male) 
≥ 0.5 v/v (Female) 
28 days/1 month to 23 months old: > 0.42 v/v 
24 months/2 years to <16/18 years old: > 0.47 v/v 
 
 
 
Erythrocyte Count 
 
  
High (adults)  
≥ 6 Tera/L 
 
 
 
 
Platelet Count 
 
 
Low 
< 100 Giga/L 
< 100 Giga/L 
High 
≥ 700 Giga/L 
> 700 Giga/L 
 
 
 
Leukocytes 
 
 
Low 
< 3.0 Giga/L (Non-Black);  
< 2.0 Giga/L (Black) 
Birth/0 to 23 months old : <4.0 Giga /L  
24 months/2 years to <6 years old: <3.0 Giga /L  
6 to <12 years old : <5.0 Giga /L  
12 to 16/18 years old : <4,5 Giga /L  


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Laboratory parameter  
      PCSA criteria n/N1 (%) 
Adults 
Children 
High 
≥ 16.0 Giga/L 
Birth/0 to 27 days old : >25.0 Giga /L  
28 days/1 month to 23 months old: >20.0 Giga /L  
24 months/2 years to <6 years old: >16.0 Giga /L  
6 to <12 years old : >17.0 Giga /L  
12 to 16/18 years old : >13.5 Giga /L 
 
 
 
Neutrophils 
 
 
Low 
< 1.5 Giga/L (Non-Black);  
< 1.0 Giga/L (Black) 
Birth/0 to 27 days old :  
<4 Giga /L (1 day old) 
<1.5 Giga /L (2-7 days old) 
<1.25 Giga /L (>7 day-1 month old) 
28 days/1 month to 23 months old:  
<1.0 Giga /L (1-3 months) 
<1.2 Giga /L (3-24 months) 
24 months/2 years to <16/18 years old: <1.2 Giga /L  
High (children) 
 
>1 ULN 
 
 
 
Lymphocytes 
 
 
Low (children) 
 
Birth/0 to 27 days old : <1.2 Giga /L  
28 days/1 month to 23 months old: <2.0 Giga /L  
24 months/2 years to <12 years old: <1.0 Giga /L  
12 to 16/18 years old : <0.6 Giga /L 
High 
> 4.0 Giga/L 
Birth/0 to 27 days old : >17.0 Giga /L  
28 days/1 month to 23 months old: >13.5 Giga /L  
24 months/2 years to <6 years old: >9.5 Giga /L  
6 to <12 years old : >8.0 Giga /L  
12 to 16/18 years old : >6 Giga /L 
 
 
 
Monocytes 
 
 
High (adults) 
> 0.7 Giga/L 
 
 
 
 
Basophils 
 
 
High (adults) 
> 0.1 Giga/L 
 
 
 
 
Eosinophils 
 
 


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Laboratory parameter  
      PCSA criteria n/N1 (%) 
Adults 
Children 
High 
> 0.5 Giga/L or > ULN  
(if ULN ≥ 0.5 Giga/L) 
> 0.5 Giga/L or > ULN (if ULN > 0.5 Giga/L) 
 
 
 
Glucose 
 
 
Low  
≤ 3.9 mmol/L and < LLN 
<2.7 mmol/L  
 
High 
≥11.1 mmol/L (unfasted);  
≥ 7 mmol/L (fasted) 
≥10.0 mmol/L (unfasted)  
≥7 mmol/L (fasted after >12 hours of fast) 
 
 
 
Albumin 
 
 
Low (adults) 
≤ 25 g/L 
 
 
 
 
Creatine Kinase 
 
 
High, all grades 
> 3 ULN 
≥ 3 ULN 
At least grade 1 (adults) 
> 3 ULN 
 
At least grade 2 (adults) 
> 10 ULN 
 
 
 
 
Sodium 
 
 
Low 
≤ 129 mmol/L 
≤129 mmol/L  
High 
≥ 160 mmol/L 
≥150 mmol/L  
 
 
 
Potassium 
 
 
Low 
< 3 mmol/L 
Birth/0 to 27 days old : ≤3.0 mmol/L  
28 days/1 month to 16/18 years old : ≤3.5 mmol/L  
High 
≥ 5.5 mmol/L 
Birth/0 to 27 days old : ≥7.0 mmol/L  
28 days/1 month to 23 months old : ≥6.0 mmol/L  
24 months/2 years to 16/18 years old : ≥5.5 mmol/L  
 
 
 
Creatinine 
 
 
High 
≥ 150 µmol/L 
Birth/0 to <6 years old : >53 μmol/L  
6 years to <12 years old: >90 μmol/L 
12 years to 16/18 years old: >132 μmol/L 


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Laboratory parameter  
      PCSA criteria n/N1 (%) 
Adults 
Children 
Increase from baseline 
 
 
At least grade 1 (adults) 
≥ 30% change from baseline 
 
At least grade 2 (adults) 
≥ 100% change from baseline 
 
 
 
 
Creatinine Clearance 
 
 
Low, all grades 
< 90 mL/min* 
Birth/0 to 27 days old : < 25 ml/min/1.73m² ** 
28 days/1 month to 23 months old:  < 45 ml/min/1.73m² ** 
From 2 years old : < 60 ml/min/1.73m² **  
Mild (adults) 
[60 – 90[ mL/min* 
 
Moderate (adults) 
[30 – 60[ mL/min* 
 
Severe (adults)  
[15 – 30[ mL/min* 
 
End stage (adults) 
< 15 mL/min* 
 
*MDRD or Cokcroft-Gault equation 
 
 
**GFR Bedside Schwartz Formula  
Based on normal ranges: 20 to 50 (<8 days), 25 to 80 (8 days to 1 month), 30 
to 90 (1-6 months), 40 to 115 (6-12 months), 60 to 190 (12-23 months), 90 to 
165 (2-12 years), 80-120 (After 12 years)  
BUN 
 
 
High 
≥ 17 mmol/L 
Birth/0 to 27 days old : ≥4.3 mmol/L  
28 days/1 month to 16/18 years old: ≥6.4 mmol/L 
 
 
 
Alanine Aminotransferase 
 
 
High, at least grade 1 
> 3 ULN 
≥ 3 ULN 
High, at least grade 2 
> 5 ULN 
≥ 5 ULN 
High, at least grade 3 
> 10 ULN 
≥ 10 ULN 
High, at least grade 4 
> 20 ULN 
≥ 20 ULN 
 
 
 
Aspartate Aminotransferase 
 
 
High, at least grade 1 
> 3 ULN 
≥ 3 ULN 
High, at least grade 2 
> 5 ULN 
≥ 5 ULN 
High, at least grade 3 
> 10 ULN 
≥ 10 ULN 
High, at least grade 4 
> 20 ULN 
≥ 20 ULN 
 
 
 


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Laboratory parameter  
      PCSA criteria n/N1 (%) 
Adults 
Children 
Alkaline phosphatase 
 
 
High 
> 1.5 ULN 
≥ 1.5 ULN 
 
 
 
Total Bilirubin 
 
 
High, all grades 
> 1.5 ULN 
≥ 1.3 ULN 
At least grade 1 (adults) 
> 1.5 ULN 
 
At least grade 2 (adults) 
> 2 ULN 
 
 
 
 
Alanine Aminotransferase and tot
bilirubin 
 
 
High 
ALT > 3 ULN and TBILI > 2 
ULN 
ALT ≥ 3 ULN and TBILI ≥ 2 ULN 
 
 
 
Direct bilirubin and total bilirubin  
 
High 
BILDIR >35% TBILI and 
TBILI >1.5 ULN 
BILDIR >35% TBILI and TBILI≥1.3 ULN  
 
 
 
 
References: 
- 
for adults: Criteria for Potentially Significant Abnormalities – for Phase 2/3 studies (oncology excepted) - Version 3.0 - 21-MAY-2014 
- 
for children: Criteria for Potentially Clinically Significant Abnormalities for Studies in Children - Version 3.0 - 21-MAY-2014 
 
 
ECG Parameter  
      PCSA criteria n/N1 (%) 
Adults 
Children 
Heart rate 
 
 
Low, at least grade 1 (adults) 
<50 bpm  
 
Low, at least grade 2 (adults) 
<40 bpm 
 
Low, at least grade 3 (adults) 
<30 bpm 
 
 
 
 


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ECG Parameter  
      PCSA criteria n/N1 (%) 
Adults 
Children 
Low and decrease from baseline, all 
grades 
<50 bpm and decrease 
from baseline ≥20 bpm 
Birth/0 to 27 days old : ≤ 90 bpm and decrease from baseline ≥20 bpm  
28 days/1 month to 23 months old: ≤ 80 bpm and decrease from baseline ≥20 bpm 
24 months/2 years to <6 years old: ≤ 75 bpm and decrease from baseline ≥20 bpm 
6 to <12 years old : ≤ 50 bpm and decrease from baseline ≥20 bpm 
12 to 16/18 years old : ≤ 50 bpm and decrease from baseline ≥20 bpm 
At least grade 1 (adults) 
<50 bpm and decrease 
from baseline ≥20 bpm  
 
At least grade 2 (adults) 
<40 bpm and decrease 
from baseline ≥20 bpm 
 
At least grade 3 (adults) 
<30 bpm and decrease 
from baseline ≥20 bpm 
 
 
 
 
High, at least grade 1 (adults) 
>90 bpm  
 
High, at least grade 2 (adults) 
>100 bpm 
 
High, at least grade 3 (adults) 
>120 bpm 
 
 
 
 
High and increase from baseline, all grades 
>90 bpm and increase 
from baseline ≥20bpm 
Birth/0 to 27 days old : ≥ 190 bpm and increase from baseline ≥20 bpm  
28 days/1 month to 23 months old: ≥ 175 bpm and increase from baseline ≥20 bpm 
24 months/2 years to <6 years old: ≥ 140 bpm and increase from baseline ≥20 bpm 
6 to <12 years old : ≥ 120 bpm and increase from baseline ≥20 bpm 
12 to 16/18 years old : ≥ 120 bpm and increase from baseline ≥20 bpm 
At least grade 1 (adults) 
>90 bpm and increase 
from baseline ≥20bpm 
 
At least grade 2 (adults) 
>100 bpm and increase 
from baseline ≥20bpm 
 
At least grade 3 (adults) 
>120 bpm and increase 
from baseline ≥20bpm 
 
 
 
 
PR 
 
 
High, all grades  
>200 ms  
Birth/0 to 27 days old : ≥ 120 ms  
28 days/1 month to 23 months old: ≥ 140 ms  
24 months/2 years to <6 years old: ≥ 160 ms  
6 to <12 years old : ≥ 170 ms  
12 to 16/18 years old : ≥ 180 ms  
At least grade 1 (adults) 
>200 ms 
 


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ECG Parameter  
      PCSA criteria n/N1 (%) 
Adults 
Children 
At least grade 2 (adults) 
>220 ms 
 
At least grade 3 (adults) 
>240 ms 
 
 
 
 
High and increase from baseline (adults) 
 
 
At least grade 1  
>200 ms and increase 
from baseline ≥25%  
 
At least grade 2  
>220 ms and increase 
from baseline ≥25% 
 
At least grade 3  
>240 ms and increase 
from baseline ≥25% 
 
 
 
 
QRS 
 
 
High, all grades  
>110 ms 
Birth/0 to 27 days old : ≥ 85 ms  
28 days/1 month to 23 months old: ≥ 85 ms  
24 months/2 years to <6 years old: ≥ 95 ms  
6 to <12 years old : ≥ 100 ms  
12 to 16/18 years old : ≥ 110 ms 
At least grade 1 (adults) 
>110 ms  
 
At least grade 2 (adults) 
>120 ms 
 
 
 
 
High and increase from baseline (adults) 
 
 
At least grade 1  
>110 ms and increase 
from baseline ≥25%  
 
At least grade 2  
>120 ms and increase 
from baseline ≥25% 
 
 
 
 
QTc Fridericia 
 
 
Increase from baseline, Grade 1 
Increase from baseline 
]30-60] ms  
All age classes: Increase from baseline (30-60] ms 
Increase from baseline, Grade 2 
Increase from baseline 
>60 ms 
All age classes: Increase from baseline >60 ms 
References: 
- 
for adults: Criteria for Potentially Significant Abnormalities – for Phase 2/3 studies (oncology excepted) - Version 3.0 - 21-MAY-2014 


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- 
for children: Criteria for Potentially Clinically Significant Abnormalities for Studies in Children - Version 3.0 - 21-MAY-2014 
 
Vital signs parameter  
      PCSA criteria n/N1 (%) 
Adults 
Children 
Systolic blood pressure supine 
 
 
Low and decrease from baseline 
≤95 mmHg and decrease from 
baseline ≥20 mmHg 
Birth/0 to 27 days old : ≤ 60 mmHg and decrease from baseline ≥20 mmHg  
28 days/1 month to 23 months old: ≤ 70 mmHg and decrease from baseline ≥20 mmHg 
24 months/2 years to <6 years old: ≤ 70 mmHg and decrease from baseline ≥20 mmHg 
6 to <12 years old : ≤ 80 mmHg and decrease from baseline ≥20 mmHg 
12 to 16/18 years old : ≤ 90 mmHg and decrease from baseline ≥20 mmHg 
High and increase from baseline 
≥160 mmHg and increase from 
baseline ≥20 mmHg 
Birth/0 to 27 days old : ≥ 85 mmHg and increase from baseline ≥20 mmHg  
28 days/1 month to 23 months old: ≥ 98 mmHg and increase from baseline ≥20 mmHg 
24 months/2 years to <6 years old: ≥ 101 mmHg and increase from baseline ≥20 mmHg 
6 to <12 years old : ≥ 108 mmHg and increase from baseline ≥20 mmHg 
12 to 16/18 years old : ≥ 119 mmHg and increase from baseline ≥20 mmHg 
 
 
 
Diastolic blood pressure supine 
 
 
Low and decrease from baseline 
≤45 mmHg and decrease from 
baseline ≥10 mmHg 
Birth/0 to <6 years old : ≤ 34 mmHg and decrease from baseline ≥10 mmHg  
6 to <12 years old : ≤ 48 mmHg and decrease from baseline ≥10 mmHg 
12 to 16/18 years old : ≤ 54 mmHg and decrease from baseline ≥10 mmHg 
High and increase from baseline 
≥110 mmHg and increase from 
baseline ≥10 mmHg 
Birth/0 to 27 days old : ≥ 50 mmHg and increase from baseline ≥10 mmHg  
28 days/1 month to 23 months old: ≥ 54 mmHg and increase from baseline ≥10 mmHg 
24 months/2 years to <6 years old: ≥ 59 mmHg and increase from baseline ≥10 mmHg 
6 to <12 years old : ≥ 72 mmHg and increase from baseline ≥10 mmHg 
12 to 16/18 years old : ≥ 78 mmHg and increase from baseline ≥10 mmHg 
 
 
 
Heart rate supine (adults) 
 
 
Low and decrease from baseline 
≤50 bpm and decrease from 
baseline ≥20 bpm 
 
High and increase from baseline 
≥120 bpm and increase from 
baseline ≥20 bpm 
 
References: 
- 
for adults: Criteria for Potentially Significant Abnormalities – for Phase 2/3 studies (oncology excepted) - Version 3.0 - 21-MAY-2014 
- 
for children: Criteria for Potentially Clinically Significant Abnormalities for Studies in Children - Version 3.0 - 21-MAY-2014 


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Appendix D 
Flags used in the safety PCSA and abnormality analysis 
Table 2 - Flags for laboratory parameters 
Flags 
Definition 
B 
Baseline value 
L 
Value < LLN 
H 
Value > ULN 
- 
Value reaching the lower PCSA limit of the list 
-- 
Value reaching the second lower PCSA limita 
+ 
Value reaching the upper PCSA limit of the list 
++ 
Value reaching the second upper PCSA limit of the listb 
* 
Value of ALT≥ 3 ULN and total bilirubin ≥ 2 ULN 
# 
Conjugated bilirubin > 35% total bilirubin and total bilirubin > 1.5 ULN  
a applicable to creatinine clearance only for which several potential classes of PCSA are defined 
(moderate and severe classes are flagged in the same way “- -“). 
b for more than 2 upper PCSA limit, “++” flag will be used 
 
Table 3 - Flags for vital signs parameters 
Flags 
Definition 
“B” 
Baseline value 
“-“ 
Value reaching the lower PCSA limit of the list 
“+” 
Value reaching the upper PCSA limit of the list 
 


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Table 4 - Flags for ECG 
Flags 
Definition 
“B” 
Baseline value 
“-“ 
Value reaching the lower PCSA limit of the lista 
“+" 
Value reaching the upper PCSA limit of the listb 
“++” 
Value reaching the second upper PCSA limit of the listc 
a “-“ is applicable to HR 
b “+”is applicable to HR, PR, QRS, borderline QTc ([431-450] ms for males or [451-470] ms for females) and borderline delta 
QTc (delta QTc [30-60] ms). 
c “++” is applicable to prolonged QTc (>450 ms for males or >470 ms for females) and prolonged delta QTc (delta QTc > 60 
ms).