Conditions: New-onset Type 1 Diabetes
Keywords: Type 1 diabetes
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 25
Healthy volunteers: no

Brief summary:
The objective of this clinical trial was to assess whether ladarixin treatment is effective to improve glycemic control in newly diagnosed Type 1 Diabetes (T1D) adult patients with preserved β-cell function.

The safety of ladarixin in the specific clinical setting was also evaluated.

Detailed description:
This was a phase II clinical trial designed as a randomized, double-blind, placebo-controlled, multicenter study to evaluate whether ladarixin is effective in preserving β-cell function and slowing-down the progression of T1D in adult patients with new-onset T1D and preserved β- cell function (fasting C-peptide ≥0.205 nmol/L) at baseline.

Seventy-five (75) patients were to be randomized based on an unbalanced randomization allocation ratio (2:1) to ladarixin hard gelatine capsules for oral administration (2 x 200 mg two times a day \[b.i.d.\] for 13 cycles of 14 days on/14 days off) or matched placebo. Assuming a 10% drop-out rate, approximately 84 patients were expected to be enrolled and to be treated for 1 year.

Each patient was to be involved in the study for a run-in period (screening and baseline assessments) followed by a randomization visit, a treatment period of 12 months, and a post-randomization period up to 18 months from the 1st treatment dose.

The study enrolment was stopped, though, on 28 March 2022, due to low enrolment rate, at the randomization of the 25th patient. The study terminated early, on 11 October 2023 (LPLV).

Due to the early termination of the study, efficacy analyses were reduced in scope given the limited sample size of the study compared with the one expected.

Arms:
arm 1: The treatment group received 400 mg b.i.d. for 13 cycles of 14 days on/14 days off) arm 2: The control group received matched placebo

Interventions: intervention 1: Ladarixin intervention 2: Placebo
Intervention descriptions: intervention 1: 400 mg b.i.d. for 13 cycles of 14 days on/14 days off intervention 2: Placebo was administered orally with the same scheme of administration of LDX to preserve blinding

Protocol document:
Prot_000.pdf: 
St u d y L D X 0 4 1 9  
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P a ge 1  of  6 9  
 
 
 
Versi o n N o. 2  –  fi nal 3 0 J ul y 2 0 2 0   
 
 
 
 
 
 
 
 
C LI NI C A L S T U D Y P R O T O C O L  
A P P LI C A B L E T O T H E U S I N V E S TI G A TI O N A L SI T E S  O N L Y  
 
 
 
St u d y N u m ber:  
L D X 0 4 1 9  
 
E u dr a C T N u m ber:  
2 0 2 0 -0 0 2 9 6 6 -1 5  
 
I N D n u m ber: 
 
 
I n vesti g ati o n al Pr o d uct: 
La d ari xi n  
 
St u d y P h ase:  
2  
 
 
 
 
Title:  A p hase 2 , m ultice nter, ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d st u d y t o assess t he 
efficac y a n d safet y of 4 0 0  m g t wice a da y oral la dari xi n i n patie nts wit h ne w -o nset t y pe 1 
dia betes  a n d preser ve d  -cell f u ncti o n at baseli ne . 
 
 
 
P r ot oc ol Versi o n  - D ate : 
Versi o n N o. 2  fi n al–  3 0  J u l y 2 0 2 0  
 
T his pr ot oc ol versi o n res ults fr o m revisi o n of pr ot oc ol versi o n N o. 1  ( Fi n al, 
) 
acc or di n g t o A me n d me nt N o. 1 ( Fi n al, 3 0 J uly 2 0 2 0 ). Si nce A me n d me nt No. 1 is a p plic a ble t o 
t he U S sites o nly, als o t his pr ot oc ol versi o n will n ot be i m ple me nte d i n a ny of t he ot her 
p artici p ati n g sites o utsi de t he U S.  
 
N O T E : E ve n if t he pr ot oc ol str uct ure  re mai ns m ostl y u naltere d a n d a ntici pates 1 year of  treat me nt ( 1 3 
c ycles), patie nts will be n ot be tre ate d l o n ger t h a n 3 m o nt hs  u ntil a d diti o nal 6/ 9 m o nt h t o xic ol o g y 
data i n rats/ d o gs ha ve bee n re vie we d b y t he F D A.  All pr oce d ures affecte d b y treat me nt le n gt h are eit her 
m o difie d or clearl y la belle d; s pecifi call y, a n y “ gre y para gra p h ” t hr o u g h o ut t he e ntire pr ot oc ol 
te xt/a p pe n dices m ust be re a d i n c o nj u ncti o n wit h t his N O T E . 
 
 
 
 
 
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STATEMENT OF CONFIDENTIALITY 
Information in this protocol and accompanying documents contains privileged or confidential 
information that is the property of Dompé farmaceutici s.p.a. It is understood that the information will 
not be used, divulged, or published without prior written consent of Dompé farmaceutici, except to the 
extent such disclosure is required by applicable laws and regulations. 
 
 


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C O N T A C T I N F O R M A TI O N  
S P O N S O R  
D o m pé far mace utici s. p.a. [ D o m pé] 
Via Sa nta L ucia 6 ; 2 0 1 2 2 Mila n , Ital y 
Me dic al M o nit or i n g 
 
 
Cli nic al O per ati o n  M a n a ger  
 
  
P r oject Direct or 
 
C O N T R A C T R E S E A R C H  
  
O R G A NI Z A TI O N S  ( C R Os) 
 
P r oject Direct or 
 
      
 
      
 
P r oject Direct or  
 
 
P h ar m ac o vi gil a nce:  
 
 
C O O R DI N A TI N G I N V E S TI G A T O R S A N D I N V E S TI G A TI O N A L SI T E S  
F ull l ist of c o or di nati n g i n vesti gat ors a n d i n vesti gati o nal sites f or eac h c o u ntr y i n v ol ve d will be ke pt i n 
t he Trial Master File. A n y up date d  versi o ns, will be file d c hr o n ol o gicall y. C o pies  will be pr o vi de d t o 
t he sites. 
C E N T R A LI Z E D L A B O R A T O RI E S  
A  list of ce ntralize d la b orat ories will be ke pt i n t he Trial Master File. U p date d versi o ns will be file d 
c hr o n ol o gicall y. 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


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P R O T O C O L A P P R O V A L SI G N A T U R E S  
 
S P O N S O R : 
 
Me dical M o nit or i n g 
 
Si g nat ure:   _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
Date:  
 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
 –  Ass ociate Direct or Cli nical De vel o p me nt - Dia betes  
 
Pr oj ect Direct or  
 
Si g nat ure:   _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
Date:  
 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
 –  C hief Me dical Officer  
 
 
C LI NI C A L C E N T E R :  P RI N CI P A L IN V E S TI G A T O R  
I ha ve rea d t he st u d y pr ot oc ol L D X 0 4 1 9  “A p hase 2 , m ultice nter, ra n d o mize d, d o u ble-bli n d, place b o -
c o ntr olle d st u d y t o assess t he efficac y a n d safet y of 4 0 0  m g t wice a da y oral la dari xi n i n patie nts wit h 
ne w -o nset t y pe 1 dia betes a n d preser ve d β -cell f u ncti o n at baseli ne ” a n d a gree t o c o n d uct t he st u d y as 
o utli ne d i n t he pr ot oc ol, a n d i n acc or da nce wit h t he Declarati o n of Helsi n ki, I C H-G C P a n d a n y l ocal 
re g ulati o ns, bei n g res p o nsi ble f or pers o nall y s u per vise t he st u d y c o n d uct a n d e ns ure st u d y st aff c o m plies 
wit h pr ot oc ol re q uire me nt .     
 
Na me of Pri nci pal I n vesti gat or  ( bl oc k letters):_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
Si g nat ure:   _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
Date:  
 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   
 
 
 
 
P P D
P P D


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T A B L E O F C O N T E N T S  
1.  
S T U D Y S Y N O P SI S  A N D O V E R A L L D E SI G N  ........................................................... 1 1  
2.  
B A C K G R O U N D I N F O R M A TI O N  ............................................................................... 1 7  
2. 1.  
R E L E V A N T N O N -C LI NI C A L P H A R M A C O L O G Y  ...................................................... 1 7  
2. 1. 1.  
Mec ha nis m of acti o n a n d i n vitr o acti vit y ......................................................................... 1 7  
2. 1. 2.  
I n viv o ge neral st u dies  ....................................................................................................... 1 7  
2. 1. 3.  
Effects i n m o dels of t y pe 1 dia betes  .................................................................................. 1 8  
2. 2.  
A S U M M A R Y O F T O XI C O L O G Y D A T A  ..................................................................... 1 8  
2. 3.  
P H A R M A C O KI N E TI C S A N D  P R O D U C T M E T A B O LI S M  .......................................... 2 0  
2. 4.  
A S U M M A R Y O F C LI NI C A L D A T A  ............................................................................. 2 1  
2. 4. 1.  
P har mac o ki netics a n d pr o d uct meta b olis m i n h u ma ns  ...................................................... 2 1  
2. 4. 2.  
Efficac y  .............................................................................................................................. 2 1  
2. 4. 3.  
Safet y  ................................................................................................................................. 2 2  
2. 5.  
DI S E A S E R E VI E W A N D S T U D Y R A TI O N A L E  ........................................................... 2 4  
2. 5. 1.  
Selecti o n of d ose a n d treat me nt sc he d ule i n t he st u d y  ...................................................... 2 6  
2. 5. 2.  
Alter nati ve treat me nts  ........................................................................................................ 2 7  
2. 5. 3.  
Ris k - be nefit e val uati o n  .................................................................................................... 2 7  
3.  
O V E R A L L S T U D Y D E SI G N  A N D I N V E S TI A G A TI O N A L P L A N  ......................... 2 9  
3. 1.  
S T U D Y O BJ E C TI V E S  ..................................................................................................... 2 9  
3. 2.  
S T U D Y A D MI NI S T R A TI V E  S T R U C T U R E S, S T A F F A N D R E S P O N SI BI LI T Y  ........ 2 9  
3. 3.  
O V E R A L L S T U D Y D E SI G N  ........................................................................................... 2 9  
3. 4.  
S T U D Y TI M E T A B L E  ..................................................................................................... 3 0  
3. 5.  
E N D O F S T U D Y  ............................................................................................................... 3 0  
4.  
S T U D Y E N D P OI N T S  ..................................................................................................... 3 1  
4. 1.  
E F FI C A C Y E N D P OI N T S  ................................................................................................. 3 1  
4. 2.  
 
4. 3.  
S A F E T Y E N D P OI N T S  ..................................................................................................... 3 1  
5.  
S T U D Y P O P U L A TI O N  .................................................................................................. 3 2  
5. 1.  
I N C L U SI O N C RI T E RI A  .................................................................................................. 3 2  
5. 2.  
E X C L U SI O N C RI T E RI A  ................................................................................................. 3 2  
5. 3.  
A S SI G N M E N T O F P A TI E N T N U M B E R  ........................................................................ 3 3  
6.  
S T U D Y M E DI C A TI O N  .................................................................................................. 3 4  
6. 1.  
P R E S E N T A TI O N, S T O R A G E, P A C K A GI N G A N D L A B E LI N G O F T H E 
I N V E S TI G A TI O N A L M E DICI N A L P R O D U C T  ............................................................ 3 4  
6. 1. 1.  
Prese ntati o n of  I n vesti gati o nal Me dici nal Pr o d uct ............................................................ 3 4  
6. 1. 2.  
Ma n ufact uri n g, Pac ka gi n g a n d La belli n g of I M P ............................................................. 3 4  
6. 1. 3.  
S u p pl y, St ora ge a n d Ha n dli n g of I M P ............................................................................... 3 4  
6. 1. 4.  
Bli n di n g  ............................................................................................................................. 3 5  
6. 2.  
I M P DI S P E N S A TI O N....................................................................................................... 3 5  
6. 3.  
D O S E, R O U T E A N D S C H E D U L E O F  I M P A D MI NI S T R A TI O N ................................ 3 5  
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6.4. 
CRITERIA FOR SCHEDULE ADJUSTMENT/DOSE-MODIFICATION OR 
DISCONTINUATION OF THE IMP................................................................................ 35 
6.4.1. 
Criteria for schedule adjustment or dose modification ...................................................... 35 
6.4.2. 
Criteria for discontinuation of the IMP.............................................................................. 36 
6.5. 
ACCOUNTABILITY OF THE IMP ................................................................................. 36 
6.5.1. 
Assessment of compliance ................................................................................................. 37 
6.6. 
CONCOMITANT MEDICATION ................................................................................... 37 
6.6.1. 
Reporting of prior and concomitant medications .............................................................. 37 
6.6.2. 
Restriction on allowed prior and concomitant medications ............................................... 37 
6.7. 
INSULIN TITRATION ..................................................................................................... 38 
7. 
STUDY PROCEDURE AND ASSESSMENTS ............................................................ 39 
7.1. 
ENROLMENT, SCREENING AND RANDOMIZATION .............................................. 39 
7.1.1. 
Enrolment and Intensive Diabetes Management ............................................................... 39 
7.1.2. 
Run-in period ..................................................................................................................... 39 
7.2. 
RANDOMIZATION & START OF DRUG ADMINISTRATION .................................. 40 
7.3. 
TREATMENT PERIOD AND CHECK OF TREATMENT DISCONTINUATION 
CRITERIA ......................................................................................................................... 40 
7.4. 
ADDITIONAL VISITS DURING TREATMENT AND FOLLOW-UP STUDY 
ASSESSMENTS ............................................................................................................... 42 
7.4.1. 
Additional visits during treatment ..................................................................................... 42 
7.4.2. 
Follow-up assessment ........................................................................................................ 42 
7.5. 
EARLY PATIENT WITHDRAWAL ............................................................................... 43 
7.5.1. 
Withdrawal criteria ............................................................................................................ 43 
7.5.2. 
Replacement policy ........................................................................................................... 43 
7.6. 
PATIENT MANAGEMENT AFTER STUDY COMPLETION ...................................... 43 
8. 
ADVERSE EVENTS ....................................................................................................... 44 
8.1. 
DEFINITIONS .................................................................................................................. 44 
8.1.1. 
Adverse Event .................................................................................................................... 44 
8.1.2. 
Adverse Drug Reaction...................................................................................................... 44 
8.1.3. 
Serious Adverse Event/Reaction ....................................................................................... 44 
8.1.4. 
Unexpected Adverse Events .............................................................................................. 45 
8.1.5. 
Suspected serious unexpected adverse reaction ................................................................. 45 
8.2. 
MONITORING FOR ADVERSE EVENTS ..................................................................... 45 
8.3. 
RECORDING .................................................................................................................... 45 
8.3.1. 
Relationship of AEs to the Investigational Product ........................................................... 45 
8.3.2. 
Severity of AEs .................................................................................................................. 46 
8.4. 
SERIOUS ADVERSE EVENT REPORTING .................................................................. 46 
8.4.1. 
Reporting Procedure for Investigators to Dompé .............................................................. 46 
8.4.2. 
Conditions that should not be reported as serious adverse events ..................................... 47 
8.4.3. 
Follow-Up of Serious Adverse Events .............................................................................. 47 
8.4.4. 
Reporting Procedure to IEC and to Regulatory Authorities in the European Union ......... 47 
8.4.5. 
Reporting Procedure to IRB and to Regulatory Authorities in the United States.............. 48 
8.5. 
EXPOSURE TO INVESTIGATIONAL PRODUCT DURING PREGNANCY .............. 49 
8.6. 
ADVERSE EVENTS CAUSING TREATMENT DISCONTINUATION ....................... 49 
8.7. 
OVERDOSE ...................................................................................................................... 49 
8.8. 
EMERGENCY PROCEDURES ....................................................................................... 50 
9. 
STATISTICAL ISSUES .................................................................................................. 51 


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9. 1.  
S A M P L E SI Z E  .................................................................................................................. 5 1  
9. 2.  
R A N D O MI Z A TI O N  ......................................................................................................... 5 1  
9. 3.  
O V E R VI E W O F P L A N N E D S T A TI S TI C A L A N A L Y S E S  ............................................ 5 1  
9. 4.  
A N A L Y SI S P O P U L A TI O N  ............................................................................................. 5 1  
9. 5.  
S T A TI S TI C A L M E T H O D O L O G Y  .................................................................................. 5 2  
9. 5. 1.  
De m o gra p hic a n d baseli ne c haracteristics  ......................................................................... 5 2  
9. 5. 2.  
A nal ysis of efficac y varia bles  ............................................................................................ 5 2  
9. 5. 3.  
A nal ysis of 
 ...................................................................................... 5 3  
9. 5. 4.  
A nal ysis of safet y varia bles  ............................................................................................... 5 3  
9. 5. 5.  
S pecificati o n of s u b gr o u ps f or a nal ysis  ............................................................................. 5 3  
9. 5. 6.  
Missi n g data  ....................................................................................................................... 5 4  
1 0.  
E T HI C A L C O N SI D E R A TI O N S  ................................................................................... 5 5  
1 0. 1.  
I N D E P E N D E N T E T HI C S CO M MI T T E E (I E C) / I N S TI T U TI O N A L R E VI E W 
B O A R D (I R B)  ................................................................................................................... 5 5  
1 0. 2.  
I N F O R M E D C O N S E N T ................................................................................................... 5 5  
1 0. 3.  
C O N FI D E N TI A LI T Y  ....................................................................................................... 5 6  
1 0. 4.  
C O M P E N S A TI O N F O R M E DI CI N E -I N D U C E D I NJ U R Y A N D 
I N D E M NI FI C A TI O N ....................................................................................................... 5 6  
1 1.  
D A T A H A N D LI N G A N D R E C O R D K E E PI N G  .......................................................... 5 7  
1 1. 1.  
C A S E R E P O R T F O R M S  .................................................................................................. 5 7  
1 1. 2.  
DI A R Y  ............................................................................................................................... 5 7  
1 1. 3.  
D A T A M A N A G E M E N T  .................................................................................................. 5 7  
1 1. 4.  
D O C U M E N T A TI O N R E Q UI R E D P RI O R T O I NI TI A TI O N O F A N D D U RI N G 
T H E S T U D Y  ..................................................................................................................... 5 8  
1 1. 5.  
E S S E N TI A L D O C U M E N T R E T E N TI O N  ....................................................................... 5 8  
1 2.  
S T U D Y M A N A G E M E N T  ............................................................................................... 5 9  
1 2. 1.  
R E G U L A T O R Y B O D Y A P P R O V A L  .............................................................................. 5 9  
1 2 . 2. 
S T A F F I N F O R M A TI O N & R E S P O N SI BI LI TI E S  .......................................................... 5 9  
1 2. 3.  
M O NI T O RI N G  ................................................................................................................. 5 9  
1 2. 3. 1.  
Access t o rec or ds  ............................................................................................................... 5 9  
1 2. 4.  
A U DI T A N D I N S P E C TI O N  ............................................................................................. 6 0  
1 2. 5.  
P R O T O C O L D E VI A TI O N S/ A M E N D M E N T S  ................................................................ 6 0  
1 2. 6.  
DI S C O N TI N U A TI O N O F T H E S T U D Y  ......................................................................... 6 0  
1 2. 7.  
P U B LI C A TI O N S  .............................................................................................................. 6 0  
1 3.  
R E F E R E N C E S  ................................................................................................................ 6 2  
1 4.  
A P P E N DI C E S  .................................................................................................................. 6 4  
1 4. 1.  
A P P E N DI X 1 4. 1 - P A C K A GI N G A N D  L A B E LI N G D E T AI L S ..................................... 6 4  
1 4. 2.  
A P P E N DI X 1 4. 2 –  S T U D Y F L O W C H A R T  ................................................................... 6 5  
1 4. 3.  
A P P E N DI X 1 4. 3 - M E T H O D O L O GI C A L D E T AI L S  ..................................................... 6 7  
1 4. 3. 1.  
Ha n dli n g of sa m ples f or ce ntralize d assa y  ........................................................................ 6 7  
1 4. 3. 2.  
Calc ulati o n of e G F R  .......................................................................................................... 6 7  
1 4. 3. 3 . 
Calc ulati o n of e G D R  ......................................................................................................... 6 8  
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14.3.4. 
Handling of CGM device ................................................................................................... 68 
14.3.5. 
Mixed Meal Tolerance Test ............................................................................................... 69 
 


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Versi o n N o. 2  –  fi nal 3 0 J ul y 2 0 2 0   
 
 
List of A b bre vi ati o ns a n d Defi niti o ns of Ter ms  
 
A E  
A d verse E ve nt  
A D R  
A d verse Dr u g Reacti o n  
A L T  
Ala ni ne A mi n otra nsferase  
A N C O V A  
A nal ysis of C o varia nce  
A S T  
As partate A mi n otra nsferase  
A U C  
Area U n der t he C ur ve  
b.i. d.  
Bis i n die  
B MI  
B o d y Mass I n de x  
B P  
B ull o us P e m p hi g oi d  
 
 
º C 
De grees Celsi us  
C G M  
C o nti n u o us Gl uc ose M o nit ori n g  
C SII  
C o nti n u o us S u bc uta ne o us I ns uli n I nf usi o n  
C K D -E PI  
C hr o nic Ki d ne y Disease E pi de mi ol o g y C olla b orati o n  
C Y P 2 C 9  
C yt oc hr o me P 4 5 0 2 C 9  
C ma x  
Ma xi m u m Plas ma C o nce ntrati o n  
C M E D  
C o nc o mita nt Me dicati o n  
C O N G A -n  
C o nti n u o us O verall Net Gl yce mic Acti o n  
C R A  
Cli nical Researc h Ass ociate  
C R F  
Case Re p ort F or m  
C R O  
C o ntract Researc h Or ga nizati o n  
C X C L 8  
C X C li ga n d 8 [f or merl y i nterl e u ki n (I L)-8]  
C X C R 1/ 2  
C X C L 8 rece pt ors  
D P P -I V i n hi bit or 
Di pe pti d yl p e pti dase -I V i n hi bit or 
E C G  
Electr ocar di o gra m  
e G F R  
Esti mate d Gl o mer ular Filtrati o n Rate  
e G D R  
Esti mate d Gl uc ose Dis p osal Rate  
F A S  
F ull A nal ysis Set  
f M L P 
f or m yl-met -le u-p he  
G A D  
Gl uta mic Aci d Decar b o x ylase  
H b A 1c  
Gl ycate d he m o gl o bi n  
HI V  
H u ma n I m m u n o deficie nc y Vir us  
H L A  
H u ma n Le u k oc yte A nti ge n C o m ple x  
 
  
I A-2  
Islet A nti ge n-2  
I A A 
I ns uli n A ut o A nti b o d y 
I C F 
I nf or me d C o nse nt F or m 
I C H-G C P  
I nter nati o nal C o nfere nce o n H ar m o nizati o n o n G o o d Cli nical Practice 
I E C 
I n de p e n de nt Et hics C o m mitte e 
 
 
I M P 
I n vesti gati o nal Me dici nal Pr o d uct 
I R B 
I nstit uti o nal Re vie w B oar d 
C CI
C CI


St u d y L D X 0 4 1 9  
L a d arixi n i n ne w-o nset T 1 D wit h preserve d -cell f u ncti o n 
P a ge 1 0  of  6 9  
 
 
 
Versi o n N o. 2  –  fi nal 3 0 J ul y 2 0 2 0   
 
 
I T T 
I nte nti o n T o Treat 
I U 
I nter nati o nal U nit 
i. v. 
I ntra ve n o us 
L D 5 0 
Let hal D ose 5 0 
M A G E  
Mea n A m plit u de Gl yce mic E xc ursi o ns  
Me d D R A  
M e dical Dicti o nar y f or Re g ul at or y Acti vities  
 
 
M L D -S T Z  
M ulti ple L o w D ose -Stre pt oz ot oci n  
M DI  
M ulti ple Dail y I nj ecti o ns  
M M R M  
Mi xe d M o dels for Re peate d Meas ures  
M M T T  
Mi xe d Meal T olera nce T est  
M O D D  
Mea n Of t he Dail y Differe nces  
 
 
N G S P  
Nati o nal Gl yc o he m o gl o bi n St a n dar dizati o n Pr o gra m  
N O D  
N o n -O bese Dia betic  
N O E L  
N o O bser va ble Effect Le vel  
P K  
P har mac o ki netics  
P M N  
P ol y m or p h o n uclear le u k oc yte  
p. o.  
per os (ta ke n b y m o ut h)  
P P G  
2 -h o ur p ost pra n dial gl uc ose  
P T  
Preferre d T er m  
Q T c F  
Fri d ericia's c orrecte d Q T i nter val  
S A E  
Seri o us A d verse E ve nt  
S A F  
Safet y P o p ulati o n  
S A P  
Statistical A nal ysis Pla n  
s.c. 
S u bc uta ne o us  
S D  
Sta n dar d De viati o n  
S G L T 2  
S o di u m -Gl uc ose c o -tra ns p orter-2  
S M B G  
Self -M o nit ori n g of Bl o o d Gl uc ose  
S O C  
S yste m Or ga n Class  
T E A E  
Treat me nt E mer ge nt A d verse E ve nt  
T E S A E  
Treat me nt E mer ge nt Seri o us A d verse E ve nt  
TI R  
Ti me i n Ra n ge  
T 1 D  
T y pe 1 Dia b etes  
U L N  
U p per Li mit of N or mal  
Z n T 8  
Zi nc Tra ns p orter Is of or m 8  
C CI
C CI


St u d y L D X 0 4 1 9  
L a d arixi n i n ne w-o nset T 1 D wit h preserve d -cell f u ncti o n 
P a ge 1 1  of  6 9  
 
 
 
Versi o n N o. 2  –  fi nal 3 0 J ul y 2 0 2 0   
 
 
1.  
S T U D Y S Y N O P SI S A N D O V E R A L L D E SI G N   
 
St u d y title  
A p hase 2 , m ultice nter, ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d st u d y t o assess t he efficac y a n d 
safet y of 4 0 0  m g t wice a da y oral la dari xi n i n patie nts wit h ne w -o nset t y pe 1 dia betes a n d preser ve d β -
cell f u ncti o n at baseli ne . 
 
St u d y N u m ber  L D X 0 4 1 9  
  
 
 
[E u dr a C T N u m ber:  2 0 2 0 -0 0 2 9 6 6 -1 5 ]  
 
 
 
 
St u d y peri o d  
Pr oj ecte d  starti n g date (first -patie nt -i n): Q 4 -2 0 2 0  
 
Pr oj ecte d c o m pleti o n of patie nt accr ual (last -patie nt -i n): Q 2 -2 0 2 2  
 
 
 
Pr oj ecte d st u d y e n d date (last -patie nt -last-visit):  Q 4 -2 0 2 3  
 
 
St u d y desi g n  
T he st u d y will be a p hase 2, m ultice nter, d o u ble -bli n d, place b o -c o ntr olle d st u d y. It will ra n d o mize 
a p pr o xi matel y 7 5 a d ult patie nts wit h ne w -o nset t y pe 1 dia betes ( T 1 D ) a n d preser ve d -cell f u ncti o n 
(fasti n g C -pe pti de > 0. 2 0 5 n m ol/l ) at baseli ne . Patie nts will be assi g ne d ( 2: 1) t o recei ve eit her oral 
la dari xi n treat me nt ( 4 0 0 m g b.i. d. f or 1 3 c ycles of 1 4 da ys o n/ 1 4 da ys off - treat me nt gr o u p) or place b o 
(c o ntr ol gr o u p). Recr uit me nt will be c o m petiti ve a m o n g t he st u d y sites, u ntil t he pla n ne d n u m ber of 
patie nts is ra n d o mize d.  
 
La dari xi n a n d place b o will be b ot h a d mi nistere d f or 1 year. All patie nts will be f oll o we d -u p f or 1 8  
m o nt hs  fr o m t he 1st a d mi nistrati o n of t he st u d y me dicati o n. T he st u d y data base will be l oc ke d a n d data 
a nal yze d w he n t he last patie nt ra n d o mize d has c o m plete d m o nt h 1 2 f oll o w -u p visit . After t his ti me 
p oi nt , t he f oll o w-u p will c o nti n ue u n der o pe n -la bel c o n diti o ns u p t o m o nt h 1 8,   
 
O bjecti ves/e n d p oi nts  
T he o bjecti ve of t his cli nical trial is t o e val uate w het her a 1 2 m o nt h treat me nt wit h la dari xi n is effecti ve 
t o i m pr o ve gl yce mic c o ntr ol i n ne wl y dia g n ose d T 1 D a d ult patie nts  wit h preser ve d -cell f u ncti o n . T he 
safet y of la dari xi n i n t he s pecific cli nical setti n g will be als o e val uate d. 
Details of st u d y e n d p oi nts are re p orte d bel o w, wit h rele va nt ti me fra me w here:  
M o nt h 6 = Wee k 2 6 + 2; M o nt h 1 2 = Wee k 5 2 + 2; M o nt h 1 8 = Wee k 7 8 + 2;    
 
Effic ac y e n d p oi nts will be : 
- Pr o p orti o n of patie nts wit h H b A 1c < 7 % a n d dail y i ns uli n re q uire me nt < 0. 5 0 I U/ K g/ da y [P ri m ar y 
e n d p oi nt.  Ti me fra me: M o nt h 1 2]  
 
Sec o n dar y e n d p oi nts : 
- Pr o p orti o n of patie nts wit h H b A 1c <  7 % a n d dail y i ns uli n re q uire me nt < 0. 5 0 I U/ K g/ da y [ Ti me 
fra me: M o nt h 6 a n d 1 8 ] 
- Pr o p orti o n of patie nts wit h a re d ucti o n i n H b A 1c %  > 0. 5 % fr o m baseli ne a n d  dail y i ns uli n 
re q uire me nt < 0. 5 0 I U/ K g [ Ti me fra me: M o nt h 6 , 1 2, 1 8 ] 
- 2 -h o ur A U C of C -pe pti de res p o nse t o t he M M T T [ Ti me fra me: M o nt h 6, 1 2, 1 8]    
- Ti me i n ra n ge ( TI R ) b y C o nti n u o us Gl uc ose M o nit ori n g (C G M ) [ Ti me fra me: M o nt h 6, 1 2, 1 8 ]  
- H b A 1c le vels [ Ti me fra me: M o nt h 6, 1 2, 1 8 ]    
- Pr o p orti o n of patie nts wit h H b A 1c <  7 % w h o di d n ot e x perie nce se vere h y p o gl yce mic e ve nts 
d uri n g treat me nt [ Ti me fra me: M o nt h 6, 1 2, 1 8 ] 
- A d diti o nal Gl uc ose Varia bilit y I n dices  deri ve d fr o m C G M ( gl uc ose A U C o utsi de t he tar get ra n ge 
of 7 0 –  1 8 0 m g/ d L, 2 -h o ur p ost pra n dial gl uc ose ( P P G ), Mea n A mplit u de Gl yce mic E xc ursi o ns 
(M A G E ), c o nti n u o us o verall net gl yce mic acti o n (C O N G A )-n, Mea n Of t he Dail y Differe nces 
(M O D D ), a n d mea n dail y bl o o d gl uc ose, S D ( Sta n dar d De viati o n) . [ Ti me fra me: M o nt h 6, 1 2, 1 8 ]. 
- N u m ber of self -re p orte d e pis o des of se vere h y po gl yce mia [ Ti me fra me: M o nt h 6, 1 2, 1 8 ] 
C CI


St u d y L D X 0 4 1 9  
L a d arixi n i n ne w-o nset T 1 D wit h preserve d -cell f u ncti o n 
P a ge 1 2  of  6 9  
 
 
 
Versi o n N o. 2  –  fi nal 3 0 J ul y 2 0 2 0   
 
 
- A vera ge ( pre vi o us 3 da ys) dail y i ns uli n re q uire me nts (I U/ k g/ da y) [ Ti me fra me: M o nt h 6, 1 2, 1 8 ]  
- E sti mate d Gl uc ose Dis p osal Rate (e G D R) [ Ti me fra me: M o nt h 6, 1 2, 1 8 ]  
 
  
 
 
 
 
 
 
 
 
      
 
 
S af et y e n d p oi nts will be:  
- Vital si g ns ( bl o o d press ure a n d heart rate) [ti me fra me: e n d of t he 3 r d ( Wee k 1 1), 6 t h ( Wee k 2 3), 9t h 
( Wee k 3 5) treat me nt c ycle, M o nt h 1 2  a n d 1 8] 
- Safet y L a b orat or y T ests (he mat ocrit, he m o gl o bi n, re d bl o o d cells, platelets, w hite bl o o d cells, 
differe ntial w hite bl o o d cells c o u nt, s o di u m, p otassi u m, ser u m creati ni ne, ser u m al b u mi n, t otal 
bilir u bi n, A L T, A S T ) [ti me fra me: e n d of t he 3 r d ( Wee k 1 1), 6 t h ( Wee k 2 3), 9t h ( Wee k 3 5) treat me nt 
c ycle, M o nt h 1 2 a n d 1 8 ( or wit h dra wal)] 
- I nci de nce of A d verse E ve nts ( A Es) a n d Seri o us A d verse E ve nts ( S A Es) [time fra me: t hr o u g h o ut t he 
st u d y]   
 
N u m ber of p atie nts: 7 5 a d ult ( 18 -4 5  years i ncl usi ve)  patie nts wit h ne w o nset T 1 D a n d preser ve d 
resi d ual β -cell f u ncti o n at baseli ne . 
 
I ncl usi o n/e xcl usi o n criteri a 
C o nse nte d male a n d fe male patie nts a ge d 18 -4 5 years , i ncl usi ve, wit h n e w-o nset T 1 D (ra n d o mizati o n 
sc he d ule d t o all o w t he a d mi nistrati o n of t he st u d y me dicati o n t o start wit hi n 1 0 0 da ys fr o m 1 st i ns uli n 
a d mi nistrati o n). Patie nts m ust be p ositi ve f or at least o ne dia betes -relate d a ut o-a nti b o d y (a nti -G A D; 
I A A, if o btai ne d wit hi n 1 0 da ys of t he o nset of i ns uli n t hera p y; I A-2 a nti b o d y; Z n T 8); m ust re q uire, or 
ha ve re q uire d i ns uli n deli vere d via m ulti ple dail y i njecti o ns ( M DI ) or C o nti n u o us S u bc uta ne o us I ns uli n 
I nf usi o n (C SII ); m ust ha ve a fasti n g C-pe pti de ≥0. 2 0 5 n m ol/ L  o n t w o occasi o ns . 
 
Patie nts will be e xcl u de d if t he y ha ve a n y  ot her c hr o nic disease (i ncl u di n g t y pe 2 dia betes), a part fr o m 
patie nts wit h a ut oi m m u ne h y p ot h yr oi dis m re q uiri n g t h yr oi d h or m o ne re place me nt o nl y; m o derate t o 
se vere re nal i m pair me nt calc ulate d b y esti mate d Gl o mer ular Filtrati o n Rate ( e G F R) < 6 0 m L/ mi n/ 1. 7 3 
m 2  as deter mi ne d usi n g C hr o nic Ki d ne y Disease E pi de mi ol o g y C olla b orati o n  (C K D -E PI ) creati ni ne 
e q uati o n;  he patic d ysf u ncti o n (i ncrease d A L T/ A S T > 3 x u p per li mit of n or mal a n d i ncrease d t otal 
bilir u bi n > 3 m g/ d L [ > 5 1. 3 μ m ol/ L]); h y p oal b u mi ne mia (ser u m al b u mi n < 3 g/ d L); a Q T c F > 4 7 0 msec.; 
a hist or y of si g nifica nt car di o vasc ular disease/a b n or malit y; occ urre nce of a n e pis o de of ket oaci d osis or 
h y p o gl yce mic c o ma i n t he past 2 wee ks; a k n o w n h y perse nsiti vit y t o n o n -ster oi dal a nti-i nfla m mat or y 
dr u gs. Patie nts o n t reat me nt wit h dr u gs meta b olize d b y C Y P 2 C 9 wit h a narr o w t hera pe utic i n de x [i.e., 
p he n yt oi n, warfari n, s ul p ha n yl urea h y p o gl yce mics a n d hi g h d ose of a mitri pt yli ne ( > 5 0 m g/ da y)]; 
patie nts wit h past ( wit hi n 2 wee ks pri or t o ra n d o mizati o n) or c urre nt use of a nt i dia betic a ge nts as 
metf or mi n, s ulf o n yl ureas, gli ni des, t hiaz oli di ne di o nes, e xe nati de, lira gl uti de, D P P -I V i n hi bit ors, S G L T-
2 i n hi bit ors or a m yli n, or a n y me dicati o ns k n o w n t o i nfl ue nce gl uc ose t olera nce (e. g. -bl oc kers, 
a n gi ote nsi n -c o n verti n g e nz y me i n hi bit ors, i nterfer o ns, q ui ni di ne a nti malarial dr u gs, lit hi u m, niaci n, 
etc.) will als o be e xcl u de d. Patie nts will be e xcl u de d as well i n case of past ( wit hi n 1 m o nt h pri or t o 
ra n d o mizati o n) or c urre nt a d mi nistrati o n of a n y i m m u n os u p pressi ve me dicati o ns (i ncl udi n g oral, 
i n hale d or s yste micall y i njecte d ster oi ds) a n d use of a n y i n vesti gati o nal a ge nts, i ncl u di n g a n y a ge nts 
t hat i m pact t he i m m u ne res p o nse or t he c yt o ki ne s yste m. A d diti o nal e xcl usi o n criteria will be: 
si g nifica nt s yste mic i nfecti o n d uri n g t he 4 weeks bef ore t he  first d ose of st u d y dr u g (e. g. i nfecti o n 
re q uiri n g h os pitalizati o n, maj or s ur ger y, or i. v. a nti bi otics t o res ol ve; ot her i nfecti o ns, e. g., br o nc hitis, 
si n usitis, l ocalize d cell ulitis, ca n di diasis, or uri nar y tract i nfecti o ns, m ust be assesse d  o n a case -b y -case 
basis b y t he i n vesti gat or re gar di n g w het her t he y are seri o us e n o u g h t o warra nt e xcl usi o n) ; he patitis A  
(I g M), he patitis B  ( n ot d ue t o i m m u nizati o n), he patitis  C a n d HI V  p ositi ve ser ol o gic stat us . Als o, 
p re g na nt or breastfee di n g w o me n or patie nts u n willi n g t o use effecti ve c o ntrace pti ve meas ures (fe males 
C CI


Study LDX0419 
Ladarixin in new-onset T1D with preserved -cell function 
Page 13 of 69 
 
 
 
Version No. 2 – final 30 July 2020  
 
 
and males) will be excluded. 
 
Investigational Medicinal Product 
The investigational medicinal product will be either ladarixin OR placebo capsules for oral 
administration. Ladarixin will be administered orally at the dose of 400 mg twice a day at about 12-hour 
interval (morning and evening) for 13 cycles of 14 days on treatment with an interval of 14 days off 
treatment between cycles. Placebo will be administered with the same schedule. IMP will be dispensed 
as Patient Kits. 
 
Discontinuation criteria 
Administration of the investigational medicinal product will be discontinued in case the QTcF becomes 
either >500 msec. or increases by >60 msec. from baseline measurement on two consecutive 
measurements 1 hour apart, or if the patient develops any significant cardiovascular disease/abnormality. 
Similarly, administration of the investigational medicinal product will be discontinued in the case the 
patient develops renal (eGFR <60mL/min/1.73 m2) or hepatic (ALT/AST >3 x ULN and total bilirubin 
>3mg/dL) dysfunction as well as hypoalbuminemia (serum albumin <3 g/dL). Lastly, administration of 
the investigational product will be immediately discontinued if the patient becomes pregnant, develops 
any significant systemic infection that must be assessed on a case-by-case basis by the investigator 
regarding whether they are serious enough to warrant discontinuation, ketoacidosis or hypoglycemic 
coma. Occurrence of any condition that qualify the patient to treatment discontinuation will be 
specifically monitored through ECG readings and laboratory tests obtained at visits scheduled at the end 
of the 3rd (Week 11), 6th (Week 23), 9th (Week 35) treatment cycles. In addition, the investigational 
medicinal product will be immediately discontinued in the event of any other possibly drug related 
occurrences that the Investigator believes might compromise patient’s safety.  
 
Procedures 
Potential study patients with a recent clinical diagnosis of T1D with a fasting C-peptide >0.205 nmol/L 
on two occasions; these patients will be considered if they fall within the definition of new-onset T1D 
(randomization scheduled to allow the administration of the study medication to start within 100 days 
from 1st insulin administration) and will have diagnosis (positive for at least one auto-antibody).  
 
Each patient will be involved in the study for a run-in period (one or more visits) and the randomization 
visit, followed by a treatment period of 12 months. During treatment, 5 visits will be scheduled at the 
end of the 3rd (Week 11) and 6th (Week 23) treatment cycles, at Month 6 (Week 26), at the end of the 9th 
(Week 35) treatment cycles, and at Month 12 (Week 52) after the 1st dose of study treatment. An 
additional post-treatment visit will be scheduled at Month 18. Study period/visits are summarized in the 
study flow chart (see Appendix 14.2) 
 
Screening to Randomization  
Screening will be performed in patients who has given consent for this LDX0419 trial.  
Patients will be admitted to an intensive diabetes management to ensure standardized glycemic control 
in the treatment groups. The Investigator will refer to a guidance for insulin regimen adjustment, with 
insulin titrated up or down to target HbA1c levels of less than 7% and self-monitoring of blood glucose 
(SMBG - fingerstick or CGM) of: 
- pre-prandial blood glucose of 70-130 mg/dL, 
- 2 hours post-prandial blood glucose <180 mg/dL, 
- bed-time blood glucose of 110-150 mg/dL. 
Glucose test strips and glucose monitor will be provided to participants for the duration of the study. 
In order to optimize insulin titration, periodic controls (e.g. telephone calls) will be put in place to ensure 
timely evaluation of metabolic control and adjustment of insulin regimen. Patients will report their 
SMBG (logs, glucose meter, etc.) at predefined intervals.    
 
Screening includes evaluation of past medical history and disease-specific clinical information, 
including date of first insulin administration, and blood sampling for measurement (centralized 


St u d y L D X 0 4 1 9  
L a d arixi n i n ne w-o nset T 1 D wit h preserve d -cell f u ncti o n 
P a ge 1 4  of  6 9  
 
 
 
Versi o n N o. 2  –  fi nal 3 0 J ul y 2 0 2 0   
 
 
la b orat or y) of a ut o-a nti b o d y (a nti -G A D; I A A, if o btai ne d wit hi n 1 0 da ys of t he o nset of i ns uli n t hera p y; 
I A-2 a nti b o d y; Z n T 8) t o c o nfir m T 1 D dia g n osis a n d of fasti n g C-pe pti de .  
 
O nce t he criteria  a b o ve ha ve bee n f ulfille d, patie nts wi ll pr o gress t o t he f oll o wi n g B aseli ne assess me nts  
(ti me f r a me: wit hi n 3 wee ks bef ore treat me nt start) : 
- 
Vital si g ns.  
- 
B o d y wei g ht, hei g ht, waist a n d waist/ hi p circ u mfere nce . 
- 
E val uati o n of e G D R a n d B MI.  
- 
Bl o o d sa m pli n g(s) f or meas ure me nt (l ocal la b orat ories) of “ Safet y La b orat or y T ests” . 
- 
E val uati o n of re nal a n d he patic f u ncti o n (t o be deri ve d fr o m t he safet y la b orat or y test res ults).  
- 
Scree ni n g 1 2 lea d E C G, perf or me d usi n g l ocal e q ui p me nt t hat all o ws a ut o matic calc ulati o n of t he 
Q T c F.  
- 
Pre g na nc y test ( uri ne di pstic k or bl o o d sa m ple), if a p pr o priate.  
- 
Baseli ne dail y i ns uli n re q uire me nt (I U/ k g/ da y a vera ge d o ver t he pre vi o us 3 da ys).  
- 
Bl o o d sa m pli n g f or meas ure me nt (ce ntralize d la b orat or y) of baseli ne H b A 1c.  
- 
Bl o o d sa m pli n g f or meas ure me nt (ce ntralize d la b orat or y) of H L A D R -D Q h a pl ot y pes a n d 
Pr oi ns uli n.  
- 
Baseli ne M M T T. Bl o o d sa m ples f or meas ure me nt (ce ntralize d la b orat or y) of C -pe pti de a n d 
gl uc ose will be dra w n pre -meal ( 2 basal sa m ples i n t he ra n ge bet wee n -2 0 t o 0) a n d 1 5, 3 0, 6 0, 
9 0, 1 2 0 mi n after t he meal.   
- 
E val uati o n  of P r oi ns uli n: C -pe pti de rati o.   
- 
C G M d o w nl oa d f or e val uati o n of baseli ne Gl uc ose Varia bilit y I n dices fr o m C G M.  * *  
- 
Bl o o d sa m pli n g f or meas ure me nt (ce ntralize d la b orat or y)  of 
 
. 
 
* * T he C G M de vice will be p ositi o ne d at least 1 0 da ys bef ore t he baseli ne assess me nt.   
 
Patie nts f ulfilli n g all  t he i ncl usi o n criteria a n d n o ne  of t he e xcl usi o n criteria will refer t o t he site f or a 
ra n d o mizati o n visit t o occ ur wit hi n ma xi m u m 3 da ys bef ore t he I M P a d mi nistrati o n is starte d; d uri n g 
t his visit a ra n d o mizati o n n u m ber will be all ocate d t o t he patie nt ; t he Patie nt Diar y will be deli vere d t o 
t he patie nt a n d t he Patie nt Kits f or t he 1 st t o 3r d treat me nt c ycles will be dis pe nse d. 
 
Tre at me nt peri o d a n d c heck of tre at me nt disc o nti n u ati o n criteri a  
T he a d mi nistrati o n of t he i n vesti gati o nal me dici nal pr o d uct will start o n D a y 1  of t he 1 st treat me nt c ycle. 
D a y 1  M U S T be sc he d ule d n o l ater t h a n 1 0 0 d a ys fr o m t he 1
st i ns uli n i njecti o n a n d is t o be sc he d ule d 
wit hi n 3 wee ks fr o m t he baseli ne assess me nts.  
 
Treat me nt will pr ocee d f or a d diti o nal 1 2 c ycles of 1 4 da ys o n/ 1 4 da ys off.  
Assess me nt s t o be d o ne bef ore t he 1st d ose i n t he 1 st treat me nt c ycle are part of t he baseli ne assess me nt .  
T hereafter, occ urre nce of a n y c o n diti o n t hat mi g ht pre ve nt c o nti n ui n g I M P a d mi nistrati o n (as per 
disc o nti n uati o n criteria a b o ve) will be verifie d at s pecific visits  sc he d ule d at t he e n d of t he 3 r d ( Wee k 
1 1) , 6t h ( Wee k 2 3) a n d 9t h ( Wee k 3 5) treat me nt c ycles.  
D uri n g t hese visits  t he f oll o wi n g will be meas ure d/ assesse d: 
- 
Vital si g ns.  
- 
Bl o o d sa m pli n g(s) f or meas ure me nt (l ocal la b orat ories) of “ Safet y La b orat or y T ests” . 
- 
E val uati o n of re nal a n d he patic f u ncti o n (t o be deri ve d fr o m t he safet y la b orat or y test res ults).  
- 
1 2 lea d E C G, perf or me d usi n g l ocal e q ui p me nt t hat all o ws a ut o matic calc ulati o n of t he Q T c F.  
- 
Pre g na nc y test ( uri ne di pstic k or bl o o d sa m ple) . 
- 
Patie nt Diar y c h ec k (I M P a d mi nistrati o n i nf or mati o n). 
 
Patie nt Kits f or t he 4 t h t o 1 3t h c ycles  will be dis pe nse d t o t he patie nt i n a p pr o priate batc hes o nl y  after 
c o m plia nce wit h criteria f or dr u g a d mi nistrati o n has bee n c o nfir me d.  
Res ults of A L T/ A S T, bilir u bi n, creati ni ne, ser u m al b u mi n, E C G rea di n g a n d pre g na nc y test s h o ul d be 
ma de a vaila ble b y t he l ocal la b orat or y i n ti me t o all o w Patie nt Kits dis pe nsati o n as s o o n as p ossi ble 
C CI


St u d y L D X 0 4 1 9  
L a d arixi n i n ne w-o nset T 1 D wit h preserve d -cell f u ncti o n 
P a ge 1 5  of  6 9  
 
 
 
Versi o n N o. 2  –  fi nal 3 0 J ul y 2 0 2 0   
 
 
d uri n g t he visit. If t his e x pe dite ti mi n g ca n n ot be ac h ie ve d, Patie nt Kits mi g ht be deli vere d t o patie nt 
na me d a d dress b y a selecte d c o urier ( C R O t o s u p p ort s hi p me nt).  
 
Ot her visits  sc he d ule d d uri n g tre at me nt  
D uri n g treat me nt , patie nt will atte n d t he ce nter f or st u d y assess me nts o n a d diti o nal 2  visits at M o nt h  6 
( Wee k 2 6) a n d M o nt h 1 2 ( Wee k 5 2). At least 1 0  da ys bef ore eac h sc he d ule d visit, t he C G M se ns or will 
be p ositi o ne d.  
 
D uri n g t hese visits  t he f oll o wi n g will be assesse d: 
- 
W aist a n d waist/ hi p circ u mfere nce  a n d calc ulati o n of e G D R.  
- 
Patie nt Diar y c hec k ( i nf or mati o n other t hat I M P a d mi nistrati o n at M o nt h 6, a n y i nf or mati o n at 
M o nt h 1 2 ) 
- 
I ns uli n re q uire me nt (I U/ k g/ da y a vera ge d o ver t he pre vi o us 3 da ys).   
- 
N u m ber of self -re p orte d e pis o des of se vere h y p o gl yce mia i n t he i nter val. 
- 
Bl o o d sa m pli n g f or meas ure me nt (ce ntralize d la b orat or y) of H b A 1c. 
- 
M M T T.  Bl o o d sa m ples f or meas ure me nt (ce ntralize d la b orat or y) of C -pe pti de a n d gl uc ose will 
be dra w n pre -meal ( 2 basal sa m ples i n t he ra n ge bet wee n -2 0 t o 0) a n d 1 5, 3 0, 6 0, 9 0, 1 2 0 mi n 
after t he meal.   
- 
Bl o o d sa m pli n g f o r meas ure me nt (ce ntralize d la b orat or y) of 
 
.  
- 
C G M d o w nl oa d f or e val uati o n of Gl uc ose Varia bilit y I n dices fr o m C G M.  
- 
Bl o o d sa m pli n g f or meas ure me nt (l ocal la b orat ories) of “ Safet y La b orat or y T ests” ( M o nt h 1 2 
o nl y).  
- 
Vital si g ns ( M o nt h 1 2 o nl y).  
 
P ost -tre at me nt f oll o w-u p visit  
At t his visit, sc he d ule d o n M o nt h 1 8 ( Wee k 7 8) t he f oll o wi n g will be e val uate d/ meas ure d: 
- 
W aist a n d waist/ hi p circ u mfere nce a n d e val uati o n of e G D R.  
- 
I ns uli n re q uire me nt (I U/ k g/ da y a vera ge d o ver t he pre vi o us 3 da ys).  
- 
N u m ber of self -re p orte d e pis o des of se vere h y p o gl yce mia i n t he i nter val.  
- 
Bl o o d sa m pli n g f or meas ure me nt (ce ntralize d la b orat or y) of H b A 1c.  
- 
M M T T.  Bl o o d sa m ples f or meas ure me nt (ce ntraliz e d la b orat or y) of C -pe pti de a n d gl uc ose will 
be dra w n pre -meal ( 2 basal sa m ples i n t he ra n ge bet wee n -2 0 t o 0) a n d 1 5, 3 0, 6 0, 9 0, 1 2 0 mi n 
after t he meal.  
- 
C G M d o w nl oa d f or e val uati o n of Gl uc ose Varia bilit y I n dices fr o m C G M.   
- 
Bl o o d sa m pli n g f or meas ure me n t (ce ntralize d la b orat or y) of 
 
. 
- 
Patie nt Diar y c hec k (i nf or mati o n ot her t ha n I M P a d mi nistrati o n)  
- 
Bl o o d sa m pli n g f or meas ure me nt  (l ocal la b orat ories) of “ Safet y La b orat or y T ests”. 
- 
Vital si g ns.  
 
St atistics  
T he sa m ple size of t he st u d y is calc ulate d o n t he “ pr o p orti o n of patie nts wit h a H b A 1c <  7 % a n d dail y 
i ns uli n re q uire me nt < 0. 5 0 I U/ K g/ da y”, a p ost -h oc c o m p osite e n d p oi nt  deri ve d fr o m data of t he p hase 2 
trial 
, c o nsi deri n g a lar ger effect size e x p ecte d fr o m t he l o n ger treat me nt le n gt h ( o ne year 
vers us 3 m o nt hs). Base d o n t hese ass u m pti o ns, 7 5 patie nts ra n d o mize d i n t he trial will all o w t o ac hie ve 
a p o wer of a p pr o xi mati vel y 8 0 % t o s h o w s u peri orit y of la dari xi n vs place b o i n ter ms of pri mar y 
e n d p oi nt , c o nsi deri n g a o ne-si de d al p ha of 0. 0 5 a n d a dr o p-o ut rate of 1 0 %.  
S u m mar y statistics ha ve bee n defi ne d f or q ua ntitati ve varia bles ( n u m ber of o bser vati o ns, mea n, sta n dar d 
de viati o n, me dia n, mi ni m u m a n d ma xi m u m) a n d q ualitati ve varia bles ( n u m ber a n d perce n ta ge per 
cate g or y). If a p pr o priate, c o nfi de nce i nter vals ar o u n d t he mea n or t he pr o p orti o ns will be prese nte d. 
T he pr o p orti o n of patie nts wit h H b A 1c <  7 %  a n d dail y i ns uli n re q uire me nt < 0. 5 0 I U/ K g/ da y at M o nt h 
1 2 ( p ri mar y e n d p oi nt) will be a nal yze d b y mea ns of l o gistic re gressi o n . 
C CI
C CI
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Version No. 2 – final 30 July 2020  
 
 
All secondary endpoints will be analysed at each available timepoint by means of descriptive statistics 
and by appropriate parametric tests. Change from baseline value and shift tables versus baseline will be 
summarized for all post-baseline visits.  
AEs will be presented in terms of the number of AEs and incidence. Other safety parameters will be 
summarized by treatment at each available visit by means of descriptive statistics.  
The Safety and the Full Analysis Set population will consist of all patients who will be randomized and 
received at least one dose of the investigational product. Safety population will be analyzed according 
to the actual treatment received; Full Analysis Set population will be analyzed according to ITT 
principle, i.e. by treatment allocation. Primary and secondary efficacy analyses will be conducted on the 
FAS population while the SAF population will be used for safety analyses. 
The Statistical Analysis Plan (SAP) will be issued with more technical and detailed elaboration of the 
principal features of statistical analyses. Any deviation from the original statistical plan will be described 
in the Clinical Study Report.  
    


St u d y L D X 0 4 1 9  
L a d arixi n i n ne w-o nset T 1 D wit h preserve d -cell f u ncti o n 
P a ge 1 7  of  6 9  
 
 
 
Versi o n N o. 2  –  fi nal 3 0 J ul y 2 0 2 0   
 
 
2.  
B A C K G R O U N D I N F O R M A TI O N  
La dari xi n ( la dari xi n) is a n o vel s mall m olec ule t hat i n hi bits t he bi ol o gical acti vit y of t he C X C li ga n d 8 
[C X C L 8 ; f or merl y i nterle u ki n (I L)-8] t hr o u g h i n hi biti o n of t he acti vati o n of C X C L 8 rece pt ors: C X C R 1 
a n d C X C R 2. T his s pecific i n hi bit or ste ms fr o m a pr o gra m of dr u g desi g n of m olec ules i nte n de d t o 
m o d ulate c he m o ki ne acti o n.  
Ori gi nal de vel o p me nt pla n of la dari xi n was tar gete d t o t he der mat ol o gical area wit h a p hase 2  st u d y i n 
. F oll o wi n g m ore rece nt pr o misi n g res ults i n 
m o use m o dels of t y pe 1 dia betes ( T 1 D ) a n d fi n di n gs o btai ne d fr o m t he p hase 2 cli nical trial i n ne w-
o nset T 1 D , de vel o p me nt i n ne w o nset T 1 D has bee n p urs ue d . 
Rele va nt pre -cli nical, t o xic ol o gical a n d cli nical data are s u m marize d bel o w. Please als o refer t o t he 
In vesti gat or’s Br oc h ure f or detaile d i nf or mati o n.      
2. 1.  
R E L E V A N T N O N -C LI NI C A L P H A R M A C O L O G Y  
2. 1. 1.  
Mec h a nis m of acti o n a n d i n vitr o acti vit y  
La dari xi n  is a n o vel, p ote nt a n d s pecific i n hi bit or of t he bi ol o gical acti vit y of t he c he m o ki ne C X C L 8.  
I n vitr o c he m ota xis e x peri me nts ha ve s h o w n t ha t la dari xi n, i n t he l o w na n o m olar ra n ge, i n hi bits h u ma n 
p ol y m or p h o n uclear le u k oc yte ( P M N ) mi grati o n i n d uce d b y h u ma n C X C L 8 rece pt ors acti vati o n.  
C he m ota xis of r o de nt P M N i n d uce d b y m o use a n d rat c o u nter parts of h u ma n C X C L 8 is als o i n hi bite d, 
i n dicati n g t hat mice a n d rats are a p pr o priate a ni mal s pecies f or precli nical st u dies. St u dies o n t he 
m ec ha nis m of acti o n ha ve s h o wn  t hat la dari xi n is a n o n-c o m petiti ve all osteric i n hi bit or of t he C X C L 8 
rece pt ors: C X CR 1 a n d C X C R 2  [M oric o ni , 2 0 07 ]. T he selecti vit y of la dari xi n o n C X C R 1 a n d C X C R 2 
is pr o ve n b y its lac k of efficac y a gai nst P M N mi grati o n i n d uce d b y f M L P or C 5a a n d a gai nst h u ma n 
m o n oc yte c he m ota xis i n d uce d b y C C L 2.   
D F 2 1 5 6 A ( 0. 1 n M - 1 µ M) res ults a p ote nt i n hi bit or of I L -8 -i n d uce d N E Ts release fr o m is olate d h P M N, 
wit h I C 5 0 -val ue of ≈ 1 n M a n d I C ma x -val ue of 1 µ M). C o here ntl y wit h t he selecti vit y data o bser ve d 
i n t he c he m ota xis assa y, D F 2 1 5 6 A ( 1 µ M) di d n ot affect C5a, f M L P a n d P M A -i n d uce d N E Ts release. 
D F 2 1 5 6 A ( 1 - 6 0 µ g/ m L) is als o a ble t o bl oc k I L -8 -i n d uce d N E Ts f or mati o n i n h u ma n w h ole bl o o d i n 
a c o nce ntrati o n de pe n de nt ma n ner wit h a c o m plete i n hi biti o n at 6 0 µ g/ m L. Fi nall y, t he efficac y of D F 
2 1 5 6 A ( 1 - 6 0 µ g/ m L)  is e vi de nt o n m C X C L 1-me diate d N E Ts release i n m uri ne w h ole bl o o d i n a 
c o nce ntrati o n de pe n de nt ma n ner bei n g t he i n hi biti o n c o m plete at 6 0 µ g/ m L.  
2. 1. 2.  
I n vi v o ge ner al st u dies  
I n viv o, la dari xi n ( 4-1 6 m g/ k g i. v.)  pre ve nts P M N i nfiltrati o n (i n hi biti o n ra n ge d fr o m 3 8 t o 8 0 %) a n d 
tiss ue da ma ge (i n hi biti o n ra n ge d fr o m 3 5 t o 9 0 %) i n e x peri me ntal m o dels of isc he mia/re perf usi o n i nj ur y 
of li ver a n d brai n i n rats [ G ar a u, 2 0 0 6 ]. I n a d diti o n, t he effects of la dari xi n were i n vesti gate d i n m o use 
m o dels of ac ute a n d c hr o nic s m o ke e x p os ure. I n t he ac ute m o del of s m o ke e x p os ure, la dari xi n ( 3. 7 5-1 5 
m g/ k g p. o.) re d uces P M N i nfiltrati o n b y a b o ut 6 0 %, w hereas i n t he c hr o nic m o del t he c o m p o u n d ( 7. 5 -
1 5 m g/ k g p. o.) c o m pletel y pre ve nts t h e de vel o p me nt of p ul m o nar y lesi o ns.  
T he a ntifl o gistic acti vit y of orall y a d mi nistere d la dari xi n was pr o ve n i n t he ac ute m o use m o del of 
ca nt hari di n -i n d uce d ear i nfla m mati o n w here it  re d uce d t he ear e de ma f or mati o n ( 1 6 % of i n hi biti o n), t he 
cell i nfiltrati o n ( 3 4 % of i n hi biti o n o n l y m p h oc ytes T a n d 3 2 % of i n hi biti o n o n P M Ns) a n d t he ear tiss ue 
le vels of kerati n oc yte c he m o ki ne ( 3 7 %), V E G F-A ( 2 4 %) a n d T N F - ( 4 4 %) [A 0 8 1 1/ E ]. 
T he efficac y of la dari xi n i n pre ve nti n g P M N i nfiltrati o n a n d tiss ue da ma ge was als o i n vesti gate d i n a 
passi ve tra nsfer m o use m o del of B P. I n t his m o del, la dari xi n was eit her c o -i njecte d wit h a nti-m o use 
B P 1 8 0 I g G (t hera pe utic t reat me nt) or i njecte d bef ore disease i n d ucti o n ( pre ve nti ve treat me nt).  
La dari xi n , a d mi nistere d b ot h i ntra der mall y a n d i ntra perit o neall y, d ose-de pe n de ntl y re d uces b ot h t he 
cli nical disease sc ore a n d P M N recr uit me nt  as s h o w n b y re d ucti o n i n M P O le vels . At t he hi g hest d ose 
teste d ( 1 6. 7 m g/ k g), t he cli nical disease sc ore a n d P M N mi grati o n were decrease d b y 9 0 % a n d 6 0 %, 
res pecti vel y [A 0 8 1 1/ E ].  
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2.1.3. 
Effects in models of type 1 diabetes 
Ladarixin was tested after oral administration (15mg/kg/day) in the Multiple Low Dose-Streptozotocin 
(MLD-STZ) model of diabetes using different treatment schedules. Results showed that ladarixin 
significantly affected the time to diabetes development with the 14-day administration starting from day 
-1 of fist STZ injection being the more efficient treatment schedule in prolonging the median diabetes 
free time. When a 14-day treatment was started from day +5, ladarixin still maintained a good 
performance. Even after diabetes development, glycemic levels during the first 2 months remained 
constantly lower in the ladarixin treated group as compared with the vehicle group [Citro, 2012a]. 
Ladarixin was also tested after oral administration (15 mg/kg/day for 14 days) in Non-Obese Diabetic 
(NOD) mice, starting treatment at different ages to explore its effects in a “prevention” setting (animals 
treated at 4, 8 and 12 weeks of age) or at “onset of diabetes” (animals at about 16 weeks of age, after 
fasting hyperglycemia was developed). In the “prevention” setting, the incidence of diabetes was 
reduced by ladarixin administration, regardless of the age when the treatment was started. In particular, 
when ladarixin was administered in animals at 8 weeks of age, the incidence of diabetes was 47% and 
11% in the vehicle and ladarixin treated group, respectively (p=0.029).  The ability of ladarixin to protect 
damage of -cells was confirmed in the “onset” setting. Animals presenting two consecutive blood 
glucose readings above 250 mg/dL over 24 h were randomized to receive either ladarixin or vehicle with 
the same dosing schedule as used in the prevention setting. Treatment with ladarixin at diabetes onset 
blocked the progression of hyperglycemia while hyperglycemia worsened in animals receiving vehicle.  
Three animals treated with ladarixin at diabetes onset that subsequently developed diabetes (about 30 
days from end of treatment) were re-treated with the test compound starting from day 35. In 2 animals 
with “mild” diabetes (animals with glycaemia between 300 mg/dl and 450 mg/dl) out of the 3 animals 
re-treated, ladarixin apparently reverted increased glycaemia [Citro, 2012b]. In parallel, ladarixin 
modifies leukocyte infiltration in the pancreas and the inflammatory process (insulitis) as well as affects 
the leukocyte subpopulations that express CXCR2, among which one subpopulation of B-lymphocytes 
[Citro, 2014]. 
2.2. 
A SUMMARY OF TOXICOLOGY DATA 
DF 2156A was tested for toxicity in rodent and non-rodent animal species after single and/or repeated 
dose administrations.   
In the four-week studies performed in rats, the administration by gavage for 28 days up to the dose of 
200 mg/kg followed by a 2-weeks recovery period, did not cause relevant toxicity. There was no 
mortality. The immune system was not affected by the treatment with DF 2156A. The liver and kidney 
weights increased in males in all dose groups and in females at 200 mg/kg. Hepatocellular hypertrophy 
was seen in the liver of all male treated groups and in females at 200 mg/kg that resolved after 2 weeks. 
The no-observed-adverse-effect-level (NOAEL) was settled at 200 mg/kg/day.   
Treatment of rats with DF 2156A orally for a 3 months’ period at dose levels of 35, 70 and 150 mg/kg 
did not induce mortality or toxicologically relevant changes in body weight and food consumption, 
ophthalmoscopic, hematology, and urinalysis parameters. Changes in biochemistry were only minimal 
and occurred mostly in males. They included increased activity of some liver enzymes (males at 150 
mg/kg), dose-dependently decreased protein levels (males at all dose levels and females at 150 mg/kg 
in Week 8 only), and dose-dependently decreased cholesterol and phospholipid concentrations (males 
from 70 mg/kg). Microscopic examination revealed treatment-related findings in the liver, thyroid gland 
and kidneys. In the liver, hepatocellular hypertrophy was noted in Week 8 in males at all treated groups 
and females at 150 mg/kg. Follicular cells hypertrophy of the thyroid gland was seen at 150 mg/kg and 
regarded secondary to the liver hypertrophy. In the kidneys hyaline droplet accumulation was present at 
increased incidence in males at 150 mg/kg after 8 weeks of treatment only (interim sacrifice). This 
change is male rat sex-specific not relevant for humans. After the 4-week recovery period, full recovery 
or a clear trend to recovery was noted for all findings.  
   


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In studies with up to 1week administration in dogs by oral route, the dose of DF 2156A had to be reduced 
from 500 to 150 mg/kg, due to poor tolerability and severe clinical signs, namely tremor, vomiting, 
uncoordinated movements. No macro or microscopic findings were present; organ weights were not 
affected. In the 4-week oral toxicity study in dogs, DF 2156A was administered up to the dose of 120 
mg/kg. No mortality occurred. Vomiting was seen at 120 mg/kg. An increase in the absolute and 
corrected-for-heart rate QT interval was observed at the doses of 60 and 120 mg/kg. Inflammatory 
changes were seen in the duodenum of two males treated with 120 mg/kg. After 2 weeks all values 
returned to normal. It was concluded that the no observed-effect-level (NOEL) is 30 mg/kg/day.  
In the 3-month study, the initial dose levels were 30, 60 and 120 mg/kg/day. However, due to test item-
related moribundity of one high dose male and changes in body weight and food intake of a few other 
animals in the group, the highest dose level was lowered from 120 to 80 mg/kg/day from Day 24 onward. 
At 120/80 mg/kg/day, one male and one female showed weight loss (up to -7%) and lower food intake 
during the first weeks of treatment and the clinical condition was reduced in Week 4. Food supplements 
were provided, which resulted in an improved clinical condition and normal body weight (gain) of these 
animals during the remainder of the treatment period after reduction of the dose level from 120 to 80 
mg/kg/day.  Prolongation of the QT and/or corrected QT intervals was observed in males and females 
treated at 120/80 mg/kg/day in Weeks 4, 8 and/or 13, generally more pronounced in females. In addition, 
higher heart rates were noted for males and (individual) females treated at 120/80 mg/kg/day in Weeks 
4, 8 and/or 13. At the end of the Recovery period, only one male and one female at 120/80 mg/kg/day 
were still on study, and all electrocardiography parameters were returned to the normal limits.   For one 
female at 60 mg/kg/day, mixed cell inflammation of the brain parenchyma and meninges, with neuronal 
necrosis and gliosis was recorded at moderate degree. There were no correlating clinical signs or 
necropsy alterations noted for this animal. Furthermore, no inflammation was recorded in the brain for 
any of the other dogs of the study; therefore, this change in a single dog at 60 mg/kg/day (mid dose) was 
regarded to be an incidental change, although rare and the origin of the lesions could not be determined. 
No test item-related changes were noted in any of the remaining parameters investigated in this study 
(i.e. ophthalmoscopy, coagulation parameters, urinalysis, macroscopic examination and organ weights). 
Based on the results of this study, the no-observed-adverse effect level (NOAEL) was considered to be 
60 mg/kg/day after 13 weeks of dosing.  
Testing of DF 2156A for mutagenic potential gave negative results for the in vitro chromosomal 
aberration test, for the Ames test and for the micronucleus assay test in vivo in bone marrow of rats.  
Phototoxicity potential of DF2156A was evaluated on Balb/c 3T3 cells. At dose levels of 100, 50.0, 
25.0, 12.5, 6.25, 3.13, 1.56 and 0.781 µg/mL, in the absence or presence of UVA light, neither reductions 
of the cell layer nor changes in cell morphology were observed after treatment with DF2156A at any 
concentration tested. No reduction in neutral red uptake was seen in any treatment condition. The IC50 
values were not calculable, thus the Photo Irritation Factor (PIF) could not be determined. The Mean 
Photo Effect value (MPE) was 0.009. The score values obtained with DF2156A (i.e. PIF not calculable 
and MPE lower than 0.1) are predictive of no phototoxicity   
A study of fertility and early embryonic development to implantation was performed in male and female 
Han Wistar rats at the daily oral dose of 50, 100 and 200 mg/kg. There were no treatment-related effects 
in females in any dose levels and in males at 50 and 100 mg/kg/day. At the highest dose, effects were 
observed on spermatid counts, motility and morphology of spermatozoas. Changes were seen in the 
testes of some animals and consisted degeneration/atrophy of the seminipherous tubules. According to 
the results obtained in this study, the fertility effects are likely associated with a stress effect, even if a 
secondary effect of the test item in the affected animals cannot be excluded with certainty. The NOEL 
was 100 mg/kg/day for males and of 200 mg/kg/day for females.  
In order to clarify the changes seen in the testes at 200 mg/kg/day, a specific study was designed in male 
Wistar and Sprague Dawley rats. DF 2156A was orally administered at the dose level of 200 mg/kg 
bw/day for a period of 6 weeks followed by a 4 weeks of treatment-free recovery period.  In both strains, 
the treatment with DF 2156A caused a minimal increase in incidence of reduced size of testes and 
epididymides and a mean decrease of testes and epididymides weights. A mean decrease of sperm 
motility, of normal complete sperms and of the mean sperm count in the epididymides was observed. 


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CONFIDENTIAL 
After the recovery period, the decrease of the motility was not seen in Wistar rats whereas it was 
observed in Sprague Dawley rats. The weight reduction of testes and epididymides and the sperm 
analyses correlated with microscopic changes in the testes (degeneration/atrophy) and epididymides 
(aspermia/oligospermia) of some treated animals of both strains. After 4 weeks of recovery period, none 
of the Wistar rats allocated to the recovery group presented any change in the testes or epididymides, 
while some of the Sprague-Dawley rats allocated to the recovery group had degeneration/atrophy of the 
testes and atrophy, oligospermia or cell debris in the epididymides. The incidence of the testicular 
changes was very likely associated to the stress induced by the treatment with the test item. In both 
strains, a decrease in body weight and body weight gain (associated to a decrease in food consumption) 
was observed particularly in the first 2 weeks of the treatment period. Ruffled fur and weakness were 
also present in some treated rats and a reduction of thymus weight was observed in treated Wistar rats. 
All these changes indicate a condition of stress and/or distress that caused the testicular changes. At the 
end of the recovery period, in the Wistar rat there were no changes in any of the parameters examined 
as well as no changes in the testes and epididymides; in Sprague Dawleys rats, testes and epididymides 
changes were present in some animals at the end of the recovery period.  
The prenatal developmental toxicity studies were conducted in Wistar Han rats and New Zealand White 
rabbits. In rats no maternal toxicity and no developmental toxicity were observed up to the highest dose 
level tested (150 mg/kg/day). The NOAEL in rats was established as being at least 150 mg/kg/day for 
both the maternal and developmental toxicity. 
In rabbits, no maternal toxicity was observed up to the highest dose level tested (100 mg/kg/day). The 
NOAELwas established as being at least 100 mg/kg/day for both the maternal and developmental 
toxicity.   
Carcinogenicity studies have not been performed. 
In conclusion, based on the toxicology testing performed through in vivo studies, the dose of 200 mg/kg 
appears to represent the NOAEL in rats for general toxicity while in dog in the 3-month oral toxicity 
study, the NOAEL was established at 60 mg/kg. In rats, 150 mg/kg is the NOAEL for developmental 
toxicity while in rabbits it was 100 mg/kg. 
The toxicity studies conducted up to date support the dose schedule proposed for this study up to 3 
months of continuous treatment. According to the toxicology development program, a 6 and 9 month 
study in rats and dogs, respectively, are ongoing to further support the chronic administration in humans. 
2.3. 
PHARMACOKINETICS AND PRODUCT METABOLISM  
The pharmacokinetics of DF2156Y was studied in rats and mice after single i.v. and oral administration 
and after multiple oral administrations in rats and dogs within the toxicity studies.  
DF2156Y is almost completely absorbed after oral administration in rats with an absolute bioavailability 
higher than 90%.  DF2156Y is slowly eliminated from plasma in all the three species tested (t½ ranging 
from 25 hours to 30 hours). Gender differences in pharmacokinetic profile after oral administration 
(slightly lower exposure in females than in males) were observed in rats but not in dogs.  
A metabolite of DF2156Y named DF2108Y (R enantiomer) was identified, using a non-chiral analytical 
method, in both rats and dogs. On the basis of the chiral analytical determination, the S enantiomer 
(DF2227Y) was noted in the plasma of both rats and dogs. The in vivo interconversion of DF2108Y into 
DF2227Y was about 90% in rats.  
In male and female rats DF2227Y was the major and long lasting circulating metabolite. After repeated 
daily oral administration of DF 2156A, this metabolite showed an accumulation ratio ranging between 
1.4 and 2.4. After the daily oral administration of DF 2156A at 200 mg/kg for 6 weeks, the parent 
compound and the metabolites showed comparable exposure in Wistar and Sprague Dawley rats either 
at day 1 or after repeated administrations.  
In humans, single oral doses of ladarixin (25 to 400 mg) provided quantifiable plasma concentration of 
DF2156Y within 1 hour, with peak concentration being reached between 1 and 3 hours. After single 
doses, DF 2156A was excreted mainly as unmodified in human urine. The presence of the two 


St u d y L D X 0 4 1 9  
L a d arixi n i n ne w-o nset T 1 D wit h preserve d -cell f u ncti o n 
P a ge 2 1  of  6 9  
 
 
 
Versi o n N o. 2  –  fi nal 3 0 J ul y 2 0 2 0   
 
 
meta b olites f o u n d i n a ni mal s pecies ( D F  2 1 0 8 Y a n d D F  2 2 2 7 Y) was c o nfir me d i n h u ma ns. D ose 
pr o p orti o nalit y o ver t he e ntire d ose ra n ge i n vesti g ate d was o bser ve d as well as t ½  ( 1 1-1 9 h) re mai ne d 
c o nsta nt acr oss t he ra n ge of d oses e val uate d. Re nal cleara nce acc o u nte d f or a p pr o xi matel y 6 0 -8 0 % of 
t he t otal cleara nce of D F 2 1 5 6 Y. T he d ose pr o p orti o nalit y f or t he mai n P K para meters was als o see n f or 
t he t w o meta b olites ( D F  2 1 0 8 Y a n d D F  2 2 2 7 Y).  
After m ulti ple d ose, D F 2 1 5 6 Y reac he d t he stea d y state ar o u n d Da y 5 a n d 6 f oll o wi n g 5 0, 1 0 0, 2 0 0, 3 0 0 
a n d 4 0 0 m g b.i. d. S yste mic e x p os ure t o D F  2 1 5 6 Y, D F  2 1 0 8 Y a n d D F  2 2 2 7 Y a p peare d t o i ncrease i n a 
d ose -pr o p orti o nal ma n ner. T he cleara nce a n d t he v ol u me of distri b uti o n of D F  2 1 5 6 Y a p peare d t o be 
d ose -i n de pe n de nt o n b ot h Da ys 1 a n d 8 f or all d oses. Si milarl y, t½  (ra n gi n g fr o m 1 1 t o 1 8 h) re mai ne d 
c o nsta nt o n Da y 1 a n d o n Da y 8 acr oss t he ra n ge of d oses e val uate d.   
C o -a d mi nistrati o n of D F  2 1 5 6 Y i ncrease d t he e x p os ure a n d uri nar y e xcreti o n of t ol b uta mi de w hile 
decreasi n g t he e x p os ure a n d t he uri nar y e xcreti o n of t ol b uta mi de meta b olites. Plas ma t ol b uta mi de A U C 
val ues i ncrease d b y a b o ut 2 -f ol d a n d t he A U Cs of t he meta b olites decrease d b y a b o ut 2-f ol d. T h us, 
la dari xi n ca n be classifie d as a m o derate i n hi bit or of C Y P 2 C 9. 
I n vitr o la dari xi n a p pears t o be a str o n g i n hi bit or of t he e nz y me C Y P 2 C 9 i n h u ma ns ( 8 3 %) a n d a 
m o derate i n hi bit or i n rats ( 5 1 %). N o i n hi biti o n was o bser ve d i n d o gs.  N o i n hi biti o n was detecte d i n a n y 
s pecies wit h re gar d t o C Y P 2 D 6. Als o, n o i n hi biti o n was s h o w n f or  C Y P 1 A 2, 2 C 1 9, a n d 2 E 1 wit h 
res pect t o h u ma ns a n d d o gs, b ut a m o derate  i n hi biti o n was s h o w n i n rats (a b o ut 5 0 % ). As t o C Y P 3 A 4, 
a sli g ht i n hi biti o n was see n i n all s pecies w hic h was hi g her t ha n 2 0 %  o nl y i n rats ( a b o ut 2 8 %). I n 
h u ma ns, c o -a d mi nistrati o n of la dari xi n ( 2 0 0 m g t wice a da y f or 5 da ys) a p pr o xi matel y d o u ble d t he 
e x p os ure t o t ol b uta mi de ( pr o be f or C Y P 2 C 9 is oe nz y me).  
Preli mi nar y i n-vitr o pr otei n bi n di n g st u dies s h o we d t hat la dari xi n is hi g hl y b o u n d t o plas ma pr otei ns; 
bi n di n g varies acc or di n g t o la d ari xi n c o nce ntrati o ns a n d a p pears t o be sat ura ble: mice 9 7. 7 %, rats 9 1. 8 -
9 9. 4 %, d o gs 8 0. 4 -9 9. 5 % a n d h u ma ns 9 3. 0 -9 9. 9 %. Re peate d at 4 0 0 m g b.i. d. a d mi nistrati o ns i n h u ma ns 
c o nfir me d t he ver y hi g h bi n di n g t o plas ma pr otei ns ( > 9 9. 9 9 %).  
2. 4.  
A S U M M A R Y O F C LI NI C A L D A T A  
Cli nical de vel o p me nt i ncl u des 3 p hase 1 P K a n d t olera bilit y st u dies wit h si n gle 
 
 a n d m ulti ple 
 asce n di n g d ose 
oral a d mi nistrati o n. T he first m ulti ple asce n di n g d ose st u d y 
 als o i ncl u de d t he e val uati o n of 
p ote ntial i nteracti o n bet wee n la dari xi n 2 0 0 m g a n d t ol b uta mi de. A p hase 2 efficac y a n d safet y st u d y 
was als o c o n d ucte d wit h 1 5 0 m g t wice  a da y (f or 1 4 c o nsec uti ve da ys) oral la dari xi n i n patie nts wit h 
m o deratel y acti ve B P.    
T o date, a t otal of 1 9 5 s u bjects were i n v ol ve d i n cli nical trials, of w h o m 1 4 3 ( 8 9 healt h y v ol u nteers 5 0 
T 1 D patie nts a n d 4 patie nts wit h B P) were e x p ose d t o la dari xi n.  
2. 4. 1.  
P h ar m ac o ki netics a n d pr o d uct met a b olis m i n h u m a ns  
T hree p hase 1 P K/safet y/t olera bilit y st u dies i n healt h y male v ol u nteers were perf or me d w hic h i ncl u de d 
si n gle 
 a n d m ulti ple 
 
 asce n di n g d ose oral a d mi nistrati o n. A n i nteracti o n e val uati o n f or t he 2 0 0 m g d ose was als o 
i ncl u de d i n t he first m ulti ple asce n di n g d ose st u d y. Assa y of la dari xi n a n d its meta b olite D F 2 1 0 8 Y a n d 
D F 2 2 2 7 Y was perf or me d i n sa m ples c ollecte d at stea d y state c o n diti o ns, o n da y 5 a n d 8 of treat me nt 
i n 3 B P patie nts. P K res ults are disc usse d i n d etail i n I B versi o n  Fi nal 
. 
2. 4. 2.  
Effic ac y  
A p hase 2, m ultice nt er, si n gle ar m, pil ot st u d y was i nitiate d t o assess t he safet y a n d efficac y of la dari xi n 
i n patie nts wit h m o deratel y acti ve B P 
. T he c o m p o u n d was gi ve n b y t he oral r o ute at 1 5 0 
m g t wice a da y ( ma xi m u m of 1 4 da ys), a  l o w d ose t hat c o ul d be selecte d acc or di n g t o t he p hase 1 trial 
c o m plete d at t he ti me of pr ot oc ol i m ple me ntati o n (treat me nt u p t o 2 0 0 m g t wice a da y). F o ur male 
patie nts a ge d 6 5 -7 5 years, wit h eit her ne wl y dia g n ose d or rela psi n g B P of mil d t o m o derate de gree , were 
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St u d y L D X 0 4 1 9  
L a d arixi n i n ne w-o nset T 1 D wit h preserve d -cell f u ncti o n 
P a ge 2 2  of  6 9  
 
 
 
Versi o n N o. 2  –  fi nal 3 0 J ul y 2 0 2 0   
 
 
e nr olle d at o ne Italia n a n d t hree Ger ma n sites. Of t he 4 patie nts e nr olle d, o nl y o ne c o m plete d t he 1 4 -
da y treat me nt peri o d. T he re mai ni n g 3 patie nts were wit h dra w n fr o m t he st u d y ( o ne patie nt d ue t o 
treat me nt fail ure a n d t he ot her 2 patie nts beca use a d missi o n t o resc ue t hera p y). N o disease re missi o ns 
were  o bser ve d wit h t he l o w d ose teste d i n t his trial a n d t he st u d y was pre mat urel y disc o nti n ue d d ue t o 
lac k of acti vit y.   
A p hase 2, m ultice nt er, ra n d o mize d, d ou ble -bli n d, place b o -c o ntr olle d st u d y has rece ntl y bee n c o m plete d 
i n patie nts wit h ne w o nset T 1 D (first i ns uli n wit hi n 1 0 0 da ys fr o m ra n d o mizati o n) 
. T he 
trial i n v ol ve d 8 sites i n Ital y, Ger ma n y a n d Bel gi u m. Se ve nt y-si x patie nts ( 3 1 fe males, 4 5 males) wit h 
mea n a ge of a b o ut 2 7 years ha ve bee n ra n d o mize d ( 2: 1) t o recei ve eit her la dari xi n ( 4 0 0 m g t wice a da y 
f or 3 c ycles of 1 4 da ys o n/ 1 4 da ys off) or place b o. T he pri mar y e n d p oi nt was t he A U C of C-pe pti de 
meas ure d d uri n g a n M M T T perf or me d o n wee k 1 3 fr o m ra n d o mizati o n. F oll o w -u p was e xte n de d u p t o 
o ne year. O ut of 8 5 patie nts e nr olle d (c o nse nt si g ne d), 7 6 were ra n d o mize d, 5 0 t o recei ve d la dari xi n a n d 
2 6 all ocate d t o place b o; 4 8 patie nts i n t he la dari xi n gr o u p a n d 2 5 i n t he place b o c o m plete d t he trial 
( wee k 5 2 o bser vati o n).  
T he  pri mar y a n d sec o n dar y a nal yses were perf or me d o n t he I T T p o p ulati o n. T he pri mar y efficac y 
a nal ysis of l o g ( A U C [ 0-2 hrs]  + 1) of C -pe pti de res p o nse t o M M T T s h o we d n o statisticall y si g nifica nt 
differe nce ( p = 0. 3 3 0 3) bet wee n t he la dar i xi n a n d place b o gr o u p at Wee k 1 3. O verall, t here were n o 
cli nicall y rele va nt treat me nt effect differe nces bet wee n t he treat me nt gr o u ps f or ot her sec o n dar y 
e n d p oi nts, s uc h as C -pe pti de at ot her ti me -p oi nts, o verall i ns uli n re q uire me nt, gl uc ose le vels a n d 
g l uca g o n le vels d uri n g t he st u d y. O n t he ot her ha n d, t he pr o p orti o n of patie nts wit h H b A 1c < 7 % a n d 
a bse nce of e pis o des of se vere h y p o gl yce mia was si g nifica ntl y hi g her at Wee k 2 6 ( p = 0. 0 2 4 8) i n patie nts 
recei vi n g la dari xi n as c o m pare d wit h place b o ( w h ole I T T p o p ulati o n ). Si milarl y, t he pr o p orti o n of 
patie nts wit h H b A 1c < 7 % a n d dail y i ns uli n re q uire me nt < 0. 5 0 I U/ k g/ da y, a p ost -h oc c o m p osite 
e n d p oi nt, was hi g her ( 7 6. 6 % ) at wee k 2 6 i n t he la dari xi n gr o u p vs. place b o ( 4 5. 8 % ) i n t he w h ole I T T 
p o p ulati o n  ( p = 0. 0 1). 
W he n c o nsi deri n g t he pre -s pecifie d s u b gr o u p a nal ysis of patie nts ha vi n g fasti n g C-pe pti de at scree ni n g 
< me dia n val ue of t he w h ole I T T p o p ulati o n, a statisticall y si g nifica nt differe nce i n fa v or of la dari xi n f or 
b ot h t he C -pe pti de l o g  ( A U C[ 0-2  hrs]+ 1) ( p = 0.0 4 1 1) a n d t he l o g (A U C ( 1 5-1 2 0 mi n) + 1) ( p = 0. 0 3 10 ) at Wee k 
2 6 was e vi de nce d. T he statisticall y si g nifica nt c o m paris o n bet wee n treat me nt gr o u ps at Wee k  2 6 i n t his 
s u b gr o u p of patie nts was rei nf orce d b y data rele va nt t o t he pr o p orti o n of patie nts wit h H b A 1c  < 7 % a n d 
a bse nce of se vere h y p o gl yc e mic e ve nts ( p = 0. 0 0 7 4)  a n d t he p ost -h oc e n d p oi nt of t he pr o p orti o n of 
patie nts  wit h H b A 1c < 7 % a n d dail y i ns uli n re q uire me nt < 0. 5 0 I U/ k g/ da y ( p = 0. 0 0 4). 
I n t he pre-s pecifie d s u b gr o u p a nal ysis of patie nts ha vi n g fasti n g C-pe p ti de at scree ni n g ≥ me dia n val ue 
of t he w h ole I T T p o p ulati o n , n o statisticall y si g nifica nt differe nce c o ul d be o bser ve d f or a n y of t he 
efficac y e n d p oi nts. H o we ver, i n t his s u b gr o u p of patie nts wit h fasti n g C-pe pti de ≥0. 2 0 5 n m ol/ L at 
scree ni n g, t he perce nta ge of patie nts wit h H b A 1c < 7 % a n d dail y i ns uli n re q uire me nt < 0. 5 0 I U/ k g / da y 
w as 6 8. 2 % i n la dari xi n gr o u p vs. 5 3. 3 % i n place b o gr o u p  ( p = 0. 3 6 1). 
2. 4. 3.  
S af et y  
A t otal of 8 9 male healt h y s u bj ects a ge d 1 8 t o 5 2 years , 4 male B P patie nts a ge d 6 5 -7 5 yeas , a n d 5 0 
T 1 D patie nts a ge d 1 8 -4 6 years were e x p ose d t o la dari xi n  i n t he cli nical trials c o n d ucte d t o date.  
E x p os ure i ncl u de d si n gle ( 2 5 t o 4 0 0 m g) as well as re peate d ( 5 0 t o 4 0 0 m g t wice a da y u p t o 6 da ys) 
oral a d mi nistrati o ns i n healt h y v ol u nteers, 1 5 0 m g t wice a da y u p t o a ma xi m u m of 1 4 da ys i n B P 
patie nts, a n d 4 0 0 m g t wice a da y f or 3 c ycles of 1 4 da ys o n -1 4 da ys off i n T 1 D patie nts. I n a s u bset of 
s u bj ects, la dari xi n ( 2 00 m g t wice a da y) was c o -a d mi nistere d wit h t ol b uta mi de.    
T o xic ol o g y a n d safet y p har mac ol o g y i n a ni mals p oi nte d o ut t he car di o vasc ular s yste m ( Q T 
pr ol o n gati o n) as p ote ntial safet y c o ncer n i n h u ma ns. A p pare nt is olate d pr ol o n gati o ns of t he Q Tc F were 
o bser ve d at s o me ti me -p oi nts i n p hase 1 st u dies; c ore la b orat or y a nal ysis of t he E C G rea di n gs, i ncl u di n g 
t he re vie w of c ha n ges i n t he Q T c F i nter vals a n d of t he p har mac o ki netic-p har mac o d y na mic relati o ns hi p, 
re veale d n o cli nicall y si g nifica nt effect of D F 2 1 5 6 A o n car diac re p olarizati o n.  
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St u d y L D X 0 4 1 9  
L a d arixi n i n ne w-o nset T 1 D wit h preserve d -cell f u ncti o n 
P a ge 2 3  of  6 9  
 
 
 
Versi o n N o. 2  –  fi nal 3 0 J ul y 2 0 2 0   
 
 
O verall, D F 2 1 5 6 was safe a n d well t olerate d. N o deat hs or Seri o us A d verse E ve nts ( S A Es ) were 
re p orte d fr o m p hase 1 trials, as well as n o safet y c o ncer ns were raise d d uri n g c o -a d mi nistrati o n of 
la dari xi n wit h t ol b uta mi de. All  t he A d v erse E ve nts ( A Es ) were mil d or m o derate i n i nte nsit y.   
Safet y was c o nfir me d i n el derl y B P patie nts treate d wit h se veral c o nc o mita nt me dicati o ns. T hree o ut of 
4 patie nts re p orte d mil d A Es w hic h were all c o nsi dere d relate d t o la dari xi n wit h t he e xce pti o n of  o ne  A E 
i n one patie nt ( h y pere osi n o p hilia).  T w o patie nts ha d a series of a b n or mal E C Gs at baseli ne t hat 
c o nti n ue d t hr o u g h o ut t he st u d y neit her of w hic h were c o nsi dere d cli nicall y si g nifica nt b y t he 
i n vesti gat or, s u p p orti n g t he car di osafet y i n el derl y patients . T here were n o ot her safet y fi n di n gs 
c o nsi dere d cli nicall y si g nifica nt b y t he i n vesti gat or. T here were n o deat hs, S A Es, or disc o nti n uati o ns 
fr o m t he st u d y d ue t o A Es. 
T he p hase 2 trial i n ne w o nset T 1 D f urt her e xte n de d t he e x perie nce wit h la dari xi n. T he fre q ue nc y a n d 
pr ofile of A Es/ A D Rs was si milar i n patie nts recei vi n g la dari xi n or place b o . A t otal of 3 7 patie nts 
( 7 4. 0 %) i n t he la dari xi n gr o u p a n d 2 2 patie nts ( 8 4. 6 %) i n t he place b o gr o u p e x perie nce d T E A Es d uri n g 
t he st u d y. T he m ost c o m m o n T E A Es presente d b y pri mar y S O Cs were i nfecti o ns a n d i nfestati o ns (a b o ut 
4 6 % i n b ot h gr o u ps), f oll o we d b y gastr oi ntesti nal dis or ders (a b o ut 3 5 %) a n d ner v o us s yste m dis or ders 
( 3 4. 0 % la dari xi n vs 2 6. 9 % place b o). T he maj orit y of t he T E A Es re p orte d i n t he st u d y were c o nsidere d 
mil d i n se verit y. A t otal of 3 patie nts i n t he la dari xi n gr o u p a n d 1 patie nt i n t he place b o gr o u p re p orte d 
T E S A Es. O ne patie nt i n t he la dari xi n gr o u p re p orte d 2 T E S A Es ( h y per gl yc e mia a n d me ntal dis or der); 
a n d 1 patie nt eac h i n t he la dari xi n gr o u p re p orte d T E S A Es of gastr oi ntesti nal dis or der a n d cla vicle 
fract ure, res pecti vel y. O ne patie nt i n t he place b o gr o u p re p orte d T E S A E of lacerati o n. N o ne of t he S A Es 
were relate d t o t he st u d y treat me nt. O ne patie nt i n t he la dari xi n gr o u p was disc o nti n ue d fr o m t he  st u d y 
treat me nt d ue t o A Es of ala ni ne a mi n otra nsferase i ncrease d a n d as partate a mi n otra nsferase i ncrease d, 
a n d 1 patie nt i n t he place b o gr o u p was disc o nti n ue d fr o m t he st u d y treat me nt d ue t o a n A E of ras h. 
T we nt y patie nts ( 4 0. 0 %) i n t he la dari xi n gr o u p ha d 5 2 A D Rs a n d 8 patie nts ( 3 0. 8 %) i n t he place b o 
gr o u p ha d 1 7 A D Rs d uri n g t he st u d y.  
C u m ulati ve a d verse dr u g re acti o ns  (A D Rs ), i.e. treat me nt-e mer ge nt A E j u d ge d at least p ossi bl y 
relate d t o la dari xi n, are prese nte d i n t he T a ble bel o w. 
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St u d y L D X 0 4 1 9  
L a d arixi n i n ne w-o nset T 1 D wit h preserve d -cell f u ncti o n 
P a ge 2 4  of  6 9  
 
 
Versi o n N o. 2  –  fi nal 3 0 J ul y 2 0 2 0   
 
 
 
T he  s yste m or ga n classes ( S O C S) m ost fre q ue nt l y ( > 1 0 %) affecte d b y A D Rs were:  
Gastr oi ntesti nal Dis or ders : (a b o ut 5 0 %) i ncl u di n g d ys pe psia, d ys p ha gia, a b d o mi nal pai n, m o ut h 
ulcerati o n, na usea.  
Ner v o us S yste m Dis or ders : (a b o ut 3 0 %) i ncl u di n g hea dac he, dizzi ness. 
D ys pe psia a n d d ys p ha gia were b ot h c o nsi dere d as defi nitel y relate d t o la dari xi n beca use t he y occ urre d 
s h ortl y after a d mi nistrati o n; als o, d ys pe psia c o nsiste ntl y rec urre d o n s u bse q ue nt dr u g a d mi nistrati o n.  
All t he A D Rs res ol ve d.  
2. 5.  
DI S E A S E R E VI E W A N D S T U D Y R A TI O N A L E  
T 1 D is a n or ga n -s pecific a ut oi m m u ne disease i n w hic h t he i m m u ne s yste m attac ks t he i ns uli n-pr o d uci n g 
-cells. T he onset of t he disease t y picall y occ urs bef ore a d ult h o o d a n d seri o usl y affects a pers o n’s q ualit y 
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Study LDX0419 
Ladarixin in new-onset T1D with preserved -cell function 
Page 25 of 69 
 
 
 
Version No. 2 – final 30 July 2020  
 
 
of life. Incidence of T1D is rapidly increasing, with a predicted 70% increase in incidence over the next 15 
years in Europe [Atkinson, 2014; Waldron-Lynch, 2011]. 
T1D is treated with life-long daily exogenous insulin injections and monitoring of blood glucose levels.  
However, even optimization of glucose control through the most recent technologies cannot adequately 
substitute for the finely tuned normal balance of the glucose levels. Pancreatic islet or whole pancreas 
transplantation still has limited success due to graft loss and immunosuppression derived side-effects.   
Therefore, despite marked improvements in diabetes care in recent years, insulin-dependent diabetes results 
in secondary long-term complications and is one of the leading causes of end-stage renal disease, blindness 
and amputation. Additionally, hypoglycemia unawareness is a serious consequence of recurrent 
hypoglycemia often requiring emergency care [Atkinson, 2014; Waldron-Lynch, 2011].   
Maintenance of residual -cell function (as measured by C-peptide response) was demonstrated to be 
associated with reduced rate of microvascular complications and hypoglycemia, improved quality of life, 
and overall reduction in morbidity and associated management costs. Therefore, pharmacological 
approaches aimed at controlling the autoimmune response and restoring self-tolerance to pancreatic -cells 
had attracted the clinical/scientific interest.  [Steffes, 2003; Barnard, 2010; Waldron-Lynch, 2011]. 
Among these, rituximab, CD3-specific monoclonal antibodies, GAD65, DiaPep277 have progressed to 
phase 3 clinical trials. Other agents, including cytokines modulators such as anti-TNF or anti-IL1, are under 
clinical evaluation. Unfortunately, even if safe preservation of -cell function and improvement of glycemic 
control have been evidenced for some of the pharmacological approaches evaluated so far, none has been 
definitely approved for the “treatment” of diabetes onset [Ludvigson, 2008; MacroGenics, 2010; 
Mastrandrea, 2009; Peskovitz, 2009; Waldron-Lynch, 2011; Raz, 2014].  
New strategies are being evaluated which combine agents targeting sequential arms of the immune and 
inflammatory response involved in -cell disruption. In this regard, IL-8 appears to be an important 
mediator in the progression of type 1 diabetes. Production and secretion of pro-inflammatory IL-8 has been 
demonstrated from human pancreatic islets upon enterovirus infections, and LPS-induced production of IL-
8 by neutrophils is increased in type 1 pre-diabetic and diabetic patients. In parallel, circulating levels of IL-
8 were elevated in children with T1D compared to non-diabetic controls. Specifically, levels of IL-8 
correlate with glycemic control, higher level being associated to poorer or unfavorable glucose control 
[Aboelasrar, 2012; Erbağci, 2001; Glowacka, 2002; Diana, 2014; Van Sickle, 2009] 
As a result of these findings, the modulation or inhibition of CXCL8 activity is considered a valid target 
for the development of innovative treatments aimed to control the progression of T1D. 
Results obtained with ladarixin in mouse models of T1D, and particularly reversal of “diabetes” in the 
NOD mice, clearly shows the ability of this CXC1/2 inhibitor to protect -cells and either prevent or 
delay the progression of hyperglycemia.   
Results obtained in the phase 2 trial in new-onset T1D patients could not show a statistically significant 
difference (p=0.337) between the two groups in the primary endpoint (2-hour AUC of C-peptide 
response to MMTT at week 13). On the other hand, the proportion of patients with HbA1c <7% and 
absence of episodes of severe hypoglycemia was significantly higher at Week 26 (p=0.0248) in patients 
receiving ladarixin as compared with placebo (whole ITT population). Similarly, the percentage of 
patients with HbA1c <7% and daily insulin requirement <0.50 IU/kg/day, a post-hoc composite 
endpoint, was higher (76.6%) at week 26 in the ladarixin group vs. placebo (45.8%) in the whole ITT 
population (p=0.01). 
When considering the pre-specified sub-group analysis based on fasting C-peptide, a statistically 
significant effect of ladarixin was reached for some efficacy endpoints at week 26 only in the 
subpopulation with “severe T1D onset” (fasting C-peptide <0.205 nmol/L at baseline (median value of 
trial population). Notwithstanding, in the sub-group with fasting C-peptide at baseline ≥ 0.0205 nmol/L, 
the proportion of patients with HbA1c <7% and daily insulin requirement <0.50 IU/kg/day was higher 
in the ladarixin group at week 26, as compared to placebo. Considering that this effect is evident after a 
short treatment course (3 months), data obtained in the phase 2 trial support the hypothesis that a longer 
exposure (12 months) to ladarixin can delay disease progression also in patients with fasting C-peptide 
at screening ≥0.205 nmol/l).  


St u d y L D X 0 4 1 9  
L a d arixi n i n ne w-o nset T 1 D wit h preserve d -cell f u ncti o n 
P a ge 2 6  of  6 9  
 
 
 
Versi o n N o. 2  –  fi nal 3 0 J ul y 2 0 2 0   
 
 
T he  res ults o btai ne d fr o m t he p hase 2 trial c o u ple d wit h t he safet y s h o w n i n p hase 1 a n d 2 cli nical trials,  
“mil d ” (fasti n g C-pe pti de > 0. 2 0 5 n m ol/ L  pr o vi de a rati o nale t hat s u p p orts t he c o n d uct als o of t his P hase 
2 cli nical st u d y  i n ) patie nts wit h less se vere disease o nse t (fasti n g C-pe pti de > 0. 2 0 5 n m ol/ L ) 
2. 5. 1.  
Selecti o n of d ose a n d tre at me nt sc he d ule i n t he st u d y  
T he d ose a n d treat me nt sc he d ule pr o p ose d i n t his p hase 2 st u d y is 4 0 0 m g oral la dari xi n t wice a da y f or 
1 3  c ycles of 1 4 da ys  o n - 1 4 da ys  off.   H o we ver, l a d ari xi n will N O T be a d mi nistere d t o tri al p atie nts 
f or l o n ger t h a n 3 m o nt hs ( 3 c ycles) bef ore  c hr o nic t o xicit y d at a i n r ats a n d d o gs h a ve bee n dee me d 
s ufficie nt b y t he F D A t o s u p p ort l a d ari xi n e x p os ure u p t o o ne ye ar.   
T he oral r o ute has bee n selecte d base d o n t he ver y g o o d oral bi oa vaila bilit y of la dari xi n, t he l o n g half -
life a n d its g o o d t olera bilit y w he n gi ve n b y t his r o ute.  
T he 4 0 0 m g b.i. d. d osa ge is s u p p orte d b y b ot h precli nical st u dies a n d efficac y/safet y res ults fr o m phase 
2 cli nical st u d y 
 i n T 1 D a d ult patie nts. Act uall y, t his d ose was alrea d y esta blis he d t o be safe 
i n p hase 1 cli nical st u dies i n a d ult male healt h y s u bjects.  
T he res ulti n g a vera ge stea d y state plas ma c o nce ntrati o n of t he la dari xi n u n b o u n d fracti o n s h o ul d e ns ure 
f ull i n hi biti o n of P M N mi grati o n, c o nsi deri n g t hat t he i n vitr o I C5 0 is i n t he ra n ge of 1 n g/ m L 
A treat me nt of 1 4 da ys i n a re gi me n of 1 4 -da ys o n a n d 1 4 -da y s off res ulte d be neficial  i n t he p hase 2 
st u d y 
, i n li ne wit h t he i nitial o bser vati o ns i n N O D mice. I n fact, i n la dari xi n-treate d N O D 
mice wit h rece nt o nset -dia betes t he efficac y of t he c o m p o u n d was clearl y m ore pr o n o u nce d wit hi n t he 
1 4 da ys after treat me nt i nterr u pti o n (i n t hese a n i mals, t he a vera ge of n o n-fasti n g gl yce mia was bel o w 
2 0 0 m g/ dl) w hereas bl o o d gl uc ose c o nce ntrati o ns te n de d t o pr o gressi vel y i ncrease i n 7 7 % of re missi o n 
N O D mice at later ti me after treat me nt disc o nti n uati o n, s u g gesti n g t hat ne utr o p hil recr uit me nt as well  
t he cr oss-tal k wit h t he ot her i m m u ne cells i n t he pa ncreas c o ul d restart after 1 4 da ys of la dari xi n 
treat me nt disc o nti n uati o n. T his was f urt her s u p p orte d b y t he e vi de nce t hat a sec o n d c ycle of la dari xi n 
treat me nt i n N O D-mice wit h dia betes rec urre nce was a ble t o re verse a gai n dia betes i n 6 7 % of mice , t h us 
s u p p orti n g t he c o nce pt t hat re peate d c ycles of treat me nt are necessar y a n d a p pr o priate f or t he 
ma na ge me nt of t he c hr o nic c o n diti o n.  
F urt her m ore, la dari xi n pre ve nte d dia betes i n a m o del of β -cell i nfla m mat or y i nj ur y i n d uce d b y m ulti p le 
l o w-d ose stre pt oz ot oci n , a n d t he treat me nt f or 1 4 da ys starti n g 1 da y bef ore t he i n d ucti o n of dia betes 
a p peare d t he m ost efficie nt i n pr ol o n gi n g t he me dia n dia betes -free ti me c o m pare d t o re gi me ns i n w hic h 
t he treat me nt was o nl y a d mi nistere d f or 7 da ys a n d/ or was starte d fe w da ys after t he i n d ucti o n of dia betes 
b y stre pt oz ot oci n.  
In t he 1 4 da ys was h o ut peri o d ( w hic h is t he i nter val bet wee n t w o treat me nt c ycles), t he patie nts 
c o m pletel y clear t he dr u g fr o m t he b o d y c o nsi deri n g  t hat la dari xi n is n ot acc u m ulati n g o ver re peat 
a d mi nistrati o n, has a l o w v ol u me of distri b uti o n, it is n ot li p o p hilic a n d has a half -ti me ra n gi n g fr o m 1 1 
t o 1 8 h w hic h mea ns t hat i n a peri o d of a b o ut 9 8  h o urs (i.e. a b o ut 4 da ys) it is c o m pletel y cleare d fr o m 
t he b o d y.  
D o m pé has carrie d o ut a c o m pre he nsi ve n o ncli nical safet y pac ka ge , w hic h alrea d y s u p p ort t he 
c o nti n u o us a d mi nistrati o n of la dari xi n f or u p t o 3 m o nt hs i n h u ma n patie nts.  
T he pac ka ge alrea d y a vaila ble c o nsists of ac ute, s u bac ute a n d s u b -c hr o nic st u dies i n rats a n d d o gs b y 
oral r o ute, safet y p har mac ol o g y i n vitr o a n d i n vi v o, p har mac o ki netics a n d meta b olis m, p h ot ot o xicit y 
i n vitr o, ge netic t o xic ol o g y i n vitr o a n d i n vi v o, repr o -t o xicit y of se g me nt I a n d II i n t w o differe nt 
s pecies. T hese t o xicit y data are c o nfir me d b y safet y data i n h u ma n v ol u nteers a n d i n T 1 D patie nts w here 
la dari xi n res ulte d t o be safe at t he cli nical d oses t o be use d i n  t his p hase 2 cli nical st u d y.   
A d diti o nal c hr o nic data i n rats a n d d o gs will be c ollecte d acc or di n g t o I C H g ui deli ne , i n or der t o s u p p ort 
treat me nt u p t o 1 2 m o nt hs. 
C CI
C CI


St u d y L D X 0 4 1 9  
L a d arixi n i n ne w-o nset T 1 D wit h preserve d -cell f u ncti o n 
P a ge 2 7  of  6 9  
 
 
 
Versi o n N o. 2  –  fi nal 3 0 J ul y 2 0 2 0   
 
 
2. 5. 2.  
Alter n ati ve tre at me nts  
T here are n o sta n dar d p har mac ol o gic treat me nts, a d dresse d t o t he pre ve nti o n or treat me nt of T 1 D ot her 
t ha n i ns uli n re place me nt. Des pite rece nt a d va nces i n t he n u m ber of i m m u n o m o d ulat or y a ge nts a vaila ble 
a n d cli nical trials i n T 1 D, i ncl u di n g dr u gs tar gete d t o t he c yt o ki ne s yste m, o nl y a fe w a p pr oac hes teste d 
t o date, s uc h as Dia Pe p 2 7 7 i njecti o ns or ot her i m m u n o m o d ulat or y dr u gs , ha ve pr o vi de d s o me e vi de nce 
of s uc cessf ul c o ntr ol of disease pr o gressi o n. N o o ne dr u g has t heref ore reac he d eit her defi nite 
t hera pe utic place me nt or mar keti n g a ut h orizati o n f or t his i n dicati o n [W al dr o n -Ly nc h, 2 0 1 1 ]. 
Beca use of t his, p atie nts n ot willi n g t o partici pate i n t he st u d y ma y eit her be offere d t o partici pate i n 
a n ot her trial of e x peri me ntal treat me nts or will n ot be offere d a n y s pecific alter nati ve treat me nt ot her 
t ha n i ns uli n ma na ge me nt.   
All patie nts, re gar dless of st u d y pa rtici pati o n, will recei ve t he sta n dar d of o pti mal care f or a rece nt o nset 
T 1 D i n di vi d ual.  
2. 5. 3.  
Ris k - be nefit e v al u ati o n  
2. 5. 3. 1.  
Ris k relate d t o t he la dari xi n  
Res ults fr o m precli nical st u dies s u p p ort t he le vel of dr u g e x p os ure pla n ne d i n t his st u d y.  
P hase 1 a n d 2 cli nical e x perie nce wit h d oses as hi g h as t hat pla n ne d i n t his st u d y pr o vi des e vi de nce of 
t he safet y of la dari xi n. T he safet y was c o nfir me d i n t he p hase 2 trials; i n dee d, n o safet y c o ncer ns were 
raise d eit her i n el derl y patie nts w h o were o n se veral c o nc o mita nt me dicati o ns d ue t o c hr o nic disease, or 
i n patie nts wit h ne w-o nset T 1 D.  N o S U S A R or deat h occ urre d a n d all t he A Es e nc o u ntere d were mil d 
t o m o derate i n i nte nsit y. 
T he a vaila ble t o xicit y data s u p p orts 3 m o nt hs of c o nti n u o us treat me nt i n h u ma ns. Si x -m o nt h a n d 9 -
m o nt h c hr o nic st u dies i n rats a n d d o gs (res pecti vel y) will be c o n d ucte d, acc or di n g t o I C H g ui deli ne 
M 3( R 2), i n or der  t o s u p p ort la dari xi n a d mi nistrati o n  u p t o 1 2 m o nt hs. E ve n if t he pr ot oc ol a ntici pates , 
a n d re mai ns str uct ure d f or,  1 year of treat me nt  ( 1 3 c ycles), patie nts will n ot be tre ate d l o n ger t h a n 3 
m o nt hs  u ntil s uc h a d diti o nal c hr o nic t o xic ol o g y data i n rats/ d o gs ha ve bee n re vie we d b y t he F D A. 
[A n y p ossi ble ris k deri ve d fr o m t he a d mi nistrati o n of la dari xi n i n t he s pecific p o p ulati o n i n v ol ve d i n 
t his st u d y will be mi ni mize d b y i nte grate d m o nit ori n g w hic h i ncl u des cli nical o bser vati o ns, la b orat or y 
tests a n d E C G rea di n gs sc he d ule d at pre-pla n ne d i nter val  (see Secti o n 6. 4 . 2 - disc o nti n uati o n criteria  
f or details)].  
La dari xi n i n hi bits e nz y me C Y P 2 C 9 a n d ma y affect plas ma le vels of t h ose dr u gs t hat are meta b olize d 
b y t his s yste m.  Restricti o ns of use a n d m o nit ori n g pr oce d ures (see Secti o n 6. 5 . 2 f or details) will li mit 
a n y p ossi ble ris ks deri ve d fr o m p ote ntial meta b olic i nteracti o ns.    
2. 5. 3. 2.  
Bl o o d sa m pli n g  
Partici pati o n i n t he st u d y will re q uire a d diti o nal bl o o d sa m pli n gs ot her t ha n t he r o uti ne o n es. I n 
partic ular:  
- a bl o o d sa m ple (a b o ut 1 0 m L) will be o btai ne d at  baseli ne , e n d of 3 r d (Wee k 1 1 ), 6 t h (Wee k 2 3 ) a n d 
9 t h (W ee k 3 5) treat me nt c ycles, M o nt h 1 2  a n d M o nt h 1 8  f or Safet y La b orat or y T est;  
- bl o o d sa m ples f or dia g n ostic a ut o -a b test ( ma xi m u m 5 m L) a n d f or baseli ne H b A 1c, H L A D R -D Q 
ha pl ot y pes , 
, M M T T C -pe pti de a n d gl uc ose 
( ma xi m u m 1 0 0 m L) will be ta ke n d uri n g scree ni n g t o baseli ne;  
- bl o o d sa m ples f or H b A 1c,
, M M T T C -pe pti de a n d 
gl uc ose ( ma xi m u m 1 0 0 m L) will be ta ke n at M o nt h 6, 1 2, a n d 1 8 . 
  
C CI
C CI


Study LDX0419 
Ladarixin in new-onset T1D with preserved -cell function 
Page 28 of 69 
 
 
 
Version No. 2 – final 30 July 2020  
 
 
2.5.3.3. 
Mixed Meal Tolerance Test 
Participation in the study requires testing for -cell function through a Mixed Meal Tolerance Test 
(MMTT) to be performed in basal conditions at baseline (pre-dose) and then at the visits at month 6, 12, 
and 18. This is not a routine test in patients with new onset diabetes, but has become a standard for the 
purpose of research studies and is performed frequently by investigational sites.   
Apart from the risks due to blood samplings detailed above, the MMTT requires an overnight fast that 
may potentially increase the risk of a hypoglycemic event. However, detailed instruction for patient 
management provided by the Investigator will minimize the risk of metabolic unbalance. 
2.5.3.4. 
Continuous Glucose Monitoring (CGM) 
The Dexcom G6 Continuous Glucose Monitoring System (Dexcom G6 System) will be use to perform 
a CGM. Sensor will be positioned subcutaneously at the site at least 10 days before the concerned visits 
(baseline, Month 6, 12 and 18) and removed during the visit, as per Study Flowchart (see Appendix 
14.2).  
CGM via sensor positioning is commonly used in diabetic patients to monitor their glucose level.  
Patients can’t wear CGM (sensor, transmitter, receiver, or smart device) for magnetic resonance imaging 
(MRI), computed tomography (CT) scan, or high-frequency electrical heat (diathermy) treatment. Some 
skin care products, such as sunscreens and insect repellents, can make the plastic used in G6 crack.  
If the patient needs assistance with sensor placement/replacement, an ad-hoc visit should be performed. 
2.5.3.5. 
Potential benefit 
To the patients: 
One third of the patients will be assigned to the placebo arm and will therefore obtain 
no disease benefit. The patients assigned to receive ladarixin may possibly benefit 
with control of disease progression, but this is to be ascertained.  
 
All the patients will benefit of increased scrutiny and monitoring that comes with 
being part of a clinical trial. 
To society: 
This study may identify a useful medication that may help controlling the 
progression of T1D in patients with preserved -cell function at onset (fasting C-
peptide ≥0.205 nmol/L at baseline). 
 
 


Study LDX0419 
Ladarixin in new-onset T1D with preserved -cell function 
Page 29 of 69 
 
 
 
Version No. 2 – final 30 July 2020  
 
 
3. 
OVERALL STUDY DESIGN AND INVESTIAGATIONAL PLAN  
3.1. 
STUDY OBJECTIVES 
The objective of this clinical trial is to assess whether ladarixin treatment is effectiveto improve 
glycemic control in newly diagnosed T1D adult patients with preserved -cell function. The safety of 
ladarixin in the specific clinical setting will be also evaluated. 
3.2. 
STUDY ADMINISTRATIVE STRUCTURES, STAFF AND RESPONSIBILITY 
This study is planned to be performed at centers in EU and US. At each study center, the Principal 
Investigator (PI) will be responsible for ensuring that the investigation is conducted according to the 
signed Investigator agreement, the protocol, GCP guidelines, and local regulations.  
The PI at each study center will be responsible for the management of the study, which will consist of 
maintaining the study file and the patient records, corresponding with the IRB (specifically for US), 
reporting SAEs within required timelines, completing the case report forms (eCRFs) and any other study 
document.  
The PI is responsible for supervising any individual or party to whom he/she delegates trial related duties 
and functions conducted at the trial site. The PI/institution should ensure that any individual or party 
that performs trial related duties and functions is qualified to perform those trial related duties and 
functions and should implement procedures to ensure the integrity of the trial related duties and 
functions performed and any data generated. Similarly, it is the responsibility of the PI to ensure that all 
personnel involved in the study are fully informed of all relevant aspects of the study, including detailed 
knowledge of and training in all procedures to be followed.  
The PI will maintain a list of delegated responsibility detailing the various study tasks to be performed 
by each member of his/her study staff. Each staff member should sign in agreement to their performing 
each of the tasks delegated to them on the list. Where reference is made in this protocol to the PI, either 
the PI and/or one or more delegated members of his/her staff are meant, according to the list of delegated 
responsibility. 
3.3. 
OVERALL STUDY DESIGN 
The study will be a phase 2, multicenter, double-blind, placebo-controlled study.   
It has been designed to evaluate whether ladarixin is effective in preserving -cell function and slowing-
down the progression of T1D) in patients maintaining a high residual -cell function at onset.      
It will involve 75 adult (18-45 years, inclusive) patients with new-onset T1D.  Patients will be randomly 
(2:1) assigned to receive either ladarixin treatment (400 mg b.i.d. for 13 cycles of 14 days on/14 days 
off - treatment group) or matched placebo (control group).  The two groups will be balanced within 
centers.   
Recruitment will be competitive among the study sites, until the planned number of patients is enrolled.  
Competitive recruitment has been chosen to increase the speed of recruitment and to account for any 
difference among study sites in the rate and timing of patient referral.  
Each patient will be involved in the study for a run-in period (Screening and Baseline assessments) 
followed by a randomization visit and a post-randomization period up to 18 months from the 1st IMP 
dose, as per details below: 
- A run-in period including 2 or more visits up to a maximum of 100 days; this includes the time 
required to confirm the diagnosis, assess fasting C-peptide, and perform baseline assessment;  
- A randomization visit; 
- A treatment period of 12 months, to include 5 visits scheduled at the end of the 3rd (Week 11) and 
6th (Week 23) treatment cycles, at Month 6 (Week 26), at the end of the 9th (Week 35) treatment 
cycle and at Month 12 (Week 52) from the 1st dose of study treatment; 
- One post-treatment follow-up visits scheduled at Month 18 (week 78) from the 1st dose of study 
treatment.  


Study LDX0419 
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Page 30 of 69 
 
 
 
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Figure 1 shows the major milestones of the study design (run-in period, treatment, follow-up visits). 
First treatment administration should start within maximum 100 days from the first insulin dose 
and will continue  for 3 months. Administration will be extended up to one year only after the FDA has 
notified that such longer exposure to ladarixin is acceptable after having reviewed chronic toxicology 
data in rats and dogs. 
The time frame for the primary endpoint (HbA1c <7% and daily insulin requirement <0.5 IU/Kg/day) 
has been set at Month 12 (Week 52) in order to evaluate the potential of ladarixin effects on a long-term 
projection. Follow-up is extended up to 18 months to evaluate the potential persistency of any glycemic 
benefit.  
The study will proceed under double-blind condition up to the month 12 visit of the last patient 
randomized. Thereafter, the blind will be broken and remaining follow-up will proceed in an open 
fashion. This approach will allow to anticipate access to safety and efficacy data without significantly 
affecting data integrity.  
FIG.1: Design of Study LDX0419 
 
 
 
 
 
3.4. 
STUDY TIME TABLE 
Overall study timelines are reported below. 
 
Projected starting date (first-patient-in): Q4-2020 
 
Projected completion of patient accrual (last-patient-in):Q2-2022 
 
Projected study end date (last-patient-last-visit): Q4-2023 
 
3.5. 
END OF STUDY 
For the purpose of this trial, the End of Study is defined as the date of the last visit of the last patient. 


St u d y L D X 0 4 1 9  
L a d arixi n i n ne w-o nset T 1 D wit h preserve d -cell f u ncti o n 
P a ge 3 1  of  6 9  
 
 
 
Versi o n N o. 2  –  fi nal 3 0 J ul y 2 0 2 0   
 
 
4.  
S T U D Y  E N D P OI N T S  
St u d y e n d p oi nts are liste d bel o w wit h rele va nt ti me fra me, w here:  
M o nt h 6 = 2 6 + 2 wee ks; M o nt h 1 2 = 5 2 + 2 wee ks; M o nt h 1 8 = 7 8 + 2 wee ks . 
4. 1.  
E F FI C A C Y E N D P OI N T S  
- Pr o p orti o n of patie nts wit h H b A 1c < 7 % a n d dail y i ns uli n re q uire me nt < 0. 5 0 I U/ K g/ da y [P ri m ar y 
e n d p oi nt.  Ti me fra me: M o nt h 1 2]  
 
Sec o n d ar y e n d p oi nts:  
- Pr o p orti o n of patie nts wit h H b A 1c < 7 % a n d dail y i ns uli n re q uire me nt < 0. 5 0 I U/ K g/ da y [P ri m ar y 
e n d p oi nt.  Ti me fra me: M o nt h 6 a n d 1 8 ] 
- Pr o p orti o n of patie nts wit h a re d ucti o n i n H b A 1c %  > 0. 5 % fr o m baseli ne a n d dail y i ns uli n 
re q uire me nt < 0. 5 0 I U/ K g/ da y [ Ti me fra me: M o nt h 6 , 1 2, 1 8] 
- 2 -h o ur A U C of C -pe pti de res p o nse t o t he M M T T [ Ti me fra me: M o nt h 6, 1 2, 1 8]    
- Ti me i n ra n ge ( TI R ) b y C o nti n u o us Gl uc ose M o nit ori n g (C G M ) [ Ti me fra me: M o nt h 6, 1 2, 1 8 ]  
- H b A 1c le vels [ Ti me fra me: M o nt h 6, 1 2, 1 8 ] 
- Pr o p orti o n of patie nts wit h H b A 1c < 7 % w h o di d n ot e x perie nce se vere h y p o gl yce mic e ve nts 
d uri n g treat me nt [ Ti me fra me: M o nt h 6, 1 2, 1 8 ] 
F or t he p ur p ose of t his pr ot oc ol, a severe hy p o glyce mic eve nt is defi ne d as a n eve nt wit h o ne of 
t he f oll o wi n g sy m pt o ms: “me m ory l oss, c o nf usi o n, u nc o ntr oll a ble be h avi or, irr ati o n al be h avi o r, 
u n us u al diffic ulty i n a w ake ni n g, s us pecte d seiz ure, seiz ure, l oss of c o nsci o us ness, or vis u al 
sy m pt o ms ”, i n w hic h t he s u bject w as u n a ble t o tre at hi m/ herself a n d w hic h w as ass oci ate d wit h 
eit her a bl o o d gl uc ose level < 5 4 m g/ d L  or pr o m pt rec overy after or al c ar b o hy dr ate, i.e. gl uc ose, 
or gl uc a g o n a d mi nistr ati o n . 
- A d diti o nal Gl uc ose Varia bilit y I n dices  deri ve d fr o m C G M ( gl uc ose A U C o utsi de t he tar get ra n ge 
of 7 0 –  1 8 0 m g/ d L, 2 -h o ur p ost pra n dial gl uc ose ( P P G ), Mea n A m plit u de Gl yce mic E xc ursi o ns 
(M A G E ), c o nti n u o us o verall net gl yce mic acti o n (C O N G A )-n, Mea n Of t he Dail y Differe nces 
(M O D D ), a n d mea n dail y bl o o d gl uc ose, S D ( Sta n dar d De viati o n) . [ Ti me fra me: M o nt h 6, 1 2, 
1 8 ]  
- N u m ber of self -re p orte d e pis o des of se vere h y p o gl yce mia [ Ti me fra me: M o nt h 6, 1 2, 1 8 ] 
- A vera ge ( pre vi o us 3 da ys) dail y i ns uli n re q uire me nts (I U/ k g/ da y) [ Ti me fra me: M o nt h 6, 1 2, 1 8 ]  
- E sti mate d Gl uc ose Dis p osal Rate (e G D R) [ Ti me fra me: M o nt h 6, 1 2, 1 8 ] 
4. 3.  
S A F E T Y  E N D P OI N T S  
- Vital si g ns ( bl o o d press ure a n d heart rate) [ti me fra me: e n d of 3 r d (Wee k 1 1 ) 6t h  (Wee k 2 3 ) a n d 
9 t h (Wee k 3 5 ) treat me nt c ycle, M o nt h 1 2 a n d M o nt h 1 8]  
- R o uti ne la b orat or y tests ( he mat ol o g y, cli nical c he mistr y) [ti me fra me: e n d of 3 r d (Wee k 1 1 ) 6t h 
( Wee k 2 3) a n d 9 t h ( Wee k 3 5) treat me nt c ycle, M o nt h 1 2 a n d M o nt h 1 8 ( or wit h dra wal)]  
- I nci de nce of A d verse E ve nts ( A Es) a n d Seri o us A d verse E ve nts ( S A Es) [T ime fra me: t hr o u g h o ut 
t he st u d y] 
C CI


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5. 
STUDY POPULATION 
Seventy-five (75) adult patients with new-onset T1D will be included (randomized) in the study, selected 
from those having a fasting C-peptide ≥0.205 nmol/L on two occasions or those referring to the site for 
diagnosis confirmation (auto-antibody testing) and/or disease management. Patients can be considered 
for inclusion in this trial if they fall within the definition of new-onset T1D (randomization scheduled 
to allow the administration of the study medication to start within 100 days from 1st insulin 
administration) and have a confirmed diagnosis (positive for at least one auto-antibody). 
Each patient will be randomized provided that (s)he fully meets all of the study Inclusion Criteria and 
none of the Exclusion Criteria described in Sections 5.1. and 5.2. below. 
5.1. 
INCLUSION CRITERIA 
To be eligible for inclusion into this study, each patient must fulfil the following inclusion criteria.  
1. 
Male and female patients aged 18-45 years, inclusive;  
2. 
New-onset T1D (1st IMP dose within 100 days from 1st insulin administration); 
3. 
Positive for at least one diabetes-related auto-antibody (anti-GAD; IAA, if obtained within 10 days 
of the onset of insulin therapy; IA-2 antibody; ZnT8); 
4. 
Require, or has required at some time, insulin therapy through multiple daily injections (MDI) or 
Continuous Subcutaneous Insulin Infusion (CSII); 
5. 
Fasting C peptide ≥0.205nmol/L on two occasions; 
6. 
Patient able to comply with all protocol procedures for the duration of the study, including 
scheduled follow-up visits and examinations; 
7. 
Patients who have given written informed consent prior of any study-related procedure not part of 
standard medical care. 
5.2. 
EXCLUSION CRITERIA 
Patients who meet any of the following criteria are NOT eligible for inclusion in the study. 
1. 
Any other chronic disease, including type 2 diabetes, apart from autoimmune hypothyroidism 
requiring thyroid hormone replacement only; patients with severe (myxedema) disease potentially 
requiring immunosuppressive therapy will be excluded;  
2. 
Moderate to severe renal impairment as per estimated Glomerular Filtration Rate (eGFR) 60 
mL/min/1.73 m2, as determined using Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) creatinine equation (see Appendix 14.4.3); 
3. 
Hepatic dysfunction defined by increased ALT/AST > 3 x upper limit of normal (ULN) and 
increased total bilirubin > 3 mg/dL [>51.3 μmol/L]; 
4. 
Hypoalbuminemia defined as serum albumin < 3 g/dL; 
5. 
QTcF > 470 msec; 
6. 
A history of significant cardiovascular disease/abnormality  
7. 
Occurrence of an episode of ketoacidosis or hypoglycemic coma in the past 2 weeks; 
8. 
Known hypersensitivity to non-steroidal anti-inflammatory drugs; 
9. 
Concomitant treatment with drugs metabolized by CYP2C9 with a narrow therapeutic index [i.e., 
phenytoin, 
warfarin, 
sulphanylurea 
hypoglycemics 
(e.g. 
tolbutamide, 
glipizide, 
glibenclamide/glyburide, glimepiride, nateglinide) and high dose of amitriptyline (>50 mg/day)]; 
10. Previous (within 2 weeks prior to randomization) and concomitant treatment with antidiabetic 
agents as metformin, sulfonylureas, glinides, thiazolidinediones, exenatide, liraglutide, DPP-IV 


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inhibitors, SGLT2-inhibitors or amylin, or any medications known to influence glucose tolerance 
(e.g. -blockers, angiotensin-converting enzyme inhibitors, interferons, quinidine antimalarial 
drugs, lithium, niacin, etc.); 
11. Past (within 1 month prior to randomization) or current administration of any immunosuppressive 
medications (including oral, inhaled or systemically injected steroids) and use of any 
investigational agents, including any agents that impact the immune response or the cytokine 
system; 
12. Significant systemic infection during the 4 weeks before the first dose of the study drug (e.g., 
infection requiring hospitalization, major surgery, or IV antibiotics to resolve; other infections, e.g., 
bronchitis, sinusitis, localized cellulitis, candidiasis, or urinary tract infections, must be assessed on 
a case-by-case basis by the investigator regarding whether they are serious enough to warrant 
exclusion); 
13.  Hepatitis A (IgM), hepatitis B (not due to immunization), hepatitis C and HIV positive serologic 
status Serologic evidence of current infectious liver disease (hepatitis A, B, or C), including ant 
hepatitis A virus (immunoglobulin M), hepatitis B surface antigen, or ant hepatitis C virus and HIV; 
14.  Pregnant or breast feeding women.  Unwillingness to use effective contraceptive measures up to 2 
months after the end of study drug administration (females and males).  Effective contraceptive 
measures include a hormonal birth control (e.g. oral pills, long term injections, vaginal ring, patch); 
the intrauterine device (IUD); a double barrier method (e.g. condom or diaphragm plus spermicide 
foam). 
5.3. 
ASSIGNMENT OF PATIENT NUMBER 
At the screening visit each patient will be assigned a unique sequential patient number by an Interactive 
Response System (IRS). This number will be used for identification throughout the study and will not 
be used for any other participant.  
If a patient is dropped from the study for any reason, the patient’s randomization number will not be 
reassigned. 
 
 


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6.  
S T U D Y M E DI C A TI O N  
6. 1.  
P R E S E N T A TI O N, 
S T O R A G E, 
P A C K A GI N G 
A N D 
L A B E LI N G  O F 
T H E 
I N V E S TI G A TI O N A L M E DICI N A L P R O D U C T  
6. 1. 1.  
P rese nt ati o n of  I n vesti g ati o n al Me dici n al Pr o d uct  
I n t his stu d y t he I n vesti gati o nal Me dici nal Pr o d uct  (I M P) will be eit her la dari xi n O R  matc he d place b o . 
It will be pr o vi de d as har d gelati ne ca ps ules  f or oral a d mi nistrati o n, wit h t he f oll o wi n g c o m p ositi o n: 
C o m p ositi o n f or e ac h u nit (c a ps ule) 
 
Batc h release certificate  will be pr o vi de d t o get her wit h t he I M P .  
6. 1. 2.  
M a n uf act uri n g, P ac k a gi n g  a n d L a be lli n g of IM P  
Ca ps ules will be ma n ufact ure d b y 
 will ma na ge t he la belli n g 
a n d pac ka gi n g of ca ps ules i n blisters t o o btai n t he Patie nt Kit.      
T he st u d y me dicati o n will be pr o vi de d as a Patie nt Kit , c o ntai ni n g 2  Treat me nt  wallets, c o veri n g t he 
treat me nt peri o d of 1 c ycle. Eac h Treat me nt wallet  will c o ntai n treat me nt 2 8 ca ps ules .   
All la bels will be pre pare d t o meet l ocal re g ulat or y re q uire me nts.  Details of pac ka gi n g a n d la be lli n g are 
re p orte d i n A p pe n di x 1 4. 1 . 
6. 1. 3.  
S u p pl y, St or a ge a n d H a n dli n g of I M P 
A n a p pr o priate n u m ber of pac ka ges  will be i nitiall y se nt t o t he site as s o o n as all esse ntial d oc u me nts 
a n d re g ulat or y/et hics a p pr o vals ha ve bee n o btai ne d. I M P re -s u p pl y will be pla n ne d  o n de ma n d, 
acc or di n g t o e nr ol me nt rate.  
T he I M P m ust be ke pt at a te m perat ure n ot e xcee di n g 3 0° C  a n d m ust n ot be fr oze n .  
A te m perat ure pr o be will acc o m pa n y t he dr u g o n s hi p me nt. Te m perat ure ra n ge reac he d d uri n g s hi p me nt 
will be verifie d o n recei pt at site, s o t hat p ote ntial sta bilit y c o ncer ns d uri n g s hi p me nt ca n be i n vesti gate d 
a n d a p pr o priate acti o n ta ke n.  
O nce recei ve d at t he site, t he P har macist ( or desi g nee) will c hec k t he pac ka ge f or acc urate deli ver y a n d 
ac k n o wle d ge recei pt; a n y de viati o ns fr o m e x p ecte d pac ka ge c o nte nt (i nc o nsiste nc y, da ma ges) s h o ul d 
be i m me diatel y re p orte d t o D o m pé ( or a p p oi nte d C R O ) a n d t he use of t he dr u g s us pe n de d u ntil 
a ut h orizati o n f or its c o nti n ue d use has bee n gi ve n b y D o m pé ( or  a p p oi nte d C R O).   
T he I M P m ust be st ore d at si te i n a sec ure l ocati o n, i n a te m perat ure c o ntr olle d r o o m. Te m perat ure 
rec or ds m ust be a vaila ble f or t he C R A t o re vie w at m o nit ori n g visits; a n y de viati o ns fr o m t he 
rec o m me n de d st ora ge c o n diti o ns s h o ul d be i m me diatel y re p orte d t o D o m pé ( or a p p oi nte d C R O ) an d 
P P D
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the use of the drug suspended until authorization for its continued use has been given by Dompé (or 
appointed CRO). 
6.1.4. 
Blinding 
Appearance, including packaging and labelling, of the IMP (capsules, packaging) will not allow to 
recognize actual treatment (either ladarixin or placebo). 
During the trial, blinding will be broken by the Investigator for emergency purposes only, where 
knowledge of the blinded treatment could influence further patient care. In addition, safety reports will 
be unblinded, as per regulatory requirements. 
Study blind will be broken after database lock. 
6.2. 
IMP DISPENSATION 
The IMP will be dispensed quarterly only by the Pharmacist (or authorized designee at site).   
The IMP will be dispensed via IRS as Patient Kits during the Randomization Visit and then during the 
Visits scheduled at the end of the 3rd (Week 11), 6th (Week 23) and 9th (Week 35) treatment cycles, after 
check of inclusion/exclusion criteria (at Randomization) and discontinuation criteria at the scheduled 
visits * (see Section 6.4.2).  
A total number of 13 Patient IMP Kits will be dispensed to each randomized subject as follows: 
- at Randomization Visit dispensed 3 Patient Kits of IMP for the Cycles 1, 2 and 3 
- at Week 11 Visit dispensed 3 Patient Kits for the Cycles 4, 5 and 6 
- at Week 23 Visit dispensed 3 Patient Kits for the Cycles 7, 8 and 9 
- at Week 35 Visit dispensed 4 Patient Kits for the Cycles 10, 11, 12 and 13 
[* Results of ALT/AST, bilirubin, creatinine, albumin, ECG readings and pregnancy results should be 
made available by local laboratory in time to allow Patient Kits dispensation as soon as possible during 
the visit. If this expedite timing cannot be achieved, Patient Kits might be delivered to patient named 
address by a selected courier (CRO to support shipment). Study drug dispensation will be performed as 
soon as possible after check of discontinuation criteria.] 
6.3. 
DOSE, ROUTE AND SCHEDULE OF IMP ADMINISTRATION 
 
Ladarixin will be administered orally at the dose of 400 mg twice a day for 3 cycles of 14 days on / 14 
days off.  Placebo will be administered with the same treatment schedule. Administration will be 
extended up to 12 months (13 cycles) only after additional chronic toxicity data support such longer 
treatment. 
 
The two daily doses will be administered at about 12hour interval (morning and evening; ideally 
between 6:30/11:30 and 18:30/23:30). At each administration, 2 capsules will be swallowed with a glass 
of water, at least 2 hours apart from breakfast or dinner.  
6.4. 
CRITERIA FOR SCHEDULE ADJUSTMENT/DOSE-MODIFICATION OR 
DISCONTINUATION OF THE IMP 
6.4.1. 
Criteria for schedule adjustment or dose modification 
No schedule adjustment and/or dose modification is foreseen, except for discontinuation of IMP as 
detailed below. 


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6.4.2. 
Criteria for discontinuation of the IMP 
The IMP will be discontinued in the case: 
 
QTcF is either > 500 msec or increases by > 60 msec from screening measurement on two 
consecutive ECG readings taken 1 hour apart;  
 
The patient develops any significant cardiovascular disease/abnormality; 
 
The patient develops renal (calculated eGFR < 60 mL/min) or hepatic (increased ALT/AST > 3 x 
ULN and increased total bilirubin > 3mg/dL [>51.3 mol/L]) dysfunction as well as 
hypoalbuminemia (serum albumin <3 g/dL); 
 
Pregnancy occurs (female patient); 
 
The patient develops any significant systemic infection that must be assessed on a case-by-case 
basis by the investigator regarding whether they are serious enough to warrant discontinuation. 
 
The patient develops ketoacidosis or hypoglycemic coma. 
Occurrence of any condition that qualify the patient to treatment discontinuation will be specifically 
monitored through ECG readings and laboratory tests obtained at the visits scheduled at the end of the 
3rd (Week 11), 6th (Week 23) and Week 23) and 9th (Week 35) treatment cycles.  
In addition, the IMP will be immediately discontinued in the event of any other possibly drug related 
occurrences that the Investigator believes might compromise patient’s safety.   
If the IMP administration is prematurely discontinued, the primary reason for discontinuation must be 
recorded in the eCRF. Patients who discontinue the treatment with the IMP will NOT be withdrawn 
from the study by default, but will be asked to complete safety and efficacy observations as per the 
protocol, unless otherwise they withdraw their consent. 
6.5. 
ACCOUNTABILITY OF THE IMP 
All supplies will be maintained under adequate security by the designated member of site staff, until 
they are dispensed to the patients. The Investigator will ensure that study treatment is only dispensed by 
designated staff within the center.   
When the IMP is received at the site, designated member of site staff will check for accurate delivery 
and acknowledge receipt by signing and dating the documentation provided by or on behalf of Dompé 
and returning it to Dompé or to the appointed CRO. A copy will be retained for the 
Investigator/Pharmacy file. 
The dispensing of the IMP will be carefully recorded on the eCRF and appropriate drug accountability 
forms and an accurate accounting will be available for verification by the CRA at each monitoring visit.  
Immediately before dispensing each Patient Kit, the kit label will be completed with the required 
information (i.e. Patient ID number and Investigator Name).     
Drug accountability records will include: 
1. the confirmation of receipt of the IMP at the trial site, 
2. the dispensing of the IMP to the patient, 
3. the receipt of IMP returned from the patient,  
4. the disposition of unused product(s), 
5. accounts of any IMP accidentally or deliberately destroyed, 


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They should include dates, quantities, batch numbers, expiration dates (if applicable), and any unique 
code numbers assigned to the IMP and/or patients. Investigators should maintain records which 
document adequately that: 
1. the patients were provided the doses specified by the protocol/amendment(s), 
2. the IMP provided was fully reconciled at the site. 
The administration of the IMP (date/time for each administration) will be recorded by the patient in the 
Patient Diary whose data will be checked by the Investigator during the next study visit. 
The CRA will review the drug accountability forms/eCRF and check all IMP (both unused and used) 
prior to making arrangements for their disposal. 
IMP which has been dispensed to a patient and returned unused will not be re-dispensed to a different 
patient.  Unused IMP (capsules) must remain in the blisters within the Patient Kit and must not be 
discarded or used for any purpose. Any remaining test material at the end of the trial will be returned to 
Dompé or disposed of, as determined by Dompé. 
6.5.1. 
Assessment of compliance 
Compliance with the study product dosing schedule will be verified by a CRA during on-site monitoring 
visits, as per records in the eCRF versus accountability records and actual capsules in the Patient Kits 
returned by the patient.  
6.6. 
CONCOMITANT MEDICATION 
6.6.1. 
Reporting of prior and concomitant medications 
Administration of all prior (within 1 month before enrolment) and concomitant medications (CMEDs), 
apart from insulin and the agents listed below, will be reported in the appropriate section of the eCRF.   
All the details as per the eCRF fields (sequential number, drug name, indication, starting dose, start/stop 
date, route of administration) will be recorded. Change in dose will be tracked. 
The following agents do not need to be recorded: homeopathic medications; elective vitamins and 
minerals; osmotic laxatives and locally acting antacids; topical medication. 
6.6.2. 
Restriction on allowed prior and concomitant medications 
The following medications should not be used prior to enrolment and up to the end of study 
participation:  
Drugs that affect glucose homeostasis or its readout 
 Twice daily pre-mixed insulin  
 Metformin, sulfonylureas, glinides, thiazolidinediones, exenatide, liraglutide, DPP-IV inhibitors, 
SGLT-2 inhibitors or amylin, or any medications known to influence glucose tolerance (e.g. -
blockers, angiotensin-converting enzyme inhibitors, interferons, quinidine antimalarial drugs, 
lithium, niacin, etc) [off period before randomization = 2 weeks]; 
 Any immunosuppressive medications, including oral, inhaled or systemically injected steroid, and 
any other investigational agents, including any agents that impact the immune response or the 
cytokine system [off period before randomization = 1 month]. 
Drugs metabolized by CYP2C9 with a narrow therapeutic index (drugs that may have their plasma 
concentration and effect altered by inhibition of CYP2C9 by ladarixin). 
 Phenytoin, 
warfarin, 
sulphanylurea 
hypoglycemics 
(e.g. 
tolbutamide, 
glipizide, 
glibenclamide/glyburide, glimepiride, nateglinide) and high doses of amitriptyline (> 50 mg/day). 
 


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The following medications can be used with the restrictions detailed below:  
 Non-steroidal anti-inflammatory drugs (e.g. ibuprofen, flurbiprofen, indomethacin, piroxicam, 
naproxen, meloxicam, lornoxicam, celecoxib) can be used during treatment with ladarixin up to a 
maximum of 3 consecutive days, with a 3 days’ washout before re-treatment, if any (excluded 
patients with known hypersensitivity to non-steroidal anti-inflammatory drugs). 
 Administration of low doses amitriptyline (< 50 mg/day) is allowed under clinical monitoring for 
possible side effect (e.g. sedation and anticholinergic symptoms).  In case a concern is raised, 
treatment with either amitriptyline or ladarixin should be immediately discontinued.  
 Any drug that is known to be a substrate for cytochrome CY2C9 should be considered for possible 
drug-drug interaction as per warnings/precautions reported in the Summary of Product 
Characteristics. Any possible concern should be discussed with the sponsor Medical Expert prior to 
patient enrolment or concomitant administration with ladarixin.       
6.7. 
INSULIN TITRATION 
Patients will self-monitor glucose levels at least 4 times a day and will take insulin as prescribed by the 
Investigator throughout the study participation (see Section 7.1.1). 
To ensure standardized glycemic control in the treatment groups, the Investigator will provide guidance 
for insulin regimen adjustment, with insulin titrated up or down to target HbA1c levels of less than 7% 
and SMBG (fingerstick or CGM): 
 pre-prandial blood glucose of 70-130 mg/dL 
 2 hours post-prandial blood glucose < 180 mg/dL 
 bed-time blood glucose of 110-150 mg/dL 
Glucose test strips and glucose monitor will be provided to study participants for the duration of the 
study. In order to optimize insulin titration, telephone calls (outside scheduled visits) will be scheduled 
on a regular basis to ensure timely evaluation of glucose levels and adjustment of insulin regimen.    


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7. 
STUDY PROCEDURE AND ASSESSMENTS 
A schedule for the tests and evaluations to be conducted in this study is found in the flow chart in 
Appendix 14.2. 
For all measurements, the actual date and time of assessment, including date of sampling, will be recorded 
in the eCRF.  Time frame for each assessment is reported in the following sections. Month /Week match 
is detailed below, together with acceptable windows:  
Month 6 = Week 26+2; Month 12 = Week 52+2; Month 18 = Week 78+2. 
7.1. 
ENROLMENT, SCREENING AND RANDOMIZATION 
7.1.1. 
Enrolment and Intensive Diabetes Management 
Potential study patients with a recent clinical diagnosis of T1D will be have a fasting C-peptide ≥0.205 
nmol/L on two occasions; these patients will be considered if they fall within the definition of new-onset 
T1D (randomization scheduled to allow the administration of the study medication to start within 100 
days from 1st insulin administration) and will have a diagnosis (positive for at least one auto-antibody).  
Enrolment is defined as the signature of the Informed Consent Form (ICF) for participation in the study 
LDX0419. 
From enrolment, patients will be admitted to an intensive diabetes management, according to current 
ADA recommendation [2014].  Patients will be instructed to self-monitor their glucose values at least 4 
times a day and to report (glucose meter/log) outcome to the diabetes management team.  Insulin intake 
will be adjusted to target HbA1c levels of less than 7% and SMBG (fingers stick or CGM): 
 pre-prandial blood glucose of 70-130 mg/dL 
 2 hours post-prandial blood glucose < 180 mg/dL 
 bed-time blood glucose of 110-150 mg/dL 
Glucose test strips and glucose monitor will be provided to study participants for the duration of the 
study. Telephone calls (outside scheduled visits) will be scheduled on a regular basis to ensure 
optimization of metabolic control. It is expected that patients are contacted at least every 2 to 3 weeks 
during study participation. A telephone call will be anyway scheduled in the 2 weeks before a planned 
visits (as detailed in the sections below) to enable the Investigator to review glucose data and 
confirm/adjust insulin intake to be applied for at least 3 days before the visit. 
7.1.2. 
Run-in period 
Screening, including confirmation of T1D diagnosis, will be performed in enrolled (consented) patients. 
Screening includes the following assessments, and may be performed in one or more visits, as per details 
below:    
 time frame: from enrolment to baseline (clinical information) 
• Past medical history and disease-specific clinical information, including date of first insulin 
administration; 
• Blood sampling for measurement (centralized laboratory) of auto-antibody (anti-GAD; IAA, if 
obtained within 10 days of the onset of insulin therapy; IA-2 antibody; ZnT8) to confirm T1D 
diagnosis and of fasting C-peptide;  
     Samples will be obtained and stored as detailed in Appendix 14.3.1. 
 time frame: within 3 weeks before study treatment start (baseline measurements - consider time for 
centralized assay of MMTT C-peptide – results available)  
• 
Vital signs. 
• 
Body weight, height, waist and waist/hip circumference. 
• 
Evaluation of eGDR (see equation in Appendix 14.3.4) and BMI. 


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• 
Bl o o d sa m pli n g(s) f or meas ure me nt (l ocal la b orat ories) of “ Safet y La b orat or y T ests”.  
• 
E val uati o n of re nal a n d he patic f u ncti o n (t o be deri ve d fr o m t he safet y la b orat or y test res ults).  
• 
R e n al f u ncti o n will b e ev al u at e d b y e G F R, d et er mi n e d usi n g C K D -E PI cr e ati ni n e e q u ati o n 
(L e v ey A S. 2 0 0 9 –  A p p e n di x 1 4. 3. 3 )   
• 
H e p atic f u ncti o n will b e e v al u at e d b y bilir u bi n a n d tr a ns a mi n as es ( AL T a n d A S T). 
 
• 
Scree ni n g 1 2 lea d E C G, perf or me d usi n g l ocal e q ui p me nt t hat all o ws a ut o matic calc ulati o n of 
t he Q T c F. 
• 
Pre g na nc y test ( uri ne di pstic k or bl o o d sa m ple), if a p pr o priate.  
• 
Baseli ne i ns uli n re q uire me nt (I U/ k g/ da y a vera ge d o ver t he pre vi o us 3 da ys).  
• 
Bl o o d sa m pli n g f or meas ure me nt (ce ntralize d la b orat or y) of baseli ne H b A 1c.  
• 
Bl o o d sa m pli n g f or meas ure me nt (ce ntralize d la b orat or y) of H L A D R -D Q ha pl ot y pes a n d 
Pr oi ns uli n.  
• 
Baseli ne M M T T.  Bl o o d sa m ples f or meas ure me nt (ce ntralize d la b orat o r y) of C-pe pti de a n d 
gl uc ose will be dra w n pre -meal ( 2 basal sa m ples i n t he ra n ge bet wee n -2 0 t o 0) a n d 1 5, 3 0, 6 0, 
9 0, 1 2 0 mi n after t he meal.  Pr oce d ures f or M M T T a n d sa m ple ha n dli n g are detaile d i n 
A p pe n di x 1 4. 3. 6  a n d A p pe n di x 1 4. 3 . 1, res pecti vel y.  M M T T s h o ul d n ot be perf or me d wit hi n 
o ne wee k of res ol uti o n of a dia betic ket oaci d osis e ve nt;    
• 
E val uati o n of P r oi ns uli n: C-pe pti de rati o  
• 
C G M d o w nl oa d f or e val uati o n of Gl uc ose Varia bilit y I n dices fr o m C G M . * *  
• 
Bl o o d sa m pli n g f or meas ure me nt (ce ntralize d  la b orat or y) of 
. 
 
* * T he C G M de vice will be p ositi o ne d at least 1 0 da ys bef ore t he baseli ne assess me nt .  
Patie nts w h o d o n ot meet t he I ncl usi o n Criteria or meet E xcl usi o n Criteria will be c o nsi dere d scree n 
fail ures (scree ni n g n u m ber assi g ne d) a n d will n ot be all o we d t o be re -c o nsi dere d f or i ncl usi o n i nt o t he 
st u d y. 
7. 2.  
R A N D O MI Z A TI O N  & S T A R T O F D R U G A D MI NI S T R A T I O N 
C o m plia nce wit h i ncl usi o n/e xcl usi o n criteria will be fi nall y verifie d vs de m o gra p hic, la b orat or y test 
res ults a n d cli nical i nf or mati o n.   
Patie nts f ulfilli n g all  t he i ncl usi o n criteria a n d n o ne  of t he e xcl usi o n criteria will refer t o t he site f or a 
R a n d o miz ati o n Visit  t o occ ur wit hi n ma xi m u m 3 da ys bef ore t he I M P a d mi nistrati o n is starte d .  
D uri n g t he visit t he patie nt  will be ra n d o mize d (ra n d o mizati o n n u m ber assi g ne d b y a n I R S s yste m); t he 
Patie nt Diar y will be deli vere d a n d t he Patie nt Kits f or t he 1 st t o 3r d treat me nt c ycles will be dis pe nse d. 
It is t he res p o nsi bilit y of t he I n vesti gat or ( or desi g nee) t o e x plai n, a n d ma ke s ure patie nt f ull y 
u n dersta n ds a n y a p pr o priate treat me nt relate d i nf or mati o n.  T his i ncl u des, b ut is n ot li mite d t o treat me nt 
sc he d ule, ti me of a d mi nistrati o n, ti me i nter val fr o m meals, rec or di n g of treat me nt a d mi nistrati o n a n d 
ot her data i n the Patie nt Diar y , etc.       
T he da y w he n t he patie nt starts I M P a d mi nistrati o n is defi ne d as D a y 1  of t he 1st treat me nt c ycle. 
D a y 1  M U S T be sc he d ule d n o l ater t h a n 1 0 0 d a ys fr o m t he 1
st i ns uli n i njecti o n a n d is t o be sc he d ule d 
wit hi n 3 wee ks fr o m t he baseli ne assess me nts . 
T he a d mi nistrati o n of t he I M P ( date/ti me f or eac h a d mi nistrati o n, n u m ber of ca ps ules) will be rec or de d 
b y t he patie nt i n t he Diar y  w hic h data will be  c hec ke d b y t he I n vesti gat or d uri n g t he ne xt st u d y visit.  
7. 3.  
T R E A T M E N T P E RI O D A N D  C H E C K O F T R E A T M E N T DI S C O N T I N U A TI O N 
C RI T E RI A  
After t he treat me nt has starte d, I M P a d mi nistrati o n w ill pr ocee d f or a d diti o nal 1 2 c ycles  of 1 4 da ys 
o n/ 1 4 da ys off , u nless t here is a n y reas o n f or dr u g disc o nti n uati o n (see Secti o n 6. 4 . 2). O n eac h treat me nt 
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cycle, the IMP will be administered at 12 hours interval (morning and evening; ideally in between 
6.30/11.30 and 18.30/23.30). At each administration, 2 capsules will be swallowed with a glass of water, 
at least 2 hours apart from breakfast or dinner.   
During treatment, occurrence of any condition that might prevent continuing IMP administration will 
be verified at the visits scheduled during treatment (see below in section 7.4.1) at the end of the 3rd 
(Week 11), 6th (Week 23) and 9th (Week 35) treatment cycles. 
During these visits the following will be measured/assessed (as per center practice actual date and time 
of assessment, or the date of sampling, will be recorded in the eCRF): 
- 
Vital signs. 
- 
Blood sampling(s) for measurement (local laboratories) of “Safety Laboratory Tests”. 
- 
Evaluation of renal and hepatic function (to be derived from the safety laboratory test results).  
- 
12 lead ECG, performed using local equipment that allows automatic calculation of the QTcF. 
- 
Pregnancy test (urine dipstick or blood sample). 
- 
Patient Diary check (IMP administration information). 
As per discontinuation criteria (see Section 6.4.2), no IMP will be dispensed in the case: 
 
QTcF is either > 500 msec or increases by > 60 msec from screening measurement on two 
consecutive ECG readings taken 1 hour apart;  
 
The patient develops any significant cardiovascular disease/abnormality; 
 
The patient develops renal (calculated eGFR < 60 mL/min) or hepatic (increased ALT/AST > 3 
x ULN and increased total bilirubin > 3mg/dL [>51.3 mol/L]) dysfunction as well as 
hypoalbuminemia (serum albumin <3 g/dL); 
 
Pregnancy occurs (female patient);  
 
The patient develops any significant systemic infection that must be assessed on a case-by-case 
basis by the investigator regarding whether they are serious enough to warrant discontinuation. 
 
The patient develops ketoacidosis or hypoglycemic coma. 
 
After having confirmed the patient has not developed a condition that prevents his/her continuing 
participation into the study*, he/she will be provided with the Patient Kits matching his/her 
randomization number, together with the Patient Diary, according to the schedule reported below: (see 
also section 6.2).  
- at Week 11 Visit dispensed 3 Patient Kits for the Cycles 4, 5 and 6 
- at Week 23 Visit dispensed 3 Patient Kits for the Cycles 7, 8 and 9 
- at Week 35 Visit dispensed 4 Patient Kits of IMP for the Cycles 10, 11, 12 and 13 
* Results of ALT/AST, bilirubin, creatinine, albumin, ECG readings and pregnancy results should be 
made available by local laboratory in time to allow dispensation of Patient Kits as soon as possible 
during the visit. If this expedite timing cannot be achieved, Patient Kits might be delivered to patient 
named address by a selected courier (CRO to support shipment).  
The administration of the IMP (date/time for each administration, number of capsules) will be recorded 
by the patient in the Patient Diary which data will be checked by the Investigator during the next study 
visit.  
It is the responsibility of the Investigator (or designee) to check the information the patient will insert in 
the Patient Diary to ensure correct intake of the IMP. The Investigator will remind, and make sure patient 
still fully understands any appropriate treatment related information.     
The Patient Kits containing all the blisters, either unused or empty, will be returned to and checked by 
the Investigator during the next study visit. 


St u d y L D X 0 4 1 9  
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P a ge 4 2  of  6 9  
 
 
 
Versi o n N o. 2  –  fi nal 3 0 J ul y 2 0 2 0   
 
 
7. 4.  
A D DI TI O N A L 
VI SI T S 
D U RI N G 
T R E A T M E N T 
A N D 
F O L L O W -U P 
S T U D Y 
A S S E S S M E N T S  
At eac h visit  descri be d bel o w , t he assess me nt / meas ureme nt will be d o ne  as per ce nt er practice, u nless 
ot her wise s pecifie d. Meas ure me nts, i ncl u di n g t he act ual date a n d ti me of assess me nt, or t he date of 
sa m pli n g, will be rec or de d i n t he eC R F.   
7. 4. 1.  
A d diti o n al visits d uri n g tre at me nt  
D uri n g treat me nt,  p atie nt will atte n d t he ce nter f or st u d y assess me nts o n 2 a d diti o nal visits at M o nt h 6 
( Wee k 2 6) a n d M o nt h 1 2 ( Wee k 5 2). At least 1 0  da ys bef ore eac h sc he d ule d visit, t he C G M se ns or will 
be place d . 
D uri n g t hese visits  t he f oll o wi n g will be assesse d: 
- Waist a n d waist/ hi p circ u mfere nce a n d calc ulati o n of e G D R.   
- Patie nt Diar y c hec k (i nf or mati o n ot her t hat I M P a d mi nistrati o n at M o nt h 6, a n y i nf or mati o n at M o nt h 
1 2) . 
- I ns uli n re q uire me nt (I U/ k g/ da y a vera ge d o ver t he pre vi o us 3 da ys).  
- N u m ber of self -re p orte d e pis o des of se vere h y p o gl yce mia i n t he i nter val. 
- Bl o o d sa m pli n g f or meas ure me nt (ce ntralize d la b orat or y) of H b A 1c.  
- M M T T.  Bl o o d sa m ples f or meas ure me nt (ce ntralize d la b orat or y) of C -pe pti de a n d gl uc ose will be 
dra w n pre -meal ( 2 basal sa m ples i n t he ra n ge bet wee n -2 0 t o 0) a n d 1 5, 3 0, 6 0, 9 0, 1 2 0 mi n after t he 
meal.   
- Bl o o d sa m pli n g f or meas ure me nt (ce ntralize d la b orat or y)  of 
 
.  
- C G M se ns or d o w nl oa d f or e val uati o n of Gl uc ose Varia bilit y I n dices fr o m C G M .   
- Bl o o d sa m pli n g f or meas ure me nt (l ocal la b orat ories) of “ Safet y La b orat or y T ests” ( M o nt h 1 2 o nl y). 
- Vital si g ns ( M o nt h 1 2 o nl y).   
7. 4. 2.  
F oll o w -u p assess me nt  
After ha vi n g c o m plete d t he treat me nt, p atie nts will atte n d t he ce nter f or st u d y assess me nts o n a f oll o w-
u p visi ts sc he d ule d at m o nt h 1 8  ( Wee k 7 8). At least 1 0  da ys bef ore eac h sc he d ule d visit, t he C G M 
se ns or will be place d.  
 
At t his visit, t he f oll o wi n g will be e val uate d/ meas ure d:  
- W aist a n d waist/ hi p circ u mfere nce  a n d e val uati o n of e G D R . 
- I ns uli n re q uire me nt (I U/ k g/ da y a vera ge d o ver t he pre vi o us 3 da ys).  
- N u m ber of self -re p orte d e pis o des of se vere h y p o gl yce mia i n t he i nter val.  
- Bl o o d sa m pli n g f or meas ure me nt (ce ntralize d la b orat or y) of H b A 1c.  
- M M T T.  Bl o o d sa m ples f or meas ure me nt (ce ntralize d la b orat or y) of C -pe pti de a n d gl uc ose will be 
dra w n pre -meal ( 2 basal sa m ples i n t he ra n ge bet wee n -2 0 t o 0) a n d 1 5, 3 0, 6 0, 9 0, 1 2 0 mi n after t he 
meal.  
- C G M d o w nl oa d f or calc ulati o n of C G M deri ve d e n d p oi n ts.  
- Bl o o d sa m pli n g f or meas ure me nt (ce ntralize d la b orat or y)  of 
 
. 
- Patie nt Diar y c hec k (i nf or mati o n ot her t ha n I M P a d mi nistrati o n) . 
- Bl o o d sa m pli n g f or meas ure me nt (l ocal la b orat orie s) of “ Safet y La b orat or y T ests”.  
- Vital si g ns . 
C CI
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7.5. 
EARLY PATIENT WITHDRAWAL 
7.5.1. 
Withdrawal criteria 
Patients will be informed that they have the right to withdraw from the study at any time (withdrawal of 
consent), without prejudice to their medical care, and are not obliged to state their reasons.   
If a patient fails to return to the center for a scheduled visit, attempts should be made to contact the 
patient to ensure that the reason for not returning is not a SAE. Likewise, if a patient declares his/her 
wish to discontinue from the study e.g. for personal reasons, an attempt should be made to establish that 
the true reason is not a SAE (bearing in mind the patient is not obliged to state his/her reasons). 
Safety laboratory tests should be performed whenever possible at patient withdrawal.  
Patients who discontinue the treatment with the IMP will not be withdrawn from the study, but will be 
asked to complete observations as per the protocol, unless otherwise they withdraw their consent.  It is 
important that any randomized patient remains in the study and is followed for both efficacy and safety 
outcomes, regardless he/she has completed or discontinued the study treatment.  
Investigators will be trained about the importance of patient retention through the duration of the trial. 
In case of pregnancy, the patient will be withdrawn from the study, but she will be followed for safety 
and pregnancy outcomes monitoring, unless she withdraws her consent. 
Any withdrawals must be fully documented in the eCRF. 
7.5.2. 
Replacement policy 
No patient who has been randomized and withdraws from the study for any reason will be replaced. 
7.6. 
PATIENT MANAGEMENT AFTER STUDY COMPLETION 
After completion of the week 78 (month 18) follow-up visit, patients will receive post-study care as 
prescribed by their health care provider.  No post-study treatment will be provided by Dompé.  


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8. 
ADVERSE EVENTS 
8.1. 
DEFINITIONS  
8.1.1. 
Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not related to the medicinal product.  
8.1.2. 
Adverse Drug Reaction 
An Adverse Drug Reaction (ADR) is defined as an adverse event, which is reasonably likely to have 
been caused by the IMP. The definition covers also medication errors and uses outside what is foreseen 
in the protocol, including misuse and abuse of the product. For the purposes of IND safety reporting, 
“reasonable possibility” means there are facts (evidence) or arguments to suggest a causal relationship 
between the drug and the adverse event. 
8.1.3. 
Serious Adverse Event/Reaction 
A Serious Adverse Event (SAE)/Reaction is defined as any untoward medical occurrence that at any 
dose: 
 results in death. Death shall always be reported as SAE and cause of death shall always be specified 
when known. 
 is life-threatening (i.e. the patient was at risk of death at the time of the event.  It does not refer to 
an event which hypothetically might have caused death if it were more severe), 
 requires inpatient hospitalization or prolongation of existing hospitalization, 
NOTE: In general, hospitalization means that the individual remained at the hospital or emergency 
ward for observation and/or treatment (usually involving an overnight stay) that would not have been 
appropriate in the physician's office or an out-patient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious. When in doubt as to whether “hospitalization” occurred, the event should be 
considered serious. 
 results in persistent or significant disability/incapacity, 
NOTE: This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, or accidental 
trauma (e.g., sprained ankle) which may interfere or prevent everyday life functions, but do not 
constitute a substantial disruption.is a congenital anomaly/birth defect, 
 is an important medical event that based upon appropriate medical judgment, may jeopardize the 
patient and may require medical or surgical intervention to prevent one of the outcomes listed 
above. 
NOTE: An important medical condition is an event that may not result in death, be life-threatening, 
or require hospitalization but may be considered a SAE when, based upon appropriate medical 
judgment, it may jeopardize the patient and may require medical or surgical intervention to prevent 
one of the outcomes listed above. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in patient hospitalization, or the development of drug dependency or drug abuse. 


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8.1.4. 
Unexpected Adverse Events  
An AE or ADR is considered unexpected if it is not listed in the Investigator Brochure (Reference Safety 
Information section). An event is unexpected also when it is not listed at the specificity or severity that 
has been observed and listed in the Investigator Brochure. Events that are mentioned in the Investigator 
Brochure as occurring with a class of drugs or as anticipated from the pharmacological properties of the 
drug, but are not specifically mentioned as occurring with the particular drug under investigation are 
considered unexpected. 
The determination of expectedness shall be made on the basis of the IB Reference Safety Information 
(RSI) section. 
8.1.5. 
Suspected serious unexpected adverse reaction 
A suspected serious unexpected adverse reaction (SUSAR) is defined as an adverse reaction that is 
both unexpected (not consistent with the applicable product information) and also meets the definition 
of a Serious Adverse Reaction. 
8.2. 
MONITORING FOR ADVERSE EVENTS  
At each visit following study informed consent form signature, after the subject has had the opportunity 
to spontaneously mention any problem, the Investigator or appropriate designee should inquire about 
AEs by asking the standard questions:  
• “Have you had any health problems since your last study visit?”  
• “Have there been any changes in the medicines you take since your last study visit?”  
AEs should be reported for any clinically relevant change in concomitant condition(s) that is the result 
of an untoward (unfavorable and unintended) change in a subject’s medical health. Changes in any 
protocol-specific systemic parameter evaluated during the study are to be reviewed by the Investigator. 
Any untoward (unfavorable and unintended) change in a protocol-specific parameter or questionnaire 
response that is clinically relevant is to be reported as an AE. These clinically relevant changes will be 
reported regardless of causality. 
8.3. 
RECORDING 
AE data should be obtained through observation of the patient, from any information volunteered by the 
patient, or through patient questioning. 
All AEs (serious and non-serious) which occur from signature of the informed consent through patient 
participation in the study (last planned visit or early withdrawal date) will be reported and recorded in 
the eCRF.  It is important that the AE dedicated pages of the eCRF includes the duration of the AE 
(onset/resolution dates), the relationship to the drug, the severity, the outcome, the action(s) taken and 
relevant concomitant treatments dispensed. 
All AEs should be followed-up to determine outcome of the reaction.  The Investigator should follow 
up the event until resolution or stabilization of the condition.  It is the Investigator's responsibility to 
assure that the subjects experiencing an AE receive definite treatment for any AE, if required.   
Medical conditions/diseases present before starting study treatment shall be documented in the medical 
history section of the eCRF; these conditions are considered AEs only if they increase either in frequency 
or severity once informed consent has been signed. 
8.3.1. 
Relationship of AEs to the Investigational Product 
The Investigator will assess the causal relationship between the AE and the IMP (either ladarixin or 
placebo), according to the criteria in Table below: 


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Relationship of the Adverse Event to the IMP 
None  
(Intercurrent Event) 
An event that is not and cannot be related to the Investigational Product, e.g. a 
surgical intervention for nevus removal performed during the study, but planned 
before patient enrolment into the study 
Unlikely (remote) 
Relationship is not likely e.g. a clinical event including laboratory test abnormality 
with temporal relationship to drug administration which makes a causal relationship 
improbable and in which other drugs, chemicals or underlying disease provide 
more plausible explanations 
Possible 
Relationship may exist, but could have been produced by the patient’s condition or 
treatment or other cause 
Probable 
Relationship is likely, the AE abates upon discontinuation of Investigational 
Product and cannot be due to the patient’s condition 
Highly Probable 
Strong relationship, the event abates upon discontinuation of Investigational 
Product and, if applicable, re-appears upon repeat exposure 
Any AE reported in the study having a possible, probable or highly probable relationship to study drug 
will be considered as an ADR. 
8.3.2. 
Severity of AEs 
The Investigator will grade the severity of any AE using the definitions in the Table below.  For each 
episode, the highest severity grade attained should be reported. 
Severity of the Adverse Event 
Mild 
Grade 1 - Does not interfere with patient’s usual function (awareness of symptoms or 
signs, but easily tolerated [acceptable]). 
Moderate 
Grade 2 - Interferes to some extent with patient’s usual function (enough discomfort to 
interfere with usual activity [disturbing]). 
Severe 
Grade 3 - Interferes significantly with patient’s usual function (incapacity to work or to 
do usual activities [unacceptable]) 
8.4. 
SERIOUS ADVERSE EVENT REPORTING 
8.4.1. 
Reporting Procedure for Investigators to Dompé 
The Investigator must report all SAEs occurring during patient participation in the study, regardless of 
presumed causal relationship, to the CRO Pharmacovigilance contact and to Dompé Drug Safety 
Department, by e-mail (preferred) or fax within 24 hours of learning of the event.  Contact details for 
SAE reporting by the Investigator are provided in the section “Contact Information”.   
The Investigator should also report information on SAEs that continue after patient has completed 
his/her participation in the study (whether study completion or withdrawal), unless patient has 
withdrawn his/her consent. 
In line with CT3 Detailed Guidance and ICH E2A provisions, although the Investigator does not usually 
need to actively monitor patients for AEs once the trial has ended, if the Investigator becomes aware of 
a SAE occurring to a patient after that patient has ended his/her participation in the study (whether study 
completion of withdrawal), the SAE should be reported by the Investigator to the CRO 
Pharmacovigilance or directly to the Dompé Drug Safety department, should the whole study have been 
ended.  Such “post-study cases” should be regarded for expedited reporting purposes as though they 
were study reports.  Therefore, a causality assessment and determination of expectedness are needed for 
a decision on whether or not expedited reporting is required.  


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Information on SAEs will be recorded on a specific SAE form.  Both electronic and blank paper copies 
will be included in the Investigator’s Site File.  Follow-up reports (as many as required) should be 
completed and e-mailed/faxed following the same procedure above.   
Whenever more than one SAE is observed, the Investigator should identify which is the primary adverse 
event, i.e. the most relevant one.  If other events are listed in the same report, the Investigator, along 
with their relatedness to the Investigational Product, should identify which adverse events are serious 
and which are non-serious.  In any case, the Investigator is requested to record his/her opinion about the 
relatedness of the observed event(s) with the investigational medication. 
8.4.2. 
Conditions that should not be reported as serious adverse events 
The conditions listed below, that may require hospitalization of a patient, are not considered to be SAE 
and shall not be reported as such, but only need to be recorded in the CRF: 
 
Hospitalizations planned before entry into the clinical study which is part of the normal 
treatment or monitoring of the studied indication and not associated with any deterioration in 
condition.  
 
Hospitalization for routine treatment or monitoring of the studied indication, not associated with 
any deterioration in condition. 
 
Hospitalization for treatments, which was elective or pre-planned, for a pre-existing condition 
that is unrelated to the indication under study and did not worsen. 
 
Treatment on an emergency, outpatient basis for an event not fulfilling any of the definitions of 
SAEs given above and not resulting in hospital admission.  
In addition, the following situation shall not be considered SAE:  
 
Abnormal lab values or test results that do not induce clinical signs and/or symptoms and require 
intervention/therapy, i.e. are clinically significant. 
8.4.3. 
Follow-Up of Serious Adverse Events 
If subject was hospitalized due to a SAE, a copy of the discharge summary is to be forwarded to the 
Sponsor as soon as it becomes available. In addition, a letter from the Investigator that summarizes the 
events related to the case, as well as results of any relevant laboratory tests and redacted section of 
medical records may be provided to the Sponsor, if relevant for the SAE. In case of death, a copy of the 
autopsy report, if performed, should also be provided. 
The Investigator shall inform the Sponsor with an appropriate written communication, whenever he 
becomes aware of new available information regarding the SAE, once the condition is resolved or 
stabilized and when no more information about the event is expected. Follow-up SAE information 
should be processed as initial SAE notification (see Par. 8.4.1). 
For pharmacovigilance purposes, all SAEs should be followed-up in order to clarify as completely as 
possible their nature and/or causality and until all queries have been resolved. All SAEs will be followed 
up until the events resolve or the events or sequelae stabilize, or it is unlikely that any additional 
information can be obtained after demonstration of due diligence with follow-up efforts (i.e. subject or 
Investigator is unable to provide additional information, or the subject is lost to follow up), unless subject 
has withdrawn his/her consent. 
8.4.4. 
Reporting Procedure to IEC and to Regulatory Authorities in the European Union 
Reporting of Suspected Unexpected Serious Adverse Reaction 
Investigator must report all serious adverse events to the sponsor immediately, within 24 hours.  


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Dompé Drug Safety Department, with the support of the CRO as appropriate, shall report any SUSAR 
to the concerned IEC which approved the protocol and the Regulatory Authority (via the Eudravigilance 
Clinical Trial module) as soon as possible, and in no event later than: 
 
seven calendar days after becoming aware of the information if the event is fatal or life 
threatening; to be followed by any relevant information within eight days. 
 
fifteen calendar days after becoming aware of the information if the event is neither fatal nor 
life threatening. 
Treatment will be unblinded by Dompé Drug Safety prior to regulatory submission of a SUSAR to 
Regulatory Authorities and IEC in the European Union, and only cases referred to active treatment will 
be considered expeditable for regulatory reporting, in line with law requirements.  
If the results of an investigation show that an AE not initially determined to be reportable is reclassified 
as reportable, Dompé shall notify such SUSAR in a written safety report as soon as possible, but in no 
event later than 7/15 calendar days after the determination is made. 
Copies of all correspondence relating to reporting of any SAEs to the IEC should be maintained in the 
Investigator’s Files. 
Periodical Reporting to EU Regulatory Authorities  
The Sponsor Drug Safety Department will prepare and submit (via the CRO as applicable) to 
Investigators appropriate periodical safety updates as per applicable EU and local requirements and 
regulations. Dompé Drug Safety Department shall also be responsible to prepare and submit annual 
safety reports (Development Safety Update Report – DSUR) to relevant Regulatory Authorities and to 
IECs. 
8.4.5. 
Reporting Procedure to IRB and to Regulatory Authorities in the United States 
Reporting of Suspected Unexpected Serious Adverse Reaction 
Investigator must report all serious adverse events to the sponsor immediately, within 24 hours.  
Dompé Drug Safety Department, with the support of the CRO as appropriate, shall report any SUSAR 
and potential serious risks, from clinical trials or any other source, to the FDA and all participating 
investigators, as soon as possible, and in no event later than: 
 
seven calendar days after becoming aware of the information if the event is fatal or life 
threatening; to be followed by any relevant information within eight days. 
 
fifteen calendar days after becoming aware of the information if the event is neither fatal nor 
life threatening. 
The Investigators in turn shall notify their IRB: Investigators are required to promptly report “to the IRB 
all unanticipated problems involving risk to human subjects or others,” including adverse events that 
should be considered unanticipated problems (21 CFR 312.66). 
Dompé Drug Safety Department will unblind treatment prior to regulatory submission of a SUSAR to 
FDA and only cases referred to active treatment will be considered expeditable for regulatory reporting, 
in line with law requirements. 
The blind should ordinarily be broken for IND safety reports submitted to FDA and all participating 
investigators.  
If the results of an investigation show that an AE not initially determined to be reportable is reclassified 
as reportable, Dompé Drug Safety Department shall notify such SUSAR in a written safety report as 
soon as possible, but in no event later than 7/15 calendar days after the determination is made. 
Copies of all correspondence relating to reporting of any SAEs to the IRB should be maintained in the 
Investigator’s Files. 


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To note, Dompé Drug Safety Department shall also notify FDA in an IND safety report of potential 
serious risks, from clinical trials or any other source, as soon as possible after Dompé determines that 
the information qualifies for reporting, in particular shall notify of: 
- any suspected adverse reaction that is both serious and unexpected. Dompé must report an adverse 
event as a suspected adverse reaction only if there is evidence to suggest to the Sponsor a causal 
relationship between the drug and the adverse event. 
- findings from other studies that suggest a significant risk in humans exposed to the drug. Such a finding 
would result in a safety-related change in the overall conduct of the clinical investigation. 
- findings from animal or in vitro testing that suggest a significant risk in humans exposed to the drug 
- increased rate of occurrence of serious suspected adverse reactions.  
Periodical Reporting to US Regulatory Authorities  
Dompé Drug Safety Department will prepare and submit (via the CRO as applicable) to IRBs and 
Investigators periodical safety updates as per applicable local requirements and regulations.     
Dompé Drug Safety Department shall also be responsible to prepare and submit annual safety reports 
(Development Safety Update Report – DSUR) to FDA and IRBs as applicable. 
8.5. 
EXPOSURE TO INVESTIGATIONAL PRODUCT DURING PREGNANCY 
Women of childbearing potential are not excluded from the study as long as adequate birth control 
methods are being utilized. Women of childbearing potential are defined as all women physiologically 
capable of becoming pregnant. Adequate birth control methods are summarized in the protocol exclusion 
criteria. Prior to enrolment in the clinical trial, female patients of childbearing potential and their partners 
must be advised of the importance of avoiding pregnancy during the entire course of the study treatment 
and for the  2 months after the study treatment period ends and of the potential risks associated with an 
unintentional pregnancy. During the trial (treatment period or follow up period), female patients are to 
be instructed to contact the Investigator immediately if they suspect they might be pregnant. In the same 
way, male patients who become aware that the partner might be pregnant, are to be instructed to contact 
the Investigator immediately. 
The Investigator must report every pregnancy on a pregnancy report form as soon as possible (within 
24 hours of learning of the pregnancy to the Drug Safety Contacts specified in the section “Contact 
Information”, even if no AE has occurred, and follow it to term. If, however, the pregnancy is associated 
with an SAE (e g, if the mother is hospitalized for dehydration), in addition to the pregnancy report 
form, a separate SAE report form must be filed as described in Section 8.4, with the appropriate serious 
criterion indicated on the SAE report form. Miscarriage, stillbirth and any malformation/disease must 
be reported as a SAE. 
Any pregnancy leads to the immediate exclusion from the trial.  
8.6. 
ADVERSE EVENTS CAUSING TREATMENT DISCONTINUATION 
If a patient is withdrawn from the study as a consequence of an AE, this must be recorded and reasoned 
in the CRF, and the patient must be followed up until the resolution of the AE or as instructed by the 
medical monitor. 
8.7. 
OVERDOSE  
Accidental or intentional overdose, which may or may not result in serious adverse reactions, is to be 
reported to Dompé Drug Safety/CRO and Dompé Medical Expert, following the same procedure for 
SAE, within 24 hours from the Investigator’s knowledge of its occurrence. This includes reports related 
to drug intake through different routes (e.g. ingestion) or with suicidal intentions and consequent drug 
overdose. 


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An overdose of ladarixin is defined as the administration of 6 or more capsules on any given treatment 
day. 
The Investigator shall provide in the SAE form information about symptoms, corrective treatment and 
outcome of overdose. The Medical Expert should be contacted to discuss corrective treatment, if 
necessary. 
8.8. 
EMERGENCY PROCEDURES 
The treatment allocation for each patient will be provided via IRS to: 
- the Investigator for emergency procedures; 
- the Pharmacovigilance for safety procedures. 
The treatment assignment information will be kept confidential and will not be disclosed to any other 
person than those ones involved in these emergency and safety procedures. 
Access to individual patient treatment code will be allowed only in the event of a medical emergency 
where the knowledge of patient treatment is required to provide the patient with appropriate care. The 
investigator will be provided with a protected access to IRS so only in case of a medical emergency can 
open the treatment allocation for a specific patient.  
Any code break and the reason behind it will be recorded (when it was opened, by whom and why) in 
the relevant page of the eCRF. Code break will be immediately communicated to the CRO or Dompé, 
as appropriate.   
Dompé Pharmacovigilance contact person will be provided with a protected access to IRS in case of 
unblinding for safety procedures. 
Unblinding events will be recorded and reported in the final study report. 
 


St u d y L D X 0 4 1 9  
L a d arixi n i n ne w-o nset T 1 D wit h preserve d -cell f u ncti o n 
P a ge 5 1  of  6 9  
 
 
 
Versi o n N o. 2  –  fi nal 3 0 J ul y 2 0 2 0   
 
 
9.  
S T A TI S TI C A L I S S U E S  
9. 1.  
S A M P L E SI Z E  
T he sa m ple size of t he st u d y is calc ulate d o n t he “ pr o p orti o n of patie nts wit h a H b A 1c < 7 % a n d dail y 
i ns uli n re q uire me nt < 0. 5 0 I U/ K g/ da y”, a p ost -h oc c o m p osite e n d p oi nt  deri ve d fr o m data of t he p hase 2 
trial 
, c o nsi deri n g a lar ger effect size e x pecte d fr o m t he l o n ger treat me nt le n gt h ( o ne year 
vers us 3 m o nt hs).  
Base d o n t hese ass u m pti o ns, a n d c o nsi deri n g a ra n d o mizati o n rati o 2: 1  (la dari xi n: place b o) a n d a o ne-
si de d al p ha of 0. 0 5, se ve nt y- fi ve (7 5 ) patie nts ra n d o mize d i n t he trial will all o w t o ac hie ve a p o wer of 
a p pr o xi mati vel y 8 0 % t o detect at least 3 5 % of differe nce i n ter ms of pri mar y e n d p oi nt i n fa v or of 
la dari xi n vs place b o, ass u mi n g t hat t he pr o p orti o n of patie nts i n t he place b o gr o up wit h a H b A 1c < 7 % 
a n d dail y i ns uli n re q uire me nt < 0. 5 0 I U/ K g / da y at 1 2 m o nt hs will ra n ge bet wee n 4 5 % a n d 5 5 %.  
T he a b o ve sa m ple size will ta ke i nt o acc o u nt . a dr o p -o ut rate of a p pr o xi matel y 1 0 %.  
9. 2.  
R A N D O MI Z A TI O N  
Eli gi ble Patie nt will be ra n d o mize d i n a 2: 1 fas hi o n t o eit her la dari xi n or place b o.     
Ra n d o mizati o n will be perf or me d t hr o u g h I R S . Eac h Patie nt Kit n u m ber will be ra n d o ml y ass ociate d 
wit h a treat me nt gr o u p. T he ra n d o mizati o n list will be pr o vi de d t o t he  facilit y res p o nsi ble f or I M P 
pac ka gi n g/la belli n g f or t he p ur p ose of I M P pre parati o n. Eac h ra n d o mize d patie nt will be all ocate d wit h 
ra n d o mizati o n n u m ber acc or di n g t o t he stratifie d ra n d o mizati o n list. Dr o p o uts after ra n d o mizati o n will 
n ot be re place d  
Ra n d o mizati o n will be stratifie d b y site t o e ns ure bala nce d assi g n me nt acr oss treat me nt gr o u ps. T he 
stratifie d per m ute d bl oc k ra n d o mizati o n list will be ge nerate d wit h a c o m p uter pr oce d ure b y a n 
i n de pe n de nt statisticia n n ot i n v ol ve d i n t he c o n d uct of t he st u dy. A master ra n d o mizati o n list will be 
ge nerate d, wit h patie nts bala nce d bet wee n treat me nts /ce nters i n acc or da nce t o ra n d o mizati o n rati o ( 2: 1).    
Access t o i n di vi d ual patie nt treat me nt c o de will be all o we d o nl y i n t he e ve nt of a me dical e mer ge nc y 
w here t h e k n o wle d ge of patie nt treat me nt is re q uire d t o pr o vi de t he patie nt wit h a p pr o priate care. T he 
i n vesti gat or will be pr o vi de d wit h a pr otecte d access t o t he ra n d o mizati o n s yste m t o all o w o pe ni n g of   
t he treat me nt all ocati o n f or a s pecific patie nt i n case of a me dical e mer ge nc y.  
D o m pé P har mac o vi gila nce c o ntact pers o n will be pr o vi de d wit h a pr otecte d access t o t he ran d o mizati o n  
s yste m i n case of u n bli n di n g f or safet y pr oce d ures. 
U n bli n di n g e ve nts will be rec or de d a n d re p orte d i n t he fi nal st u d y re p ort.  
T he ra n d o mizati o n c o de will be br o ke n acc or di n g t o st u d y pr oce d ures after t he last e nr olle d patie nt has 
c o m plete d his/ her f oll o w -u p visit at 1 2  m o nt hs.   
9. 3.  
O V E R VI E W O F P L A N N E D S T A TI S TI C A L A N A L Y S E S  
T he st u d y pla ns f or t he f oll o wi n g statistical a nal yses:  
 
Fi nal a nal ysis: t his a nal ysis will be c o n d ucte d w he n all e nr olle d s u bjects ha ve c o m plete d t he 
M o nt h 1 2  f oll o w-u p visits, a n d t he st u d y data base has bee n  u n bli n de d a n d  l oc ke d. 
 
A d de n d u m at Fi nal a nal ysis: t his a nal ysis will be c o n d ucte d w he n all e nr olle d s u bj ect s ha ve 
c o m plete d  t he o pe n p hase st u d y p ost u n bli n di n g u p t o M o nt h 1 8 . 
9. 4.  
A N A L Y SI S P O P U L A TI O N  
T he f oll o wi n g p o p ulati o n will be defi ne d:  
C CI


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 The Safety (SAF) population will consist of all randomized patients who received at least one dose 
of the investigational product. Safety population will be analyzed according to the actual treatment 
received. The SAF population will be used to present results on safety data. 
 The Full Analysis Set (FAS) population will consist of all randomized patients who received at least 
one dose of the investigational product (either ladarixin or placebo). FAS population will be analyzed 
according to ITT principle, i.e. by treatment allocation regardless happening of intercurrent events 
(treatment policy strategy). The FAS population will be used for the primary analyses of the study 
and to present results on efficacy data. 
9.5. 
STATISTICAL METHODOLOGY 
All patient data collected on the eCRF will be listed by patient and center.  
Appropriate descriptive statistics will be produced, according to the variable. For continuous data n, 
mean, standard deviation, median and range (minimum and maximum) will be presented. For categorical 
data, frequency distributions and percentages will be presented. If appropriate, confidence intervals 
around the mean or the proportions will be presented.  
All AUC analyses will be based on actual rather than scheduled timings and will be calculated using the 
trapezoidal rule. In case of partial information collected during an assessment: 
 
if actual time is not recorded, the scheduled time will be used instead; 
 
missing values will be imputed via linear interpolation; 
 
when C-peptide values are below the limit of detection, the limit value will be assumed in the 
calculation of area under the curve. 
The last available basal sample (time and value) will be used as the first sample in the computation of 
the AUC. If required, inferential statistics will be conducted on log(x+1) transformed data, according to 
Lachin [2011]. 
Unless otherwise specified, the significance level used for statistical testing will be 0.05 and one-sided 
tests will be used.  
A Statistical Analysis Plan will be issued with more technical and detailed elaboration of the principal 
features of statistical analyses. Additional post-hoc analysis may be produced to further allow 
comparison between ladarixin and placebo, according to the results obtained.   
Any deviations from the original statistical plan (including unplanned analyses) will be clearly 
documented in the Clinical Study Report.   
9.5.1. 
Demographic and baseline characteristics 
Demographic and baseline characteristics will be summarized for all patients in the FAS population, by 
treatment group. 
9.5.2. 
Analysis of efficacy variables 
9.5.2.1. 
Primary analyses 
The proportion of patients with HbA1c < 7% and daily insulin requirement <0.50 IU/Kg/day at Month 
12 (primary endpoint) will be analyzed by means of logistic regression possibly adjusting by pre-defined 
baseline factors that will be defined in the SAP. 
The null hypothesis H0 is that the proportion of patients with a HbA1c <7% and daily insulin requirement 
<0.50 IU/Kg/day at Month 12 in ladarixin (LADARIXIN) is lower or equal the placebo one (PLACEBO): 
H0: LADARIXIN ≤ PLACEBO 
H1: LADARIXIN > PLACEBO 


St u d y L D X 0 4 1 9  
L a d arixi n i n ne w-o nset T 1 D wit h preserve d -cell f u ncti o n 
P a ge 5 3  of  6 9  
 
 
 
Versi o n N o. 2  –  fi nal 3 0 J ul y 2 0 2 0   
 
 
T he n ull h y p ot hesis will be rejecte d, a n d s u peri orit y of la dari xi n i n ter ms of pri mar y e n d p oi nt c o ncl u de d 
if p-val ue will be  l o wer t ha n 0. 0 5 o ne-si de d. 
I n case of missi n g assess me nt of t he pri mar y e n d p oi nt , pri mar y a nal yses will be perf or me d a d o pti n g a 
refere nce-base d M ulti ple I m p utati o n a p pr oac h ( C o p y Refere nce) t o c o nsi der  a missi n g n ot at ra n d o m  
mec ha nis m f or missi n g data: i m p utati o n of val ues i n t he la dari xi n ar m will be d o ne as if t he s u bject ha d 
bee n a me m ber of t he place b o ar m. T his a p pr oac h d oes n ot ass u me be nefits f or la dari xi n i n case of 
disc o nti n uati o n a n d li mits a  p ost -disc o nti n uati o n cli nical effect t o t hat of place b o.  
Se nsiti vit y a nal yses will be defi ne d i n t he S A P t o assess t he r o b ust ness of res ults o n pri mar y e n d p oi nts 
vers us t he ass u m pti o ns o n  t he mec ha nis m of missi n g ness (missi n g n o n at ra n d o m vs missi n g at r a n d o m). 
9. 5. 2. 2.  
Sec o n dar y a nal yses  
All se c o n dar y e n d p oi nts will be a nal yz e d at eac h a vaila ble ti me p oi nts b y mea ns of descri pti ve statistics 
a n d b y a p pr o priate para metric tests de pe n di n g o n t he nat ure of t he varia ble a n d its distri b uti o n. Data 
tra nsf or mati o n mi g ht be use d i n or der t o satisf y t he ass u m pti o n of n or malit y re q ueste d b y para metric 
statistical tests. I n case s uc h ass u m pti o ns are n ot met, n o n -para metric c o u nter part tests will be use d. 
Details will be pr o vi de d i n t he S A P. C ha n ge fr o m baseli ne val ue (f or c o n ti n u o us varia bles) a n d s hift 
ta bles vers us baseli ne (f or cate g orical varia bles) will als o be s u m marize d f or all p ost-baseli ne visits.  
A d diti o nal a nal yses will i ncl u de t he a nal ysis of t he A U Cs, dail y i ns uli n re q uire me nts a n d H b A 1c val ues 
b y re peate d meas ure me nts m o dels. T he a dj uste d least s q uares mea ns will be esti mate d f or eac h 
c o m bi nati o n of ti me p oi nt a n d treat me nt.  T he tests of t he fi xe d effects will be prese nte d, t o get her wit h 
t he esti mate d least s q uares mea ns. T he esti mate d treat me nt differe nce bet ween la dari xi n a n d place b o at 
eac h ti me p oi nt will be prese nte d t o get her wit h t he c orres p o n di n g 9 5 % c o nfi de nce i nter val.  
T he effect of treat me nt o n t he c u m ul ati ve n u m ber of se vere h y p o gl yc e mic e ve nts will be e val uate d usi n g 
a n A n derse n -Gill a nal ysis wit h r o b ust sa n d wic h -t y pe varia nce esti mate. 
9. 5. 3.  
A n al ysis of e x pl or at or y v ari a bles  
I n a d diti o n t o descri pti ve statistics at eac h a vaila ble ti me p oi nt, e x plorati ve varia bles will be a nal yz e d b y 
mea ns of i nfere ntial tests de pe n di n g o n t heir nat ure a n d distri b uti o n (all c o nfi de nce i nter vals a n d 
statistical tests o n e x pl orati ve e n d p oi nts are of descri pti ve nat ure). C ha n ge fr o m baseli ne val ue (f or 
c o nti n u o us varia bles) a n d s hift ta bles vers us baseli ne (f or cate g orical varia bles) mi g ht be re p orte d f or 
all p ost -baseli ne visits . 
9. 5. 4.  
A n al ysis of s afet y v ari a bles  
T E A Es, A D Rs a n d  T E S A E  will be prese nte d b y treat me nt ar ms i n ter ms of n u m ber of A Es a n d i nci de nce 
b y S yste m Or ga n Class ( S O C) a n d Preferre d T er ms ( P T) usi n g Me d D R A. A nal yses will be pr o vi de d 
als o b y se verit y a n d relati o ns hi p t o t he st u d y dr u g. I n a d diti o n, ti me -t o-e ve nt met h o d s ( Ka pla n-Meier 
esti mates) will be use d t o s u m marize t he ti me t o o nset of se vere  h y p o gl yce mic  e ve nts. 
Vital si g ns a n d la b orat or y tests will be prese nte d usi n g descri pti ve statistics at eac h a vaila ble visit. 
A d diti o nall y, t he fre q ue nc y of s u bjects re p orti n g  a n a b n or mal or a b n or mal cli nicall y si g nifica nt 
la b orat or y val ue will be prese nte d f or eac h la b orat or y para meter. S hift ta bles vers us baseli ne will 
c o m pare a b n or mal la b orat or y fi n di n gs at eac h p ost -baseli ne visit.  
9. 5. 5.  
S pecific ati o n of s u b gr o u ps f or a n al ysis  
S u b -gr o u p a nal yses of efficac y a n d safet y e n d p oi nts will be perf or me d o n s u b gr o u p of patie nts defi ne d 
b y a ge,  B MI, H L A, 
. Statistical details a n d ne w s u b gr o u ps 
defi niti o ns will be re p orte d i n t he S A P.  
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9.5.6. 
Missing data 
All reasonable efforts will be made to reduce the rate of missing data. Investigators will be trained about 
the importance of patient retention and full data capture. Also, any reasonable attempts should be made 
by the Investigators to emphasize continued patient’s participation for the full duration of the trial.  
However, in order to minimize missing data, if a patient cannot refer to the site for a planned follow-up 
visit, the Investigator will try to obtain any relevant information from the patients, including 
documents/laboratory results available from local medical care. 


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10. 
ETHICAL CONSIDERATIONS 
10.1. 
INDEPENDENT ETHICS COMMITTEE (IEC) / INSTITUTIONAL REVIEW 
BOARD (IRB) 
It is the responsibility of the CRO appointed by Dompé or of the Investigator (US sites) to obtain 
approval of the trial protocol/amendments from the appropriate IEC/IRB. 
Prior to the initiation of the study, the followings will be submitted to the IEC/IRB for approval: 
- 
the study protocol, 
- 
the ICFs, 
- 
the current version of the Investigator’s Brochure, 
- 
Investigator’s current curriculum vitae, 
- 
Insurance certificate 
- 
any other requested document(s). 
A copy of the IEC/IRB approval will be sent to Dompé along with relevant correspondence with the 
IEC/IRB, a roster of IEC/IRB members or the US Department of Health and Human Services (DHHS) 
general assurance number.   
The study will not be started until full written approval has been obtained from the appropriate IEC/IRB.  
The letter of approval should be dated, and should specify the type (e.g. protocol number) and the date 
of the documents which were reviewed and approved.   
The CRO appointed by Dompé or the Investigator will submit any future amendment to the protocol to 
the IEC/IRB which granted the original approval.  Any amendment will be implemented only when full 
approval has been obtained from the appropriate IEC/IRB, except for those amendments which involve 
only logistical or administrative aspects of the study. 
The CRO appointed by Dompé or the Investigator will send to the IEC/IRB any updated Investigator’s 
Brochure. 
The CRO appointed by Dompé or the Investigator will also submit to the IEC/IRB which approved the 
protocol at least annually any required progress reports and study update, and will inform the IEC/IRB 
of the termination of the study. 
The CRO appointed by Dompé or the Investigator will report any serious ADRs, life-threatening 
problems or deaths occurred at other sites participating to this clinical trial and/or in other clinical studies 
conducted with ladarixin.   
10.2. 
INFORMED CONSENT 
No study-related procedures (including non-invasive and diagnostic procedures) will be undertaken 
prior to completion of the consenting process.   
Each potentially eligible patient will be informed of the study’s objectives and overall requirements.  
The Investigator will explain the study fully to him/her using the ICF. Although patients will be 
informed that they can withdraw consent at any time, the Investigator will also emphasize that missing 
data diminish the scientific value of all patients’ contributions. Similarly, patients will be informed that 
safety data might have to be collected after their participation in the study have been completed.  If the 
patient is willing to participate in the study, (s)he will be requested to give written informed consent 
after being given sufficient time to consider his/her participation and the opportunity to ask for further 
details. 
The ICF will be signed and personally dated by both the patient and the Investigator. A copy of the 
signed form will be provided to the patient, and the original signed ICF will be retained and filed in the 
Investigator Site File. Patient consent will be documented in the hospital records.  


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Individual (i.e. site specific; local language) ICFs will be provided to the site once approved by the 
IEC/IRB.  Any changes requested by the IEC/IRB must be approved by Dompé prior to the documents 
being used.   
10.3. 
CONFIDENTIALITY 
All information obtained during the conduct of the study will be regarded as confidential.  An agreement 
for disclosure will be obtained in writing by the patient and will be included in the ICF.  Patient’s data 
collected during (or after completion) of the study will be handled in accordance with applicable data 
protection laws and European data protection Regulation (EU) No. 679/2016 of the European Parliament 
and of the European Council regarding the protection of natural person’s personal data and the free 
circulation of said data (hereinafter GDPR EU No. 679/2016) and according the standards of Good 
Clinical Practice (Law Decree 211/2003).  
On the eCRFs patients will be identified ONLY by the assigned patient number.  If patient names are 
included on copies of documents submitted to Dompé or the CRO appointed by Dompé, the names will 
be obliterated or masked and the assigned patient number added to the document. 
The Investigator should keep a separate log (Patient Master List) of patient’s codes, names and 
addresses. 
10.4. 
COMPENSATION 
FOR 
MEDICINE-INDUCED 
INJURY 
AND 
INDEMNIFICATION 
Before the trial formally starts, Dompé will take out a study-specific insurance covering the amount 
requested by the respective national laws for patients/Investigators/Institutions participating in the 
clinical trial.   
In case of questions about medical care, cost for medical care or insurance, patients can talk to their 
Investigator. Contact details will be given in the ICF. 
Insurance and any updates will be provided to the Investigator before trial commencement for filing into 
the Investigator Site File.  


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11. 
DATA HANDLING AND RECORD KEEPING  
11.1. 
CASE REPORT FORMS 
An electronic CRFs (eCRF) will be used for this study and will be made available to investigational 
sites.  eCRFs are the sole property of Dompé and should not be made available in any form to third 
parties, except for authorized Dompé’ designee or representatives of appropriate Health/Regulatory 
Authorities, without written permission from Dompé. 
A eCRF is required and should be completed for each patient enrolled (consented). The Investigator will 
be responsible for the accuracy of the data entered in the eCRFs.  
Source documents should be available to support all the data recorded in the eCRF; location of source 
documents, including those for which the eCRF might be accepted as being the sole source document, 
will be specified and listed at the center Initiation Visit. 
The eCRF must be available for review to designated Dompé’s representatives at each scheduled 
monitoring/audit visit.  
11.2. 
DIARY  
A Diary (local language version) will be provided to each patient randomized into the trial.   
The patient will report in the Diary the details (date, time, number of capsules) of each administration 
of the IMP, values of daily SMBG, daily insulin doses, carbohydrates intake at each meal if patient is 
able to apply carbs counting, hypoglycemia episodes. It is responsibility of the Investigator to explain 
to each patient how to enter the data in the Diary and to check the data inserted in the Diary to ensure 
correct completion as well as correct intake of the IMP.  
The information collected in the Diary will be part of the patient’s eCRF. 
Diary is the sole property of Dompé and should not be made available in any form to third parties, except 
for authorized Dompé designee or representatives of appropriate Health/Regulatory Authorities, without 
written permission from Dompé. 
11.3. 
DATA MANAGEMENT 
Data management will be performed by the CRO appointed by Dompé. 
The eCRF for all patients will constitute the study database, and the data will be verified for missing 
data, inconsistencies, and for any necessary medical clarifications. Queries arising from these checks 
will be sent by the appointed CRO to the Investigator for response and resolution.     
Once all data queries have been resolved, the eCRF will be signed by the Investigators. This approval 
method will include applying an electronic signature, a uniquely assigned username and password that 
together will represent a traditional handwritten signature. After each Investigator will have signed the 
eCRFs related to the patients enrolled the study database will be declared to be “clean” and the study 
data will be locked ready for analysis.   
After the database lock has been achieved, the Investigator may archive the pdf copies of the eCRFs to 
be retained at the center. All data collected in the context of this study will be stored and evaluated per 
regulatory requirements and any applicable guidance for electronic records. Also, data will be stored 
and evaluated in such a way as to guarantee patient confidentiality in accordance with the legal 
stipulations applying to confidentiality of data. Study records (e.g., copies of eCRFs, regulatory 
documents) will be retained at the study center, along with adequate source documentation, according 
to FDA and ICH requirements. 


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11.4. 
DOCUMENTATION REQUIRED PRIOR TO INITIATION OF AND DURING 
THE STUDY  
In addition to the documents mentioned in Sections 10.1 and 12.1, the following documents will be 
required from the Investigator prior to the initiation visit (and during the course of the study in case of 
any update): 
- 
Current, signed and dated Curriculum Vitae of Principal Investigator and any 
Sub-Investigators/co-workers.  Updates should be provided at least every two years. 
- 
Confidential disclosure agreement Form in accordance also with European data protection 
Regulation (EU) No. 679/2016 (GDPR) 
- 
Normal ranges of all laboratory tests to be performed at the study site and a recent certification 
or accreditation of established quality control (or other documentation of established quality 
control or external quality assessment or other validation).  Updates should be provided as soon 
as any reference value has changed. 
- 
A signed page of the final protocol and any amendments. 
- 
A signed copy of the study Financial Agreement/Clinical Study Agreement with Dompé (or 
CRO appointed by Dompé), including all study specific costs. 
- 
List and any updates of delegated responsibility (Study Team Signature List / Delegation of 
Responsibilities form).  
- 
Form 1572 and financial disclosure form 3455 from all the persons listed on the 1572. If 
applicable, the PI will provide an updated financial disclosure agreement to the Sponsor 1 year 
after the completion of the study.  
11.5. 
ESSENTIAL DOCUMENT RETENTION 
The Investigator will retain copies of all the essential documents (as defined by ICH-GCP) until at least 
2 years after the last approval of a marketing application in an ICH region, and until there are no pending 
or contemplated marketing applications in an ICH region, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the Investigational Product. These documents should 
be retained for a longer period however if required by the applicable regulatory requirements. The 
Investigator should take measures to prevent accidental or premature destruction of these documents. 
The essential documents include, but are not limited to: the signed protocol, copies of the completed 
eCRFs, and Diary, signed Patient Informed Consent Forms from all patients who consented, hospital 
records and other source documents, and all other documentation included in the Investigator Site File 
and Pharmacy/Dispensing File. 
The Investigator will inform Dompé (or designee) of the storage location of these essential documents 
and must contact Dompé before disposing of any. If the Investigator wishes to assign the files to 
someone else or to remove them to another location, he/she should consult with Dompé about this 
change. 
Dompé will inform the Investigator in writing when these documents no longer need to be retained. 


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12. 
STUDY MANAGEMENT 
The study will be performed in accordance with the protocol, the Declaration of Helsinki (64th WMA 
General Assembly, Fortaleza, October 2013) and ICH Harmonised Tripartite Guideline for Good 
Clinical Practice (ICH-GCP) and any local regulations. 
12.1. 
REGULATORY BODY APPROVAL 
Dompé or the CRO or other consultant appointed by Dompé will obtain the necessary approval from 
the Competent Authorities, as needed, prior to initiation of the study. 
The study will not be started until written approval from the relevant Competent Authorities (or no 
objection within the timeframe set by the local regulation, as applicable) has been received by Dompé. 
12.2. 
STAFF INFORMATION & RESPONSIBILITIES 
It is the responsibility of the Investigator to ensure that all personnel involved in the study are fully 
informed of all relevant aspects of the study, including detailed knowledge of and training in all 
procedures to be followed. 
The Investigator will maintain a list of delegated responsibility detailing the various study tasks to be 
performed by each member of his/her study staff.  Each staff member should sign in agreement to their 
performing each of the tasks delegated to them on the list. 
12.3. 
MONITORING 
Monitoring will be carried out by CRAs of CRO appointed by Dompé.  
The purpose of the monitoring visit is to verify that the rights and the wellbeing of the patient are 
protected, that the reported data are accurate, complete and verifiable from source documents and that 
the conduct of the trial complies with the currently approved protocol and any amendments, with ICH 
GCP, and with regulatory requirements.  
Prior to study start, the Investigator will be informed of the anticipated frequency of the monitoring 
visits.  (S)He will also receive a notification prior to each monitoring visit during the course of the study.  
It is expected that the Investigator and/or his/her sub-Investigator(s) and other appropriate staff will be 
available on the day of the visit to discuss study conduct and to cooperate with the monitor to ensure 
that any problems detected during the course of these monitoring visits are resolved. 
12.3.1. 
Access to records 
The Investigator will allow designated Dompé representatives, including staff from the appointed CRO, 
and regulatory/ethics bodies to have direct access to the source documents to verify the data reported in 
the eCRFs.  Source documents are the originals of any documents used by the Investigator or 
hospital/institution that allow verification of the existence of the patient and substantiate the integrity of 
the data collected during the trial. The investigator/institution should maintain adequate and accurate 
source documents and trial records that include all pertinent observations on each of the site’s trial 
subjects. Source data should be attributable, legible, contemporaneous, original, accurate, and complete. 
Changes to source data should be traceable, should not obscure the original entry, and should be 
explained if necessary via an audit trail.    
All study records must be available for audit by Dompé farmaceutici s.p.a., its authorized 
representatives, and Regulatory Inspection by Regulatory Authority.  
      


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Page 60 of 69 
 
 
 
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12.4. 
AUDIT AND INSPECTION 
Audit activities will be performed by the Dompé Quality Assurance Unit or any other third party 
delegated by Dompé or by the CRO, as appropriate. 
12.5. 
PROTOCOL DEVIATIONS/AMENDMENTS 
Changes to the Protocol will be implemented only when written amendments have been signed by all 
individuals who signed the protocol.  
Any amendment will be sent to the IEC/IRB and Competent Authority/FDA as appropriate. No 
deviations from or changes to the protocol will be implemented without documented approval of an 
amendment from the IEC/IRB which granted the original approval, except where necessary to eliminate 
an immediate hazard(s) to trial patient, or when the change(s) involves only logistical or administrative 
aspects of the trial. The deviations from or changes to the protocol implemented to eliminate an 
immediate hazard to the trial patient and the proposed amendment, if appropriate, should be submitted 
to the IEC/IRB for review and approval as soon as possible.  
Any other deviation from the protocol that has not been approved by Dompé and the IEC/IR could result 
in a discontinuation from the study at the center involved. 
Any written amendment will be sent to all recipients of the protocol. 
12.6. 
DISCONTINUATION OF THE STUDY 
Dompé reserves the right to stop the study at any time on the basis of new information regarding safety 
or efficacy, or if study progress is unsatisfactory, or for other valid administrative reasons. 
After such a decision is made, the Investigator must inform all relevant persons e.g. study staff, potential 
patients etc. within 2 weeks.  All delivered study materials must be collected and all eCRFs completed 
to the extent possible. 
Study discontinuation will be notified to Competent Authorities within 15 days from decision. 
12.7. 
PUBLICATIONS 
As this study is part of a multicenter trial, publications derived from this study will be planned and 
agreed with the participating Investigators. Publications will include input from the Investigators, his/her 
colleagues, other investigators in this trial and Dompé personnel. Such input will be reflected in 
publication authorship. Criteria for selection of authors will be agreed. Subsequent to the multicenter 
publication or one year after completion of the study, whichever occurs first, an Investigator and/or 
his/her colleagues may publish the results of Investigator’s part of the study independently.  
Any manuscript, abstract or other publication or presentation of results or information arising in 
connection with the study must be prepared in conjunction with Dompé and must be submitted to the 
Dompé for review and comment at least 45 days prior to submission for publication or presentation.  
The Sponsor reviews proposed manuscripts prior to submission within a reasonable period of time (30-
90 business days in relation with the complexity of the work). If such draft contains confidential 
patentable information, the Investigator will refrain from publishing any such information for a period 
not exceeding 180 days, to enable Dompé to file for the protection of any intellectual or proprietary 
property interest. 
The Sponsor agrees that the study results (including negative and inconclusive as well as positive results) 
can be made publicly available by the Investigator publishing in peer reviewed journals; presenting 
results at scientific congresses; and posting information and results on internet-based public registers 
and databases. 
In any case, study results will be communicated in full to the CA by the submission of a complete 
Clinical Study Report. 


Study LDX0419 
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Page 61 of 69 
 
 
 
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The Investigator(s) will also be provided by the Sponsor with the clinical study report and the results of 
any additional analysis, tables, figures, etc. undertaken for the purposes of the article, in order to take 
responsibility for the content of the publication(s). 
On an exceptional basis, the Sponsor may temporarily delay registration of certain data elements (e.g. 
compound, name, outcome, measures etc.) to seek necessary intellectual property protection. This is 
because early disclosure of such a data could, in some circumstances, prevents or negatively impacts 
patentability. 
 
 


St u d y L D X 0 4 1 9  
L a d arixi n i n ne w-o nset T 1 D wit h preserve d -cell f u ncti o n 
P a ge 6 2  of  6 9  
 
 
 
Versi o n N o. 2  –  fi nal 3 0 J ul y 2 0 2 0   
 
 
1 3.  
R E F E R E N C E S  
A 0 8 1 1/ E. D o m pé I nter nal Re p ort  
A b oelasrar M A et al. i ns uli n -li ke gr o wt h fact or-1 c yt o ki nes cr oss -tal k i n t y pe 1 dia betes mellit us: relati o ns hi p t o 
micr o vasc ular c o m plicati o n a n d b o ne mi neral de nsit y. C yt o ki ne 2 0 1 2; 5 9: 8 6 -9 3.  
A merica n Dia b etes Ass ociati o n. Sta n dar ds f or me dical care i n d ia betes –  2 0 1 4. Dia betes Care 2 0 1 4; 3 7( 1): S 1 4 -
S 8 0.  
At ki ns o n M A et al. T y pe 1 dia betes. T he La ncet 2 0 1 4, 3 8 3: 6 9 -8 2 . 
Bar nar d K et al. Fear of h y p o gl ycae mia i n pare nts of y o u n g c hil dre n wit h t y pe 1 dia betes: a s yste matic re vie w. B M C 
Pe diatr 2 0 1 0; 1 0: 5 0.  
Citr o  A et al. C X C R 2/ 1 i n hi biti o n m o d ulates dia betes i n d uce d b y m ulti ple l o w d oses of stre pt oz ot oci n ( M D L -
S T Z) i nj ecti o n i n m o use. 2 n d J oi nt AI D PI T a n d E PI T A Wi nt er S y m p osi u m. I gls/I n ns br uc k 2 0 1 2a, A bstract b o o k, 
a bstract P P -1 8.  
Citr o A et al. C X C R 2/ 1 i n hi biti o n pre ve nts a n d re verts dia betes i n N O D m o use. 2 n d J oi nt AI D PI T a n d E PI T A 
Wi nter S y m p osi u m. I gls/I n ns br uc k 2 0 1 2 b , A bstract b o o k, a bstract O P-2 7 . 
Citr o A et al., C X C R 1/ 2 i n hi biti o n bl oc ks a n d re verts t y pe 1 dia betes i n mice. Dia betes 2 0 1 5 A pr; 6 4( 4): 1 3 2 9 -4 0.  
d oi: 1 0. 2 3 3 7/ d b 1 4 -0 4 4 3.  E p u b 2 0 1 4 Oct 1 4.   
C oc kcr oft a n d Ga ult M H , Pre dicti o n of creati ni ne cleara nce fr o m ser u m creati ni ne. Ne p hr o n  1 9 7 6; 1 6( 1): 3 1 -4 1.  
Dia na J a n d Le h ue n A. Macr o p ha ges a n d β -cells are res p o nsi ble f or C X R 2 -me diate d ne utr o p hil i nfiltrati o n of 
t he pa ncreas d uri n g a ut oi m m u ne dia betes. E M B O M o d Me d 2 0 1 4, 2 6: 1 0 9 0 -1 1 0 4.  
Er ba ğci A B et al. Me diat ors of i nfla m mati o n i n c hil dre n wit h t y p e 1 dia betes mellit us: c yt o ki nes i n t y pe 1 dia betic 
c hil dre n. Cli n Bi oc he m 2 0 0 1; 3 4: 6 4 5 -6 5 0.  
Gara u A et al. De vel o p me nt of a s yste micall y -acti ve d ual C X C R 1/ C X C R 2 all osteric i n hi bit or a n d its efficac y i n 
a m o del of tra nsie nt cere bral isc he mia i n t he rat . E ur C yt o ki ne Net w 2 0 0 6; 1 7( 1): 3 5-4 1.  
Gl o wac ka E et al. T he effect of L P S o n ne utr o p hils fr o m p atie nts wit h hi g h ris k of t y pe 1 dia betes mellit us i n 
relati o n t o I L-8, I L -1 0 a n d I L -1 2 pr o d ucti o n a n d a p o pt osis i n vitr o. Sca n d J I m m u n ol 2 0 0 2; 5 5: 2 1 0 -2 1 7.  
Gree n ba u m M D et al. Mi xe d -Meal t olera nce test vers us gl uca g o n sti m ulati o n test f or t he assess me nt of β -cell  
f u ncti o n i n t hera p e utic trials i n t y pe 1 dia betes. Dia betes Care 2 0 0 8; 3 1: 1 9 6 6-1 9 7 1  
Lac hi n J M et al., Sa m ple size re q uire me nts f or st u dies of t reat me nt effects o n beta-cell f u ncti o n i n ne wl y dia g n ose d 
t y pe 1 dia betes. P L o S O N E 2 0 1 1; 6:e 2 6 4 7 1. 
Le ve y A S, St e ve ns L A, Sc h mi d C H, Z ha n g Y L, Castr o A F 3r d, Fel d ma n HI, K use k J W, E g gers P, Va n Le nte F, 
Gree ne T, C ores h J; C K D -E PI ( C hr o nic Ki d ne y Disease E pi de mi ol o g y C olla b orati o n). A Ne w E q uati o n t o 
Esti mate Gl o mer ular Filtrati o n Rate. A n n I nter n Me d 1 5 0( 9): 6 0 4 -1 2.  ( 2 0 0 9); 
L u d vi gss o n et al. G A D treat me nt a n d I ns uli n secreti o n i n rece nt -o nset t y pe 1 dia betes. N E n gl J Me d 2 0 0 8, 
3 5 9: 1 9 0 9 -1 9 2 0.  
: D o m pé I nter nal R e p ort  
: D o m pé I nter nal R e p ort  
: D o m pé I nter nal R e p ort  
Macr o Ge nics. Press Release. Macr o Ge nics a n d Lill y a n n o u nce pi v otal cli nical trial of te pliz u ma b di d n ot meet 
pri mar y efficac y e n d p oi nt. Ma cr o Ge nics [ o nli ne], htt p:// macr o ge nics.c o m/ press _ release-2 8 4. ht ml  ( 2 0 10 ). 
Mastra n drea L et al. Eta nerce pt treat me nt i n c hil dre n wit h ne w -o nset t y pe 1 dia betes. Dia betes Care 2 0 0 9; 3 2: 1 2 4 4 -
1 2 4 9.  
M oric o ni A et al. Desi g n of n o nc o m petiti ve i nterle u ki n -8 i n hi bit ors acti n g o n C X C R 1 a n d C X C R 2. J Me d C he m 
2 0 0 7; 5 0: 3 9 8 4 -4 0 0 2.  
P es k o vitz M D et al. Rit u xi ma b, b -l y m p h oc yte de pleti o n, a n d preser vati o n of beta-cell f u ncti o n. N E n gl J Me d 
2 0 0 9; 3 6 1: 2 1 4 3 -2 1 5 2 . 
Raz I et al. Treat me nt of rece nt -o nset t y pe 1 dia betic patie n ts wit h Dia P e p 2 7 7: res ults of a d o u ble-bli n d, place b o -
c o ntr olle d, ra n d o mize d p hase 3 trial. Dia b etes Care  2 0 1 4; 3 7: 1 3 9 2 -1 4 0 0 . 
Si m o nie ne D. et al. I ns uli n Resista nce i n T y pe 1 Dia betes M ellit us a n d Its Ass ociati o n wit h P atie nt’s Micr o - a n d 
Macr o vasc ular C o m plicati o ns, Se x H or m o nes, a n d Ot her Cli nical D ata Dia betes T her ( 2 0 2 0) 1 1: 1 6 1 – 1 7 4  
Steffes M W et al. -cell f u ncti o n a n d t he de vel o p me nt of dia betes -relate d c o m plicati o ns i n t he dia betes c o ntr ol 
a n d c o m plicati o n trial. Dia b et es Care 2 0 0 3; 2 6: 8 3 2 -8 3 6.  
Va n Sic kle BJ et al. I ncrease d circ ulati n g I L-8 is ass ociate d wit h re d uce d I G F -1 a n d rel ate d t o p o or meta b olic 
c o ntr ol i n a d olesce nts wit h t y p e 1 dia betes mellit us. C yt o ki ne 2 0 0 9; 4 8: 2 9 0 -4.  
C CI
C CI
C CI


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Waldron-Lynch F, Herold KC. Immunomodulatory therapy to preserve pancreatic -cell function in type 1 
diabetes. Nature Reviews 2011; 10:439-452. 


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14. 
APPENDICES 
14.1. 
APPENDIX 14.1 - PACKAGING AND LABELING DETAILS 
A Patient Kit will be prepared for each patient, containing 2 Treatment wallets, one for each treatment 
week.  Each Treatment wallet will contain a total of 56 capsules (amount needed for one treatment 
cycle). 
All items will have local language labels.  The template of the English label is provided below.  Label 
content will be adjusted to meet local regulatory requirements.   
NOTE:  
Patient Kit No. XXYY 
according to the randomization list (and IRS system drug dispensation 
number) 
Patient No. ________ 
to be filled by Investigator according to Patient Randomization Number 
Investigator: _______ 
to be filled by Investigator according to PI name 
 
Specimen Label for each Patient Kit 
STUDY LDX0419 
Sponsor Dompé farmaceutici s.p.a.; Via San Martino 12, Milan – Italy 
 
INVESTIGATOR: _____________ 
 
PATIENT KIT No. XXYY                                    PATIENT No. ____                        
(contains one treatment cycle)                       
 
 
  
INVESTIGATIONAL PRODUCT: ladarixin (200 mg) or placebo oral capsules 
 
CONTAINS: 2 TREATMENT WALLETS FOR ONE TREATMENT CYCLE; TOTAL 56 CAPSULES  
 
coded BATCH No. 
coded EXPIRY DATE mm/yyyy 
DO NOT STORE AT >30°C 
 
 
DO NOT FREEZE 
 
 
 
 
 
 
 
 
 
 
 
DIRECTIONS: Dispense the Treatment Kit, corresponding to a cycle of 14 consecutive days. For any 
questions, please contact (to be identified in the final label)  
 
For clinical trial use only. Keep out of reach of children.  
Caution:  New Drug-Limited by Federal law to investigational use. 
 
Specimen Label for each Treatment Wallet  
STUDY LDX0419 
Sponsor Dompé farmaceutici s.p.a.; Via San Martino 12, Milan – Italy 
 
 
 
PATIENT KIT No. XXYY                                    TREATMENT WALLET 
 
  
INVESTIGATIONAL PRODUCT: ladarixin (200 mg) or placebo oral capsules 
 
CONTAINS: TREATMENT WALLET WITH A TOTAL 28 CAPSULES 
 
coded BATCH No. 
coded EXPIRY DATE mm/yyyy 
DO NOT STORE AT >30°C 
 
 
DO NOT FREEZE 
 
 
 
 
 
 
 
 
 
 
 
DIRECTIONS: Take the drug twice a day: 2 capsules in the morning and 2 in the evening. See 
additional instructions on administration provided by the Investigator.  
 
Contact the Investigator should you have any questions. 
 
For clinical trial use only. Keep out of reach of children. 
Caution:  New Drug-Limited by Federal law to investigational use. 


St u d y L D X 0 4 1 9  
L a d arixi n i n ne wly di a g n ose d Ty pe 1 Di a betes  
 P a ge 6 5  of  6 9  
 
 
 
Versi o n N o. 2  –  fi nal 3 0 J ul y 2 0 2 0   
 
 
1 4. 2.  
A P P E N DI X 1 4. 2  –  S T U D Y F L O W C H A R T   
                          1 0 0  d a ys (r u n -i n p h ase) 
 
1 st i ns uli n                                                    
 
first I M P d ose 
Pr oce d ures  
 
T ests t o be perf or me d at a ce ntralize d la b orat or y   
 
Test t o be perf or me d at t h e l o cal  
la b orat or y 
 
Scree ni n g  
B aseli ne  
( wit hi n 3 wee ks t o 
C 1 st art)  
R a n d o miz ati o n  
( wit hi n 3 d a ys of 
C 1  
T R E A T M E N T P E RI O D (c ycle = C)  - 1 3 C ycles ( C 1 - C 1 3)  
F O L L O W -
U P  
C 1 - C 3  
We e k 1 1  
(e n d of 3r d 
c ycle) 
C 4 - C 6  
We e k 2 3  
(e n d of 6t h 
c ycle) 
C 7 –  C 9  
M o nt h 6  
Wee k 2 6 ± 2  
Visit w hile 
o n C 7  
We e k 3 5  
(e n d of 9t h  
c ycle) 
C 1 0 - C 1 3  
M o nt h 1 2  
Wee k 5 2 ± 2  
M o nt h 1 8  
Wee k 7 8 ± 2  
I nf or me d C o ns e nt F or m 
X  
 
 
 
 
 
 
 
 
 
 
 
 
Eli gi bilit y criteri a R a n d o miz ati o n  
X  
X  
X  
 
 
 
 
 
 
 
 
 
 
A ut o -a nti b o dies 1 & F asti n g C -Pe pti de 2 
X  
 
 
 
 
 
 
 
 
 
 
 
 
M e dic al hist or y   
X  
 
 
 
 
 
 
 
 
 
 
 
 
B P/ H R  
 
X  
 
 
X  
 
X  
 
 
X  
 
X  
X  
w ei g ht, hei g ht, w aist & w aist/ hi p circ u mf ere nc e    
 
X  
 
 
 
 
 
 
X  
 
 
X  
X  
e G D R  
 
X  
 
 
 
 
 
 
X  
 
 
X  
X  
I ns uli n r e q uire me nt pre vi o us 3 da ys  
 
X  
 
 
 
 
 
 
X  
 
 
X  
X  
Self Re p orte d Se ver e H y p o gl y c e mi a  
 
X  
 
 
 
 
 
 
X  
 
 
X  
X  
H L A D R -D Q ha pl ot y pes, Pr oi ns uli n ,  
 
X  
 
 
 
 
 
 
 
 
 
 
 
H b A 1c,  
 
  
 
X  
 
 
 
 
 
 
X  
 
 
X  
X  
S afet y L a b or at or y Test  ( he mat ol o g y & 
bi o c he mistr y) 3 
 
X  
 
 
X  
 
X  
 
 
X  
 
X  
X  
M M T T 
3 
 
X  
 
 
 
 
 
 
X  
 
 
X  
X  
Pre g n a nc y Test  
 
X  
 
 
X  
 
X  
 
 
X  
 
 
 
1 2 le a d E C G  
 
X  
 
 
X 5 
 
X 5 
 
 
X 5 
 
 
 
C G M d o w nl o a d 4 
 
X  4 
 
 
  
 
 
 
X  4 
 
 
X  4 
X  4 
I M P dis pe ns ati o n 5   
 
 
X  
 
X  
 
X  
 
 
X  
 
 
 
P atie nt Di ar y deli ve r y/c he c k  
 
 
X  
 
X  
 
X  
 
 
X  
 
X  
X  
C hec k disc o nti n u ati o n crite ri a 5 
 
 
 
 
X  
 
X  
 
 
X  
 
 
 
P atie nt P h o ne c all 6 
 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
A E/ S A E  rec or di n g  
X ----------------------------------------------------------------------------------------------------------------------------- -------------------------------------X  
Pri or a n d C o nc o mit a nt M e dic ati o n  
X ----------------------------------------------------------------------------------------------------------------------------- -------------------------------------X  
 
1 
a nti-G A D; I A A (if o btai ne d wit hi n 1 0 da ys of t h e o nset of i ns uli n t hera p y); I A -2; Z n T 8.  
2  fasti n g C-pe pti de m ust b e > 0. 2 0 5 n m ol/ L  o n t w o occasi o ns . 
3  tests p erf or me d at Baseli ne s h o ul d be pla n ne d t o e ns ure t h e sa m ples are se nt t o t he la b orat or y a n d res ults are be a vaila ble in ti me f or ra n d o mizati o n.   
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4  sensor to be positioned at least 10 days before the scheduled visits 
        (X) CGM sensor implantation can occur at Screening Visit and Week 23 Visit if the visit is scheduled 14-10 days before Baseline and before Week 26 respectively 
5 
Dispensation of IMP (Patient Kits) must occur ONLY after check of inclusion/exclusion criteria (at the Randomization Visit) and of discontinuation criteria (at the Visits performed at the end of the 3rd, 6th, 9th 
treatment cycles). Results of ALT/AST, bilirubin, creatinine and albumin, ECG reading and pregnancy results should be made available by the local laboratory in time to allow Patient Kits dispensation as 
soon as possible during the visit. If this expedite timing cannot be achieved, Patient Kits might be delivered to patient named address by a selected courier (CRO to support shipment). As per treatment discontinuation 
criteria, no IMP will be dispensed in the case: QTcF is either > 500 msec or has increased by > 60 msec from baseline measurement on two consecutive ECG readings taken 1 hour apart; the patient develops any 
significant cardiovascular disease/abnormality, renal (eGFR <60mL/min/1.73 m2) or hepatic (increased ALT/AST > 3 x ULN and increased total bilirubin > 3mg/dL [>51.3 μmol/L]) dysfunction, hypoalbuminemia 
(serum albumin <3 g/dL), significant systemic infection that must be assessed on a case-by-case basis by the investigator regarding whether they are serious enough to warrant discontinuation, ketoacidosis or 
hypoglycemic coma; a female patient has become pregnant.  
6 
Telephone calls will be scheduled on a regular basis to ensure optimization of metabolic control.  It is expected that patients are contacted at least every 2 to 3 weeks during study participation. A telephone call 
will be anyway scheduled in the 2 weeks before a planned visit. 
 
                           
 


St u d y L D X 0 4 1 9  
L a d arixi n i n ne wly di a g n ose d Ty pe 1 Di a betes  
 P a ge 6 7  of  6 9  
 
 
 
Versi o n N o. 2  –  fi nal 3 0 J ul y 2 0 2 0   
 
 
1 4. 3.  
A P P E N DI X 1 4. 3  - M E T H O D O L O GI C A L D E T AI L S  
1 4. 3. 1.  
H a n dli n g  of s a m ples f or ce ntr alize d ass a y   
O ne or m ore ce ntralize d la b orat ories will be i n v ol ve d f or assa y of H b A 1c , H L A D R-D Q ha pl ot y pes  a n d 
, C -pe pti de a n d gl uc ose , 
. 
T he c e ntralize d la b orat or y perf or mi n g t he assa y of C -Pe pti de  a n d H b A 1c s h o ul d be certifie d b y C LI A ( or 
si milar certificati o n) a n d will perf or m t he  a nal yses u n der  strict q ualit y c o ntr ol. T his  la b orat or y s h o ul d als o 
partici pate i n t he Nati o nal Gl yc o he m o gl o bi n Sta n dar dizati o n Pr o gra m ( N G S P) wit h t he met h o d yearl y 
certifie d at t he le vel of La b orat or y 1 Certificati o n t o e ns ure t hat t he H b A 1c val ues are tracea ble t o t he D C C T 
val ues . 
A st u d y -s pecific La b orat or y 
Ma n ual will be pr o vi de d t o all sites, re p orti n g detaile d i nstr ucti o ns f or 
ce ntralize d bl o o d sa m pli n g, a n d pre parati o n, st ora ge a n d s hi p me nt of fi nal sa m ples. All t he la b orat ories 
i n v ol ve d i n t he ce ntralize d assa y s will be liste d i n t he La b orat or y Ma n ual, al o n g wit h rele va nt c o ntact details . 
T h e ce ntralize d la b orat ories  will pr o vi de t u bes a n d la be ls f or bl o o d wit h dra wal a n d sa m ple st ora ge. 
S o me s a m ples will be s hi p pe d fr o m t he site t o t he ce ntralize d la b orat ories i n a p pr o priate pac ka ge i n dr y ice 
(s oli d C O2) t o mai ntai n fr oze n c o n diti o ns, if re q uire d.  All sa m ples will be s hi p pe d o n a n o n g oi n g basis d uri n g 
t he trial, acc or di n g t o l o gistics.  H o we ver, scree ni n g/ baseli ne sa m ples a n d sa m ples fr o m t he last patie nt visits 
will be s hi p pe d as s o o n as p ossi ble t o e ns ure ti mel y a vaila bilit y of res ults  f or ra n d o mizati o n a n d data base 
cl os ure, res pecti vel y .   
Ha n dli n g of sa m ples o n recei pt at t he ce ntralize d la b orat or ies a n d assa y met h o ds will be descri be d i n detail 
i n t he La b orat or y Ma n ual.  Si milarl y, arra n ge me nts will be ma de f or bac k-c o m m u nicati o n of t h e res ults t o 
t he se n di n g site. O nce recei ve d fr o m t h e ce ntralize d la b orat or ies, eac h site will e nter val ues pertai ni n g t o its 
patie nts i n t he c orres p o n di n g eC R F.  
All ste ps will be trac ke d t o e ns ure c orrect data re p orti n g.   
All sa m ples will be destr o ye d after fi nal st u d y re p ort has bee n iss ue d or after t he  patie nt has wit h dra w n his/ her 
c o nse nt. 
T he 
C R O a p p oi nte d b y 
D o m pé  will be res p o nsi ble f or rec o ncili n g la b orat or y 
materials, 
f or 
pre pari n g/ distri b uti n g  st ora ge a n d s hi p me nt trac ki n g f or ms, a n d f or c oo r di nati n g s hi p me nt fr o m t he site t o 
t he ce ntralize d la b orat ories.   
T he pr ot oc ol re q uires t hat eit her cell -free ser u m ( bl o o d all o we d t o cl ot a n d ce ntrif u ge d) or E D T A w h ole 
bl o o d sa m ples are st ore d bet wee n -7 0° C a n d -8 0° C u ntil s hi p me nt t o t he ce ntralize d la b orat or ies. A n 
a p pr o priate refri gerate d st ora ge m us t t herefo re be a vaila ble at eac h ce nter. A refri gerate d ce ntrif u ge will als o 
be re q uire d.  
1 4. 3. 2.  
C alc ul ati o n of e G F R  
Re nal f u ncti o n will be e val uate d b y esti mate d Gl o mer ular Filtrati o n rate (e G F R), calc ulate d b y t he f oll o wi n g 
f or m ula (Levey A S . ( 2 0 0 9):  
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Version No. 2 – final 30 July 2020  
 
 
  
 
14.3.3. 
Calculation of eGDR 
 24.31 - [12.22 × waist-to-hip ratio (WHR)] - [3.29 × hypertension status (defined as 0 = no, 1 = yes)] -
 [0.57 × glycated hemoglobin (HbA1c)]  
The calculated eGDR units are milligrams per kilogram per minute. (Simoniene D. et al 2020) 
 
14.3.4. 
Handling of CGM device  
The Dexcom G6 Continuous Glucose Monitoring System (Dexcom G6 System) will be use to perform a 
CGM. CGM measures the subject’s interstitial glucose level using electrodes that measure an electric signal 
produced by glucose oxidase reaction. The system records data approximately every 5 minutes. CGM will be 
used periodically to measure the subject’s interstitial glucose level according to the schedule presented in 
study flow chart/time and event schedule. A CGM sensor will be inserted subcutaneously at the site 14-10 
days before the concerned visits (Baseline, Month 6, 12, 18) and removed during the day of the concerned 
visit, as per Study Flowchart (see Appendix 14.2).  
CGM sensor implantation can occur at Screening Visit and Week 23 Visit if the visit is scheduled 14-10 days 
before Baseline and before Week 26 respectively. In addition, sites should upload the sensor data to check 
subject’s compliance with wearing the device. The sensor requires at least one SMBG value to be entered 
every 12 hours for calibration during use. At a minimum, a SMBG value obtained in the morning (e.g. fasting 
or pre-breakfast measurement) should be entered, as well as a value in the evening (e.g. pre- or post-dinner 
measurement). Subjects may be instructed to use results from the 4 daily SMBG measures to fulfill these 
criteria. Every fourteen/ten (10/14) days the sensor needs to be replaced and subjects can return to the site for 
assistance on this if needed. If the subject needs assistance with sensor replacement, an ad-hoc visit should 
be performed, if this occurs a data upload is also recommended at this time. If subjects opt to perform sensor 
replacement at home sites should call subject 7 days after insertion as a reminder.  
The data will remain blinded to the subject, the investigator, and to the Sponsor during the recording and will 
be downloaded into a data file. The downloaded file should be printed and reviewed by the site for review of 
monitoring compliance. The subjects should make every attempt to be at 100% compliance with use of 
device. If a subject is not compliant the reason should be discussed with the subject, documented in source 
notes, and the subject should be re-educated about importance of CGM compliance. Detailed procedures 
(including calibration) will be described in an operations manual and site staff will be fully trained on the use 
of CGM. Subjects will be instructed on use of the device and calibration according to manufacturer’s 
instructions. Subjects will wear the sensor and perform calibration according to manufacturer’s instructions.  
If a subject uses a CGM device prior to entry into the study, he/she may continue to use the device during the 
study in accordance with their usual diabetes management care.  
Such a subject will be required to also use the blinded CGM device according to protocol procedures.  
 


Study LDX0419 
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Version No. 2 – final 30 July 2020  
 
 
14.3.5. 
Mixed Meal Tolerance Test 
The MMTT will be performed after an overnight fast, according to Greenbaum (2008) at baseline (within 
3week prior of randomization) and at each subsequent visit at month 6, 12 and 18. MMTT should not be 
performed within one week of resolution of a diabetic ketoacidosis event, defined as the presence of: 
- hyperglycemia (blood glucose >200 mg/dL);  
- pH <7.3 or HCO3 <15;  
 
- ketones positive in the serum or urine. 
Prior to the test, patients will withhold long-acting insulin on the morning of the test. Rapid-acting and short-
acting insulin will be allowed up to 6 hours and 2 hours, respectively, before the test. Test will be re-scheduled 
if the patient has a capillary glucose value of >200mg/dL or <70mg/dL.  
The test will be initiated before 10 a.m.  After 2 pre-meal basal samples have been drawn between -20 to 0 
min (basal 1 and basal 2), patients will be given 6mL/kg of Boost® High Protein Nutritional Drink (Nestlé 
Nutrition) up to a maximum of 360mL, to be drunk within 5 min.  Post-meal samples will be drawn at 15+5, 
30+, 60+10, 90+10, 120+15, 120+15 min after the meal. 
 

SAP_001.pdf: 
 
 
Protocol Number: 
LDX0419 
Version: 3.0 
Document Date: 07 May 2024 
 
STATISTICAL ANALYSIS PLAN 
 
PROTOCOL: LDX0419 
 A phase 2, multicenter, randomized, double-blind, placebo-controlled 
study to assess the efficacy and safety of 400 mg twice a day oral ladarixin 
in patients with new-onset type 1 diabetes and preserved β-cell function 
at baseline. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol Number: 
LDX0419 
Version: 3.0 
Document Date: 07 May 2024 
STATISTICAL ANALYSIS PLAN 
APPROVAL PAGE 
 
Document Information  
Protocol Number: 
LDX0419 
Internal Project Code: 
 
Document Date: 
07 May 2024 
Document Version:  
3.0 
Prepared for: 
Dompé farmaceutici s.p.a. [Dompé]   
Via Santa Lucia 6; 20122 Milan, Italy  
Prepared by: 
, Dompé Consultant  
 
 
 
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Protocol Number: 
LDX0419 
Version: 3.0 
Document Date: 07 May 2024 
The Statistical Analysis Plan has been completed and reviewed and the contents are approved for use 
for the analysis. 
 
Statistician details: 
Name: 
 
Job Role: 
Biostatistician Consultant 
Company: 
Dompé farmaceutici s.p.a. [Dompé]  
Via Santa Lucia 6; 20122 Milan, Italy 
Signature: 
 
 
 
 
 
Date of signature: 
(DD Mm YYYY) 
 
 
Statistician details: 
Name: 
 
Job Role: 
Associate Director, Biostatistics 
Company: 
 
Signature: 
 
 
 
 
 
Date of signature: 
(DD Mm YYYY) 
 
 
 
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Protocol Number: 
LDX0419 
Version: 3.0 
Document Date: 07 May 2024 
 
Sponsor Approver details: 
Name: 
 
Job Role: 
Clinical Program Director 
Company: 
Dompé farmaceutici s.p.a. [Dompé]  
Via Santa Lucia 6; 20122 Milan, Italy 
Signature: 
 
 
 
 
 
Date of signature: 
(DD Mm YYYY) 
 
Sponsor Approver details: 
Name: 
 
Job Role: 
Head of Clinical Medical Experts 
Company: 
Dompé farmaceutici s.p.a. [Dompé]  
Via Santa Lucia 6; 20122 Milan, Italy 
Signature: 
 
 
 
 
 
Date of signature: 
(DD Mm YYYY) 
 
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Protocol Number: 
LDX0419 
Version: 3.0 
Document Date: 07 May 2024 
Contents 
Abbreviations ............................................................................................................................................ 8 
Revision History ........................................................................................................................................ 9 
1. 
Introduction .................................................................................................................................... 12 
2. 
Study Objectives ............................................................................................................................. 12 
3. 
Study Design ................................................................................................................................... 12 
3.1 
General design and plan .......................................................................................................... 12 
3.2 
Visit Schedule and Visit Windows ............................................................................................ 13 
3.3 
Sample size justification ........................................................................................................... 16 
3.4 
Randomization and blinding .................................................................................................... 16 
3.5 
Overview of planned statistical analyses ................................................................................. 17 
3.6 
Efficacy endpoints .................................................................................................................... 17 
3.6.1 
Primary endpoint .............................................................................................................. 17 
3.6.2 
Secondary efficacy endpoints ........................................................................................... 17 
 
 
3.7 
Safety endpoints ...................................................................................................................... 18 
4. 
Statistical Analysis........................................................................................................................... 18 
4.1 
General ..................................................................................................................................... 18 
4.2 
Analysis sets ............................................................................................................................. 19 
4.2.1 
Enrolled set ....................................................................................................................... 19 
4.2.2 
Randomized set ................................................................................................................ 19 
4.2.3 
Safety set .......................................................................................................................... 19 
4.2.4 
Full Analysis set ................................................................................................................. 19 
4.3 
Primary estimand ..................................................................................................................... 19 
4.4 
Usage of analysis sets .............................................................................................................. 19 
4.5 
Sub-group analyses .................................................................................................................. 20 
4.6 
Interim analyses ....................................................................................................................... 20 
4.7 
Handling of missing and incomplete data ............................................................................... 20 
4.8 
Changes in the planned analysis .............................................................................................. 20 
4.9 
Blind Data Review Meeting ...................................................................................................... 21 
4.10 
Software ............................................................................................................................... 21 
5. 
Evaluation of Demographic and Baseline Characteristics .............................................................. 21 
5.1 
Subject enrolment and disposition .......................................................................................... 21 
5.2 
Protocol violations ................................................................................................................... 22 
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Protocol Number: 
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Document Date: 07 May 2024 
5.3 
Permanent treatment discontinuation criteria ....................................................................... 22 
5.4 
Patient phone calls ................................................................................................................... 22 
5.5 
Study discontinuations ............................................................................................................. 22 
5.6 
Demographics and baseline characteristics ............................................................................ 23 
5.7 
Medical or Surgical History and/or Concomitant Diseases ..................................................... 23 
5.8 
Prior and concomitant medications ........................................................................................ 23 
5.9 
Other baseline characteristics ................................................................................................. 24 
5.9.1 
Fasting C-Peptide .............................................................................................................. 24 
5.9.2 
Auto-Antibodies ................................................................................................................ 24 
5.9.3 
HLA DR-DQ haplotypes ..................................................................................................... 24 
6. 
Evaluation of Treatment Compliance and Exposure ...................................................................... 25 
6.1 
Compliance to study treatment regimen .................................................................................. 25 
6.1.1 
IMP intake compliance ..................................................................................................... 25 
6.1.2 
Compliance to duration of period “ON-treatment” .......................................................... 27 
6.1.3 
Compliance to duration of period “OFF” ......................................................................... 29 
6.1.4 
Compliance to Treatment regimen ................................................................................... 30 
6.1.5 
Started Cycles ................................................................................................................... 31 
6.2 
Exposure to IMP ....................................................................................................................... 31 
7. 
Evaluation of Efficacy ...................................................................................................................... 31 
7.1 
Analysis of primary endpoint ................................................................................................... 31 
7.2 
Analysis of secondary efficacy endpoints ................................................................................ 31 
7.3 
MMTT over the study .............................................................................................................. 34 
7.4 
Analysis of 
 .............................................................................. 34 
8. 
Evaluation of Safety ........................................................................................................................ 35 
8.1 
Adverse events ......................................................................................................................... 35 
8.2 
Clinical laboratory evaluation .................................................................................................. 36 
8.3 
Vital signs ................................................................................................................................. 37 
8.4 
ECGs ......................................................................................................................................... 37 
8.5 
Pregnancy test over the study ................................................................................................. 37 
9. 
Derivations and date conventions .................................................................................................. 37 
9.1 
Variable derivation ................................................................................................................... 37 
9.2 
CGM value derivation .............................................................................................................. 40 
9.3 
Partial date conventions .......................................................................................................... 42 
10. 
Tables, Figures and Listings ......................................................................................................... 45 
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Protocol Number: 
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Document Date: 07 May 2024 
10.1 
Output conventions .............................................................................................................. 45 
11. 
Reference ..................................................................................................................................... 46 
12. 
Appendices .................................................................................................................................. 47 
12.1 
R code for CGM .................................................................................................................... 47 
12.2 
SAS code for Andersen-Gill intensity model ........................................................................ 62 
12.3 
List of Tables, Listings and Figures ....................................................................................... 63 
 
Index of Tables 
Table 1: Study Flow Chart .......................................................................................................................................................12 
Table 2: Usage of analysis set .................................................................................................................................................17 
Table 3: Variable derivation rules ...........................................................................................................................................36 
Table 4: Variable in cgmanalysis .............................................................................................................................................38 
Table 5: Algorithm for Treatment Emergence of Adverse Events ..........................................................................................40 
Table 6: Algorithm for Prior/Concomitant medications .........................................................................................................42 
 
 
 
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Protocol Number: 
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Version: 3.0 
Document Date: 07 May 2024 
Abbreviations 
 
ADR  
Adverse Drug Reaction  
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical  
AUC 
Area Under the Curve 
BDRM 
Blind Data Review Meeting 
BMI 
Body Mass Index 
CGM 
Continuous Glucose Monitoring 
CONGA 
Continuous Overall Net Glycemic Action 
CS 
Clinically Significant 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form  
eGDR 
estimated Glucose Disposal Rate 
ENR 
Enrolled set 
FAS 
Full Analysis set 
HbA1C 
Glycated hemoglobin 
HLA 
Human Leukocyte Antigen Complex 
IC 
Informed Consent 
ICH 
International Council for Harmonisation 
IMP 
Investigational Medicinal Product 
IRS 
Interactive Response System 
ITT 
Intent to Treat 
MAGE 
Mean Amplitude Glycemic Excursions 
MAR 
Missing at Random 
MCMC 
Markov chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple Imputation 
MI-RD 
Multiple Imputation using retrieve dropouts 
MMRM 
Mixed Model for Repeated Measurements 
MMTT 
Mixed Meal Tolerance Test 
MNAR 
Missing Not At Random 
MODD 
Mean Of the Daily Differences 
NCS 
Not Clinically Significant 
 
 
PP 
Per Protocol set 
PPG 
PostPrandial Glucose 
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Protocol Number: 
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Version: 3.0 
Document Date: 07 May 2024 
PT 
Preferred Term 
QTcF 
corrected QT interval by Fredericia 
RND 
Randomized set 
SAE 
Serious Adverse Event 
SAF 
Safety set 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis Systems 
SD 
Standard Deviation 
SE 
Standard Error 
SI 
Standard International 
SOC 
System Organ Class 
T1D 
Type 1 Diabetes 
TEAE 
Treatment Emergent Adverse Event 
TESAE 
Treatment Emergent Serious Adverse Event 
TIR 
Time in range 
TLF(s) 
Tables, Listings and Figures 
US 
United States 
WHO DD 
World Health Organization Drug Dictionary 
 
Revision History 
Document Version 
Changes Made 
Document Date 
Final 1.0 
First release 
 
Final 2.0 
Section 4.3: Definition of primary estimand; 
 
Section 4.7: Clarification on handling of missing data; 
 
Section 4.8: Description of the main change compared 
to the planned analysis in the protocol; 
 
Section 7.1.2: Inclusion of the MI-RD as method to 
handle missing data in the primary analysis. 
 
Final 3.0 
The SAP has been revised considering the premature 
closure of the study. Efficacy analyses have been 
reduced in scope given the limited sample size of the 
study compared to the expected one. 
 
7 May 2024 
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Protocol Number: 
LDX0419 
Version: 3.0 
Document Date: 07 May 2024 
Document Version 
Changes Made 
Document Date 
The main sections impacted are:  
• Section Efficacy endpointsEfficacy endpoints: one 
single final analysis has been planned after DB 
lock; 
• Section 4.3: removal of the primary estimands; 
• Section 4.4 and 4.8: modified to reflect the 
reduction in the efficacy analyses; 
• Section 4.5 and 5.5: given the reduced sample 
size compared to the planned one, some 
analyses (subgroup analysis and Kaplan-Meier 
curve for the time-to-discontinuation analysis) 
have been removed from the statistical plan; 
• Section 7.1 and 7.2: given the reduced sample 
size compared to the planned one, some 
advanced analyses (logistic regression, multiple 
imputation approaches, sensitivity analysis)  
have been removed from the statistical plan; 
• Sections 12.1: clarifications. 
• Section 6 regarding Compliance has been 
updated 
• CGM parameters units have been added  
• Severe Hypoglicemia derivation has been 
updated in section 9.1 
• Additional information regarding Reason for 
discontinuation summaries has been added in 
5.1 section.    
• Additional details regarding stop enrollment 
and changes in planned analysis has been 
added 
• HLA DR-DQ haplotypes will be only listed 
• Section 7.2.1.6 updated 
• Details and correction of the Cox model 
• Derivation of severe hypoglicemia events has 
been added 
• Number of AEs added in AE summaries 
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Protocol Number: 
LDX0419 
Version: 3.0 
Document Date: 07 May 2024 
Document Version 
Changes Made 
Document Date 
• Section 6.1.2.2.: ON/OFF Compliance 
calculation in case of missing start/end cycle 
dates 
• Section 5.6: Difference between first IMP 
administration and first insulin administration 
will be calculated 
 
 
 
 
 
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Protocol Number: 
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Version: 3.0 
Document Date: 07 May 2024 
1.  Introduction 
This document outlines the statistical methods to be implemented in the analysis of the data of 
LDX0419 Clinical Trial. The purpose of this plan is to provide general guidelines from which the analysis 
will proceed, containing a more technical and detailed elaboration of the principal features of the 
analysis described in the protocol. Any changes to the protocol or electronic Case Report Form (eCRF) 
may necessitate updates to the Statistical Analysis Plan (SAP). In case of deviations from this updated 
SAP, explanations will be provided in the clinical study report. 
 
The SAP V1.0 and V2.0 were based on study protocol Version No. 1 final – 
 [1] and Version 
No. 2 final – 
 [2] (for US only).  
The present version of the SAP refers to the same versions of the study protocols and includes the 
updates to the analysis based on the company decision to prematurely stop the enrolment. 
More details about this decision are described in the official document “Communication of enrolment 
interruption” dated 28 March 2022 [3] sent to the sites. 
 
Please refer to section 4.8 for additional details on the changes of the originally planned analysis plan 
due to the premature closure of the study. 
2.  Study Objectives 
The objective of this clinical trial is to assess whether ladarixin treatment is effective to improve 
glycemic control in newly diagnosed T1D adult patients with preserved β-cell function. The safety of 
ladarixin in the specific clinical setting will be also evaluated. 
3.  Study Design 
3.1 
General design and plan  
The study will be a phase 2, multicenter, double-blind, placebo-controlled study. It will involve 75 adults 
(18-45 years, inclusive) patients with new-onset T1D.  Patients will be randomly (2:1) assigned to 
receive either ladarixin treatment or matched placebo (control group).  The two groups will be 
balanced within centers.   
 
Recruitment will be competitive among the study sites, until the planned number of patients is 
enrolled.   
 
Each patient will be involved in the study for a run-in period (Screening and Baseline assessments) 
followed by a randomization visit and a post-randomization period up to 18 months from the 1st IMP 
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Protocol Number: 
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Version: 3.0 
Document Date: 07 May 2024 
dose. The study will proceed under double-blind condition up to the month 12 visit of the last patient 
randomized. Thereafter, the blind will be broken and remaining follow-up will proceed in an open 
fashion. This approach will allow to anticipate access to safety and efficacy data without significantly 
affecting data integrity.  
 
 
3.2 
Visit Schedule and Visit Windows 
Assessments and study visits will be performed as listed in Table 1. Paragraph no. 7 “Study procedure 
and assessments” of Study Protocol contains additional details about scheduled visits and time 
windows. 
 
For all measurements, the actual date and time of assessment, including date of sampling, will be 
recorded in the eCRF. Time frame for each assessment is reported in the following sections. 
Month/Week match is detailed below, together with acceptable windows: 
• 
Month 6 = Week 26±2 
• 
Month 12 = Week 52±2 
• 
Month 18 = Week 78±2 
 
 
Baseline is defined as the last visit prior to randomization. It is scheduled within 3 weeks to start of 1st 
treatment cycle. Unless otherwise specified, baseline values are defined as the measurements taken 
during this visit (unscheduled visits will not be considered for the definition of baseline value). 
 
In case of multiple measurements during baseline visit, the last assessment will be considered as 
baseline evaluation.
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Protocol Number: 
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Version: 3.0 
Document Date: 07 May 2024 
Table 1: Study Flow Chart 
                          100 days (run-in phase) 
 
1st insulin                                                    
 
first IMP dose 
Procedures 
 
Tests to be performed at a centralized laboratory   
 
Test to be performed at the local  
laboratory 
 
Screening 
Baseline 
(within 3 weeks to C1 
start) 
Randomization 
(within 3 days of 
C1
TREATMENT PERIOD (cycle = C) - 13 Cycles (C1 - C13) 
FOLLOW-UP 
C1 - C3 
Week11 
(end of 3rd 
cycle) 
C4 - C6 
Week 23 
(end of 6th 
cycle) 
C7 – C9 
Month 6 
Week 26±2 
Visit while 
on C7 
Week 35 
(end of 9th  
cycle) 
C 10 - C13 
Month 12 
Week 52±2 
Month 18 
Week 78 ±2 
Informed Consent Form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria Randomization 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Auto-antibodies1 & Fasting C-Peptide2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
BP/HR 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
X 
weight, height, waist & waist/hip circumference    
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
eGDR  
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
Insulin requirement previous 3 days 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
Self Reported Severe Hypoglycemia 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
HLA DR-DQ haplotypes, Proinsulin,  
 
X 
 
 
 
 
 
 
 
 
 
 
 
HbA1c,  
  
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
Safety Laboratory Test (hematology & biochemistry)3 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
X 
MMTT 3 
 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
Pregnancy Test  
 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
12 lead ECG 
 
X 
 
 
X5 
 
X5 
 
 
X5 
 
 
 
CGM download4 
 
X 4 
 
 
  
 
 
 
X 4 
 
 
X 4 
X 4 
IMP dispensation 5  
 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
Patient Diary delivery/check  
 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
Check discontinuation criteria 5 
 
 
 
 
X 
 
X 
 
 
X 
 
 
 
Patient Phone call 6 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE/SAE recording 
X------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
Prior and Concomitant Medication 
X------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
 
 
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Document Date: 07 May 2024 
 
1 
anti-GAD; IAA (if obtained within 10 days of the onset of insulin therapy); IA-2; ZnT8. 
2  
fasting C-peptide must be >0.205 nmol/L on two occasions. 
3  
tests performed at Baseline should be planned to ensure the samples are sent to the laboratory and results are be available in time for randomization.  
4  
sensor to be positioned at least 10 days before the scheduled visits 
        (X) CGM sensor implantation can occur at Screening Visit and Week 23 Visit if the visit is scheduled 14-10 days before Baseline and before Week 26 respectively 
5 
Dispensation of IMP (Patient Kits) must occur ONLY after check of inclusion/exclusion criteria (at the Randomization Visit) and of discontinuation criteria (at the Visits performed at the 
end of the 3rd, 6th, 9th treatment cycles). Results of ALT/AST, bilirubin, creatinine and albumin, ECG reading and pregnancy results should be made available by the local laboratory in 
time to allow Patient Kits dispensation as soon as possible during the visit. If this expedite timing cannot be achieved, Patient Kits might be delivered to patient named address by a 
selected courier (CRO to support shipment). As per treatment discontinuation criteria, no IMP will be dispensed in the case: QTcF is either > 500 msec or has increased by > 60 msec 
from baseline measurement on two consecutive ECG readings taken 1 hour apart; the patient develops any significant cardiovascular disease/abnormality, renal (eGFR <60mL/min/1.73 
m2) or hepatic (increased ALT/AST > 3 x ULN and increased total bilirubin > 3mg/dL [>51.3 μmol/L]) dysfunction, hypoalbuminemia (serum albumin <3 g/dL), significant systemic 
infection that must be assessed on a case-by-case basis by the investigator regarding whether they are serious enough to warrant discontinuation, ketoacidosis or hypoglycemic coma; 
a female patient has become pregnant.  
6 
Telephone calls will be scheduled on a regular basis to ensure optimization of metabolic control.  It is expected that patients are contacted at least every 2 to 3 weeks during study 
participation. A telephone call will be anyway scheduled in the 2 weeks before a planned visit. 
 
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3.3 
Sample size justification 
Below, the calculation performed for the sample size at the time of the study planning. 
 
The sample size of the study is calculated on the “proportion of patients with a HbA1c <7% and daily 
insulin requirement <0.50 IU/Kg/day”, a post-hoc composite endpoint derived from data of the 
phase 2 trial (
), considering a larger effect size expected from the longer treatment length 
(one year versus 3 months).  
 
Based on these assumptions, and considering a randomization ratio 2:1 (ladarixin:placebo) and a 
one-sided alpha of 0.05, seventy-five (75) patients randomized in the trial will allow to achieve a 
power of approximatively 80% to detect at least 35% of difference in terms of primary endpoint in 
favour of ladarixin vs placebo, assuming that the proportion of patients in the placebo group with a 
HbA1c <7% and daily insulin requirement <0.50 IU/Kg/day at 12 months will range between 45% 
and 55%.  
 
Assuming that 10% of subjects will be not evaluable for primary analysis, a total of approximately 
84 subjects is expected to be enrolled. 
 
As reported in section 1, enrolment was prematurely stopped per company decision. 
3.4 
Randomization and blinding 
Eligible Patient will be randomized in a 2:1 fashion to either ladarixin or placebo.  
    
Randomization will be performed through IRS. Each Patient Kit number will be randomly associated 
with a treatment group. The randomization list will be provided to the facility responsible for IMP 
packaging/labelling for the purpose of IMP preparation. Each randomized patient will be allocated 
with randomization number according to the stratified randomization list. Dropouts after 
randomization will not be replaced.  
 
Randomization will be stratified by site to ensure balanced assignment across treatment groups. 
The stratified permuted block randomization list will be generated with a computer procedure by 
an independent statistician not involved in the conduct of the study. A master randomization list 
will be generated, with patients balanced between sites in accordance to randomization ratio (2:1).    
 
Access to individual patient treatment code will be allowed only in the event of a medical emergency 
where the knowledge of patient treatment is required to provide the patient with appropriate care. 
The investigator will be provided with a protected access to the randomization system to allow 
opening of the treatment allocation for a specific patient in case of a medical emergency.  
 
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Dompé Pharmacovigilance contact person will be provided also with envelopes of the 
randomization number code break (to reveal the planned treatment arm assigned at the 
Randomization Visit) in order to unblind a specific patient for safety reporting. 
Unblinding events will be recorded and reported in the final study report. 
 
The randomization code will be broken according to study procedures after the last enrolled patient 
has completed his/her follow-up visit at 12 months. 
 
3.5 
Overview of planned statistical analyses 
The study was originally planned to perform  the following statistical analyses: 
• 
Final analysis: to be conducted when all enrolled subjects have completed the Month 12 
follow-up visits, and the study database has been locked. 
• 
Addendum at Final analysis: to be conducted when all enrolled subjects have completed 
the open phase study post unblinding up to Month 18. 
Considering the premature closure of the study, a unique analysis will be performed when all 
enrolled subjects have completed all the follow-up visits and the study database has been locked. 
3.6 
Efficacy endpoints 
3.6.1 Primary endpoint  
The primary efficacy endpoint is the proportion of patients with HbA1c <7% and daily insulin 
requirement <0.50 IU/Kg/day at Month 12. 
3.6.2 Secondary efficacy endpoints 
The secondary efficacy endpoints are the following: 
• 
Proportion of patients with HbA1c <7% and daily insulin requirement <0.50 IU/Kg/day at 
Month 6 and 18; 
• 
Proportion of patients with a reduction in HbA1c > 0.5% from baseline and daily insulin 
requirement <0.50 IU/Kg/day at Month 6, 12, and 18; 
• 
2-hour Area Under the Curve (AUC) of C-peptide response to the Mixed Meal Tolerance 
Test (MMTT) at Month 6, 12, and 18; 
• 
Time in range (TIR) by Continuous Glucose Monitoring (CGM) at Month 6, 12, and 18; 
• 
HbA1c levels at Month 6, 12, and 18; 
• 
Proportion of patients with HbA1c <7% who did not experience severe hypoglycaemic 
events during treatment at Month 6, 12, and 18; 
• 
Additional Glucose Variability Indices derived from CGM at Month 6, 12, and 18; 
• 
Number of self-reported episodes of severe hypoglycaemia at Month 6, 12, and 18; 
• 
Average (previous 3 days) daily insulin requirements (IU/kg/day) at Month 6, 12, and 18; 
• 
Estimated Glucose Disposal Rate (eGDR) at Month 6, 12, and 18; 
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3.7 
Safety endpoints 
The safety endpoints are the following:  
• 
Adverse Events (AEs) and Serious Adverse Events (SAEs) throughout the study. 
• 
Safety Laboratory Tests at Week 11, Week 23, Week 35, Month 12 and Month 18 (or 
withdrawal); 
• 
Vital signs at Week 11, Week 23, Week 35, Month 12 and Month 18; 
4.  Statistical Analysis 
4.1 
General 
Appropriate descriptive statistics will be produced, according to the variable. For continuous data 
n, mean, standard deviation (SD), median and range (minimum and maximum) will be presented. 
For categorical data, frequency distributions and percentages will be presented.  
 
Unless otherwise specified, hypothesis testing will be carried out at the alpha = 0.050 level (one-
sided) when comparing treatments. For all inferential analyses, p-value will be rounded to three 
decimal places. Statistical significance will be declared if the rounded one-sided p-value will be less 
than or equal to 0.050.  
 
Additional post-hoc analysis may be produced to further allow comparison between ladarixin and 
placebo, according to the results obtained. Any unplanned analyses as well as deviations from the 
original statistical plan will be clearly documented in the Clinical Study Report. 
 
Derivation rules for efficacy and safety analyses are reported in Table 3 in section 9.  
   
All the data collected and derived in the study will be presented in subject data listings. 
 
 
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4.2 
Analysis sets 
4.2.1 Enrolled set 
The Enrolled set (ENR) will consist of all patients with signed written informed consent (IC) and 
undergoing to study evaluations/procedures. 
4.2.2 Randomized set 
The Randomised set (RND) will consist of all patients in the ENR set who are randomized to the 
study, regardless of whether they receive IMP or not. 
4.2.3 Safety set 
The Safety set (SAF) will consist of all randomized patients who receive at least one dose of the IMP. 
SAF population will be analyzed according to the actual treatment received and will be used to 
present results on safety data. 
4.2.4 Full Analysis set 
The Full Analysis Set (FAS) will consist of all randomized patients who receive at least one dose of 
the IMP (either ladarixin or placebo). FAS population will be analyzed according to ITT principle, i.e. 
by treatment allocation regardless happening of intercurrent events (treatment policy strategy). The 
FAS population will be used for the primary analyses of the study and to present results on efficacy 
data. 
4.3 
Primary estimand 
Considering the premature closure of the study, the originally planned treatment policy strategy 
and estimand definition is not applicable. Summary analysis will be performed, descriptive in nature. 
4.4 
Usage of analysis sets 
The usage of the analysis sets (see previous section) for the creation of tables and figures are 
illustrated in Table 2. Unless otherwise specified, all listings will be done for RND set. All listings will 
have planned and actual treatment names included, as well as the flag(s) of the analysis set(s) used 
to analyses the information of the listing (according to the Table 2). 
Table 2: Usage of analysis set 
Analysis 
ENR 
RND 
FAS 
SAF 
Subject enrolment and disposition 
X 
 
 
 
Protocol violations 
 
X 
 
 
Study discontinuations 
 
X 
 
 
Permanent treatment discontinuation criteria 
 
X 
 
 
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Patient phone calls 
 
X 
 
 
Demographics and baseline characteristics 
 
 
X 
 
Medical or surgical history and/or Concomitant Diseases 
 
 
X 
X 
Prior and concomitant medications 
 
 
X 
X 
Other baseline characteristics 
 
 
X 
 
Compliance to IMP 
 
 
 
X 
Exposure to IMP 
 
 
 
X 
Analysis of primary efficacy endpoint 
 
 
X 
 
Analysis of secondary efficacy endpoints 
 
 
X 
 
MMTT over the study 
 
 
X 
 
Analysis of
 
 
 
X 
 
Adverse events 
 
 
 
X 
Clinical laboratory evaluation 
 
 
 
X 
Vital signs 
 
 
 
X 
ECGs 
 
 
 
X 
Pregnancy test over the study 
 
 
 
X 
4.5 
Sub-group analyses 
Considering the premature closure of the study and the limited sample size compared to the 
originally expected, the analysis of the primary endpoint in pre-defined subgroups (by age, sex, race, 
BMI, Human Leukocyte Antigen Complex – HLA, 
, site 
geographic region) will not be performed. 
4.6 
Interim analyses 
No formal interim analysis is planned for the study.  
4.7 
Handling of missing and incomplete data 
The number of patients with missing data will be presented under the “Missing” category, if present. 
Missing values will be included in the denominator count when computing percentages. Instead, 
only the non-missing values will be evaluated for computing summary statistics for continuous 
endpoint. Any exception will be clarified as a note. 
4.8 
Changes in the planned analysis 
Due to the company decision to stop the enrolment,  fewer patients compared to the originally 
planned will be available for the analysis. Thus, he following changes were  implemented: 
• 
one single final analysis is planned after DB lock; 
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• 
no formal hypothesis testing will be performed; 
• 
all analyses will be descriptive in nature; 
• 
no advanced analytical methods will be applied, specifically; 
o Primary endpoint no more analyzed by means of logistic regression model: 
comparison between treatment arms performed by means of a Chi-square test at 
each time point. 
o No multiple imputation approaches to manage potential missing data; 
• 
no sensitivity analyses will be performed; 
• 
no sub-group analyses will be performed; 
4.9 
Blind Data Review Meeting 
A Blind Data Review Meeting (BDRM) will be held before the database lock and unblinding of the 
data. Any other details will be provided in the BDRM Report. 
4.10 Software 
All statistical analyses and data processing will be performed using Statistical Analysis Systems 
(SAS®) Software (release 9.4) on a Windows 10 operating system. 
 
CGM data at patient level will be processed using cgmanalysis package [4] in R version 3.6.1 (or 
later) before performing statistical analysis. 
5.  Evaluation of Demographic and Baseline Characteristics 
5.1 
Subject enrolment and disposition 
All presentations for subject disposition will be by treatment group, and overall.  
 
For describing the subject disposition, the following populations will be summarized:  
• 
Subjects enrolled (overall);  
• 
Subjects enrolled but not randomized and reasons for non-allocation (overall);  
• 
Subjects randomized;  
• 
Subjects in each analysis set (FAS, SAF) and reasons for exclusion; 
 
For the overall report, the percentage denominator will be the number of ENR subjects. For the “by 
treatment group” calculations, the percentage denominator will be the number of randomized 
subjects within each arm. 
 
For the second bullet point, the following information will be listed as well:  
• Reason for discontinuation. If reason for discontinuation = “Inclusion Criteria not met / 
Exclusion Criteria met” the following information will be listed: 
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o Specification about Inclusion/Exclusion criteria not met/met  
o Corresponding Parameters, whether a threshold level of a laboratory/ECG parameter 
is expected to meet the criterion (Inclusion criteria #3 and #5, Exclusion criteria #2, 
#3, #4, #5) 
o Results of corresponding parameter (for example, both C-peptide values)  
 
 
Listings will be provided based on ENR set. 
5.2 
Protocol violations 
All the protocol violations will be discussed case by case before unblinding of the treatment code 
with the clinical team during the BDRM and described in the BDRM Report. 
 
Number of occurrences and of subjects with at least one major and minor protocol violations will 
be summarized for each treatment. 
5.3 
Permanent treatment discontinuation criteria 
A summary table showing at each available time point the number and percentages of subjects who 
discontinued the study treatment along with the discontinuation criteria will be produced by 
treatment group. The number of patients still under treatment of discontinuing at the specific visit 
will be used as denominator for percentages. 
5.4 
Patient phone calls 
A summary table showing at each available time point the number and percentages of subjects who 
were contacted by phone call and who needed/not needed an adjustment in the insulin regimen 
will be produced by treatment group. The number of all patients (including subjects that have 
discontinued IMP but still in the study) at the specific visit will be used as denominator for 
percentages. 
5.5 
Study discontinuations 
The following information will be summarized for the randomized patients by treatment and overall: 
• 
Trial completers; 
• 
Number of subjects who completed each planned visit.  
• 
Subjects who discontinued the IMP and reasons (taken from EOT form) 
o Subjects who discontinued the IMP but complete the study 
o Subjects who discontinued the IMP and discontinued the trial prematurely 
• 
Subjects who discontinued the trial prematurely (and reason); 
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• 
Broken randomization code (and reason). 
5.6 
Demographics and baseline characteristics  
The baseline demographic characteristics will be summarized by treatment and overall, by means 
of descriptive statistics. No statistical testing will be carried out for demographic or other baseline 
characteristics. 
The following demographic and baseline characteristics will be reported for this study: 
• 
Geographic region of the site (EU, US, Other) 
• 
Demography 
o Age (years) 
o Sex (Male, Female) 
o If female, potential childbearing (Yes, No) 
o Race (White, Black or African American, Asian, American Indian or Alaska 
Native, Native Hawaiian or other Pacific Islander, Other) 
o Ethnicity (Hispanic or Latino, Not Hispanic or Latino)  
• 
Pregnancy test result (Positive or Negative), if appropriate 
• 
T1D diagnosis 
o Diagnosis of T1D confirmed (Yes, No) 
o Time from T1D diagnosis to inform consent (days) 
o Time from first insulin administration to first IMP administration (days). The 
following formula will be used: date of first IMP administration – date of first 
insulin administration. 
• 
BMI (BMI≤25kg/m2 vs 25kg/m2<BMI≤30kg/m2 vs BMI>30kg/m2) 
5.7 
Medical or Surgical History and/or Concomitant Diseases 
A disease is considered as medical/surgical history if it is ended before screening visit. 
 
A disease is considered as concomitant disease if it is ongoing at screening visit. 
 
Medical history and concomitant diseases will be coded using Medical Dictionary for regulatory 
activities (MedDRA) dictionary and frequency distributions and percentages will be summarized by 
treatment, by System Organ Class (SOC), and Preferred Term (PT). 
 
Medical history and concomitant diseases will be analyzed separately. Frequency distributions and 
percentages by treatment will be given for both SOC and PT by subject. Subjects experiencing more 
than one past/concomitant disease event will be counted only once within each SOC and PT. 
5.8 
Prior and concomitant medications 
Medications will be coded using World Health Organization Drug Dictionary (WHO DD). 
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Prior medications are those which stop prior to the date of informed consent. Concomitant 
medications are those which: 
• 
start prior to, on or after the date of informed consent and start no later than date of 
study completion or discontinuation, and 
• 
end on or after the date of informed consent or are ongoing at the study completion or 
discontinuation. 
 
In case of missing or incomplete dates/times not directly allowing allocation to any of the two 
categories of medications, a worst-case allocation will be done according to the available parts of 
the start and the end dates (see Table 6). The medication will be allocated to the first category 
allowed by the available data, according to the following order: 
• 
concomitant medication; 
• 
prior medication. 
 
Prior and concomitant medications will be summarized separately. Frequency distributions and 
percentages by treatment will be given by Anatomical Main Group (1st level of the Anatomical 
Therapeutic Chemical (ATC) classification), Chemical Subgroup (4th level of the ATC classification) 
and Preferred Name.  
 
Subjects experiencing more than one medication classified in the same category (prior medications 
or concomitant medications) within the same anatomical main group, chemical subgroup and 
preferred name will be counted only once. 
5.9 
Other baseline characteristics 
5.9.1 Fasting C-Peptide 
Summary statistics by treatment of fasting C-Peptide (nmol/L) at baseline will be provided. In case 
of repetition of fasting C-Peptide evaluation (according to protocol), the repeated assessment will 
be considered as the only evaluation. 
5.9.2 Auto-Antibodies 
Auto-antibodies (anti-GAD; IAA, if obtained within 10 days of the onset of insulin therapy; IA-2 
antibody; ZnT8) results to confirm T1D diagnosis and of fasting C-peptide will be descriptively 
summarized. In case of repetition of evaluation (according to protocol), the repeated value will be 
considered as the only evaluation value. 
5.9.3 HLA DR-DQ haplotypes 
HLA DR-DQ haplotypes at baseline will be listed only. 
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6.  Evaluation of Treatment Compliance and Exposure 
6.1 
Compliance to study treatment regimen 
Descriptive analyses of the following parameters will be presented by treatment group for each 
cycle and during the entire treatment period: 
• from IMP dispensation form  
o number of capsules dispensed;  
• from IMP accountability form 
o number of returned blisters; 
o number of capsules taken; 
o number of returned unused capsules; 
o IMP intake compliance, ON -treatment period compliance (only by cycle); 
 
Patients are instructed to receive study treatment (either ladarixin or placebo) as follows: 
- 
400 mg b.i.d (2 capsules at each administration, twice per day); 
- 
for 13 cycles, each lasting 28 days; 
- 
each cycle is composed by 14 consecutive days on-treatment and 14 consecutive days off-
treatment. 
Calculation of compliance to treatment regimen must consider not only the amount of treatment 
intake, but also the correct alternation between period “ON” and period “OFF” and their duration. 
To assess the overall compliance to treatment regimen, the following 3 criteria will be taken into 
account:  
- 
Compliance to IMP intake;  
- 
Compliance to duration of period “ON” (period of the cycle when the patient is ON treatment);  
- 
Compliance to duration of period “OFF” (period of the cycle when the patient is OFF 
treatment). 
 
6.1.1 IMP intake compliance  
6.1.1.1 Over the entire treatment period 
 
IMP intake compliance over the entire treatment period will be calculated as follow: 
 
𝐼𝑀𝑃 𝑖𝑛𝑡𝑎𝑘𝑒 𝑐𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒 (%)
= 
𝑡𝑜𝑡𝑎𝑙 𝑛. 𝑜𝑓 𝑐𝑎𝑝𝑠𝑢𝑙𝑒𝑠 𝑡𝑎𝑘𝑒𝑛 𝑑𝑢𝑟𝑖𝑛𝑔 𝑡ℎ𝑒 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑝𝑒𝑟𝑖𝑜𝑑
𝑡𝑜𝑡𝑎𝑙 𝑛. 𝑜𝑓 𝑐𝑎𝑝𝑠𝑢𝑙𝑒𝑠 𝑑𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑 𝑑𝑢𝑟𝑖𝑛𝑔 𝑡ℎ𝑒 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑝𝑒𝑟𝑖𝑜𝑑 ×  100 
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where “total number of capsules taken during the treatment period” is the sum of number of 
capsules taken at each cycle (CRF IMP ACCOUNTABILITY form), while the “total number of capsules 
dispensed during the treatment period” is given by the number of dispensed kits (CRF IMP 
DISPENSATION form) considering that each kit contains 56 capsules.  
For a complete treatment period over 13 cycles the dispensed number of capsules and the 
number of capsules the patient is expected to take is the same and is equal to 728. 
For a cycle that is interrupted due to treatment discontinuation the expected #capsules may differ 
from the # dispensed as follows: 
• If interrupted before the expected last intake, the expected # capsules will be derived as: 
𝐸𝑥𝑝𝑒𝑐𝑡𝑒𝑑 # 𝑐𝑎𝑝𝑠𝑢𝑙𝑒𝑠 = 56 ∗# 𝑐𝑜𝑚𝑝𝑙𝑒𝑡𝑒𝑑 𝑘 𝑐𝑦𝑐𝑙𝑒𝑠 (𝑘= 1 …  𝑖−1)  
+ 4 ∗( 𝐷𝑎𝑡𝑒 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑑𝑖𝑠𝑐𝑜𝑛𝑡 𝑖𝑛 𝐶𝑦𝑐𝑙𝑒 (𝑖) –  𝐷𝑎𝑡𝑎 𝑠𝑡𝑎𝑟𝑡 𝐶𝑦𝑐𝑙𝑒 (𝑖) + 1) 
In the expected #capsules calculation, it is assumed that the discontinuation occurs after last daily 
intake. 
• If interrupted after the expected last intake, the expected number of capsules will be: 
𝐸𝑥𝑝𝑒𝑐𝑡𝑒𝑑 # 𝑐𝑎𝑝𝑠𝑢𝑙𝑒𝑠= 56 ∗# 𝑐𝑜𝑚𝑝𝑙𝑒𝑡𝑒𝑑 𝑘 𝑐𝑦𝑐𝑙𝑒𝑠 (𝑘= 1 …  𝑖−1) +  56 
 
IMP intake compliance over the entire treatment period will be summarized by treatment by means 
of summary statistics.   
In addition, compliance to IMP over the entire treatment period will also be presented for the 
following categories: <80%, 80%-100% (excluded), 100%, >100%. 
 
6.1.1.2 By cycle 
 
Compliance by cycle with respect to IMP intake will be assessed following the formula below: 
𝐼𝑀𝑃 𝑖𝑛𝑡𝑎𝑘𝑒 𝑐𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒 𝑎𝑡 𝑐𝑦𝑐𝑙𝑒 (𝑖) (%)
= 
𝑡𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑐𝑎𝑝𝑠𝑢𝑙𝑒𝑠 𝑡𝑎𝑘𝑒𝑛 𝑑𝑢𝑟𝑖𝑛𝑔 𝑡ℎ𝑒 𝑐𝑦𝑐𝑙𝑒 
𝑡𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑐𝑎𝑝𝑠𝑢𝑙𝑒𝑠 𝑑𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑 𝑑𝑢𝑟𝑖𝑛𝑔 𝑡ℎ𝑒 𝑐𝑦𝑐𝑙𝑒  ×  100 
 
If cycle (i) is completed, the dispensed number of capsules and the number of capsules the patient 
is expected to take is the same and is equal to 56. 
If cycle (i) is interrupted due to treatment discontinuation: 
• If interrupted before the expected last intake, the expected number of capsules will be 
derived as: 
𝐸𝑥𝑝𝑒𝑐𝑡𝑒𝑑 # 𝑜𝑓 𝑐𝑎𝑝𝑠𝑢𝑙𝑒𝑠 
=  4 ∗( 𝐷𝑎𝑡𝑒 𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑑𝑖𝑠𝑐𝑜𝑛𝑡 𝑖𝑛 𝐶𝑦𝑐𝑙𝑒 (𝑖) –  𝐷𝑎𝑡𝑎 𝑠𝑡𝑎𝑟𝑡 𝐶𝑦𝑐𝑙𝑒 (𝑖) + 1) 
• If interrupted after the expected last intake, the expected number of capsules will be 56 
 
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6.1.1.3 Global criteria for IMP intake compliance  
 
A subject will be classified as “Globally Compliant to IMP intake” (=”Y”) if: 
a) IMP intake compliance over the entire treatment period in the range 80% - 100% (80 and 
100 included) 
AND 
b) no more than 2 consecutive cycles with IMP intake compliance <80% or >120%  
AND 
c) no more than 4 cycles with IMP intake compliance <80% or >120%, 
otherwise he will be classified as Non-Compliant (=”N”). 
Note: conditions (b) and (c) to be checked only for patients who completed the entire treatment 
period.  
 
The following variables will also be derived: 
- 
#cycles with IMP intake compliance <80% or >120%, (only for patients who completed the 
entire treatment period).  
- 
3 or more consecutive cycles with IMP intake compliance <80% or >120% [Y/N], (only for 
patients who completed the entire treatment period).  
6.1.2 Compliance to duration of period “ON-treatment” 
 
By study protocol for each cycle each patient is supposed to take IMP for 14 days; compliance to 
duration of “ON-treatment” period is evaluated as the comparison between the expected duration 
(14 days) and the actual (observed) duration. 
 
6.1.2.1 Over the entire treatment period 
 
Compliance to ON-Treatment period will be calculated as follow: 
 
𝑃𝑒𝑟𝑖𝑜𝑑 𝑂𝑁 𝑐𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒 (%) = 𝑇𝑜𝑡𝑎𝑙 𝑜𝑏𝑠𝑒𝑟𝑣𝑒𝑑 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑝𝑒𝑟𝑖𝑜𝑑 𝑂𝑁
𝑇𝑜𝑡𝑎𝑙 𝑒𝑥𝑝𝑒𝑐𝑡𝑒𝑑 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑝𝑒𝑟𝑖𝑜𝑑 𝑂𝑁 ×  100 
 
The total expected duration of period ON for a subject who complete regularly the study is 182 
days (14 days * 13 cycles). 
 
The actual (observed) duration of k-th period ON (k=1… 13) from each cycle is defined as: 
 
𝑘−𝑡ℎ 𝑐𝑦𝑐𝑙𝑒 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑂𝑁 =  𝐷𝑎𝑡𝑒 𝑙𝑎𝑠𝑡 𝑖𝑛𝑡𝑎𝑘𝑒 𝑖𝑛 𝐶𝑦𝑐𝑙𝑒 (𝑘) –  𝐷𝑎𝑡𝑎 𝑠𝑡𝑎𝑟𝑡 𝐶𝑦𝑐𝑙𝑒 (𝑘) + 1  
 
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The observed Total Duration period ON over the entire treatment period is given by the sum of 
the k periods ON from each cycle. 
 
In case of treatment discontinuation, the last cycle can be affected. Considering the first k 
completed cycles (k=1…. I-1): 
- Expected total duration of period ON = 14*k  
[1] 
- Actual (observed) Total Duration ON is given by the sum of the k observed periods ON  [2]. 
 
The last i-th cycle, interrupted due to treatment discontinuation is included as follows: 
• If interrupted before the expected last intake, the duration of the period ON to be added 
to [1] and [2] is derived as: 
i-th Cycle Duration ON = Date treatment discontinuation – Data start Cycle (i) +1  
With this formula we are assuming that the IMP is taken on the day of discontinuation. 
• If the trial will be discontinued after the expected last intake, the expected duration of the 
i-th period ON is 14 days. 
6.1.2.2 By Cycle 
Period ON compliance at cycle (i) will be calculated as follow: 
 
𝑃𝑒𝑟𝑖𝑜𝑑 𝑂𝑁 𝑐𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒 𝑎𝑡 𝑐𝑦𝑐𝑙𝑒 (𝑖)(%)
=  𝑜𝑏𝑠𝑒𝑟𝑣𝑒𝑑 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑝𝑒𝑟𝑖𝑜𝑑 𝑂𝑁 𝑎𝑡 𝑐𝑦𝑐𝑙𝑒 𝑖
𝑒𝑥𝑝𝑒𝑐𝑡𝑒𝑑 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑝𝑒𝑟𝑖𝑜𝑑 𝑂𝑁 𝑎𝑡 𝑐𝑦𝑐𝑙𝑒 𝑖 ×  100 
 
The observed duration of period ON for each cycle is defined as: 
 
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑝𝑒𝑟𝑖𝑜𝑑 𝑂𝑁, 𝑐𝑦𝑐𝑙𝑒 (𝑖) =  𝐷𝑎𝑡𝑒 𝑙𝑎𝑠𝑡 𝑖𝑛𝑡𝑎𝑘𝑒 𝑖𝑛 𝑐𝑦𝑐𝑙𝑒 (𝑖) –  𝐷𝑎𝑡𝑎 𝑠𝑡𝑎𝑟𝑡 𝑐𝑦𝑐𝑙𝑒 (𝑖) + 1 
 
The expected duration of period ON is 14 days. 
For a cycle that is interrupted due to treatment discontinuation the rule to be applied is the same 
as the one reported above in section 6.1.2.1: 
• If interrupted before the expected last intake, the duration of the period ON is derived as: 
▪ i-th Cycle Duration ON = Date treatment discontinuation – Data start Cycle 
(i) +1 (if the day of discontinuation the IMP was taken) 
▪ i-th Cycle Duration ON = Date treatment discontinuation – Data start Cycle 
(i) (if the day of discontinuation the IMP was not taken) 
▪ expected duration will be = observed duration 
• If interrupted after the expected last intake, the expected duration of period ON is 14 days 
Note:  
Date start cycle and date last intake in the cycle are considered as they are, regardless of whether 
the intake of the 1st day occurred only in the evening and the intake of the last day occurred only in 
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the morning. This may happen, but conventionally days and not day periods (morning / evening) 
will be considered. For these cases is possible that intake may last 15 days instead of 14. 
 
In case the kit was dispensed, it was returned, and the number of capsules taken is 0 (therefore we 
cannot define the start cycle date and end cycle date), we will follow the following convention: 
• Start Cycle x date will be as scheduled date: start cycle x-1 date (previous cycle) +28 days 
• End Cycle x date will be equal to start cycle x date 
• On period will be set to 0 days 
6.1.2.3 Global criteria for duration of ON-Treatment period 
 
A subject will be classified as “Globally Compliant to ON-treatment period” (=”Y”) if: 
a) Compliance to Period “ON” duration over the entire treatment period in the range 80% - 
120% (80 and 120 included) 
AND 
b) no more than 2 consecutive cycles with compliance to “Period ON” duration <80% or 
>120%  
AND 
c) no more than 4 cycles with compliance to “Period ON” duration <80% or >120%, 
otherwise he will be classified as Non-Compliant (=”N”). 
Note: conditions (b) and (c) to be checked only for patients who completed the entire treatment 
period.  
 
The following variables will also be derived: 
- 
#cycles with compliance to “Period ON” length <80% or >120%, (only for patients who 
completed the entire treatment period).  
- 
3 or more consecutive cycles with “Period ON” length compliance <80% or >120% [Y/N], (only 
for patients who completed the entire treatment period).  
 
6.1.3 Compliance to duration of period “OFF” 
 
By study protocol for each cycle each patient is supposed to have a 14-days period OFF treatment 
after the 14-days ON-treatment period. Compliance to duration of period “OFF” is the comparison 
between the expected duration (14 days) and the actual (observed) duration. 
 
6.1.3.1 Over the entire treatment period 
 
Period OFF compliance will be calculated as follow: 
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𝑃𝑒𝑟𝑖𝑜𝑑 𝑂𝐹𝐹 𝑐𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒 (%) = 𝑇𝑜𝑡𝑎𝑙 𝑜𝑏𝑠𝑒𝑟𝑣𝑒𝑑 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑝𝑒𝑟𝑖𝑜𝑑 𝑂𝐹𝐹 
𝑇𝑜𝑡𝑎𝑙 𝑒𝑥𝑝𝑒𝑐𝑡𝑒𝑑 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝑝𝑒𝑟𝑖𝑜𝑑 𝑂𝐹𝐹  ×  100 
 
The total expected duration of period OFF for a subject who complete regularly the study is 168 
days (14 days * 12 cycles). 
The duration of k-th period OFF (k=1,…,12) from each cycle is defined as: 
𝑘−𝑡ℎ 𝐶𝑦𝑐𝑙𝑒 𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑂𝐹𝐹 
=  𝐷𝑎𝑡𝑒 𝑠𝑡𝑎𝑟𝑡 𝐶𝑦𝑐𝑙𝑒 (𝑘+ 1) − 𝐷𝑎𝑡𝑒 𝑙𝑎𝑠𝑡 𝑖𝑛𝑡𝑎𝑘𝑒 𝑖𝑛 𝐶𝑦𝑐𝑙𝑒 (𝑘) –  1  
The total observed duration OFF is given by the sum of the k periods OFF. 
In case of treatment discontinuation during cycle (i): 
• If discontinued before last intake of the period ON: 
o Expected Total period OFF=14*( i-1) 
o Observed Total period OFF=sum from k=1 to i-1 of the i-1 period OFF 
 
• If discontinued after last intake of the period ON: 
o Expected Total period OFF=14*( i-1) + period OFF for i-th cycle (see [*]) 
o Observed Total period OFF=sum from k=1 to i-1 of the i-1 period OFF + period OFF 
for i-th cycle (see [*]) 
 
[*] In case i-th cycle is interrupted due to treatment discontinuation after the expected last intake, 
the expected and observed duration of period OFF for i-th cycle is derived as: 
𝑖−𝑡ℎ 𝐶𝑦𝑐𝑙𝑒 𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑂𝐹𝐹 =  𝐷𝑎𝑡𝑒 𝑡𝑟𝑖𝑎𝑙 𝑑𝑖𝑠𝑐𝑜𝑛𝑡𝑖𝑛𝑢𝑎𝑡𝑖𝑜𝑛 –  
𝐷𝑎𝑡𝑒 𝑙𝑎𝑠𝑡 𝑖𝑛𝑡𝑎𝑘𝑒 𝑖𝑛 𝐶𝑦𝑐𝑙𝑒 (𝑖) 
 
6.1.3.2 By Cycle 
 
No compliance by cycle defined for the “OFF-Treatment”.  
 
6.1.3.3 6.1.3.3 Global criteria for duration of OFF-Treatment period  
 
A subject will be classified as “Globally Compliant to OFF-treatment period” (=”Y”) if: 
a) Compliance to “OFF-Treatment” duration over the entire treatment period is <150% 
otherwise he will be classified as Non-Compliant (=”N”). 
 
6.1.4 Compliance to Treatment regimen 
 
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Subject will be considered compliant to study treatment regimen if conditions defined in section 
6.1.1.3, 6.1.2.3 and 6.1.3.3 are met (i.e. subject compliant to global criteria regarding IMP intake, 
ON-treatment period, OFF-treatment period). 
 
Overall compliance to treatment regimen will be presented (Y/N) by treatment and overall. 
 
6.1.5 Started Cycles 
 
Per each subject the number of cycles started during the entire treatment period will be counted.  
The i-th cycle is defined as started if at least 1 IMP intake is reported in the cycle (Data start Cycle 
(i) is not missing). 
 
The number of started cycles over the entire treatment period will be summarized by treatment 
and overall by means of summary statistics.   
 
A listing of information about IMP ACCOUNTABILITY and IMP DISPENSATION will be provided by 
cycle and overall. 
A listing will also be produced by reporting all detail regarding compliance criteria described above 
by cycles and overall. 
6.2 
Exposure to IMP 
The extent of exposure to IMP in weeks will be summarized overall with descriptive statistics by 
treatment group. The extent of exposure (weeks) will be calculated using the formula reported in 
Table 3. 
7.  Evaluation of Efficacy 
All analyses will be considered descriptive in nature. No multiplicity correction of type I error is 
required. 
7.1 
Analysis of primary endpoint 
Number and proportion along the 95% confidence interval (Clopper-Pearson’s formula) of patients 
with HbA1c < 7% and daily insulin requirement <0.5 (IU/kg/day) will be calculated at Month 12. The 
comparison between the two study treatment arms will be performed by means of a Chi-square 
test or, if more appropriate, a Fisher’s Exact test at each time point. 
7.2 
Analysis of secondary efficacy endpoints 
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All secondary endpoints will be analysed at each available time point by means of descriptive 
statistics as detailed in sections 7.2.1.1-7.2.1.10. 
The following results will be displayed graphically: 
• 
The proportion at each time point by treatment of patients with HbA1c <7% and daily 
insulin requirement <0.5 (IU/kg/day); 
• 
The means (±SEs) at each time point by treatment of the HbA1c and its change from 
baseline; 
• 
The proportion at each time point by treatment of patients with HbA1c of less than 7% 
who did not experience severe hypoglycemic events during treatment; 
• 
The means (±SEs) at each time point by treatment of the daily insulin requirement 
(IU/kg/day);  
• 
The means (±SEs) at each time point by treatment of the 2-hour AUC of C-peptide post 
MMTT and its change from baseline; 
• 
The means (±SEs) at each time point by treatment of the TIR by CGM and its change from 
baseline. 
 
In each graph, where possible, significant p-values from the below analyses will be reported in the 
plot area, in correspondence of the associated time point. 
7.2.1.1 Proportion of patients with HbA1c <7% and daily insulin requirement <0.5 (IU/kg/day) 
Number and proportion along the 95% confidence interval (Clopper-Pearson’s formula) of patients 
with HbA1c < 7% and daily insulin requirement <0.5 (IU/kg/day) will be calculated for each time 
point. The comparison between the two study treatment arms will be performed by means of a Chi-
square test or, if more appropriate, a Fisher’s Exact test at each time point. 
7.2.1.2 Proportion of patients with a reduction in HbA1c >0.5% from baseline and daily insulin 
requirement <0.50 IU/Kg/day  
Number and proportion along the 95% confidence interval (Clopper-Pearson’s formula) of patients 
with a reduction in HbA1c > 0.5% from baseline and daily insulin requirement <0.5 (IU/kg/day) will 
be calculated for each time point. The comparison between the two study treatment arms will be 
performed by means of a Chi-square test or, if more appropriate, a Fisher’s Exact test at each time 
point. 
7.2.1.3 2-hour AUC of C-peptide response to the MMTT 
2-hour AUC of C-peptide post MMTT and its change from baseline will be summarized at each 
available timepoint and comparison between treatments will be performed by means of two-
sample t-test or, if assumptions of normality are not confirmed (by Kolmogorov-Smirnov test), two-
sample Mann–Whitney U test. 
7.2.1.4 Time in range (TIR) by CGM 
TIR by CGM and its change from baseline will be summarized at each available timepoint and 
comparison between treatments will be performed by means of two-sample t-test or, if 
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assumptions of normality are not confirmed (by Kolmogorov-Smirnov test), two-sample Mann–
Whitney U test. 
7.2.1.5 HbA1c levels 
HbA1c and its change from baseline will be summarized at each available timepoint and comparison 
between treatments will be performed by means of two-sample t-test or, if assumptions of 
normality are not confirmed (by Kolmogorov-Smirnov test), two-sample Mann–Whitney U test. 
 
7.2.1.6 Proportion of patients with HbA1c <7% who did not experience severe hypoglycemic events 
during treatment  
Number and proportion along the 95% confidence interval (Clopper-Pearson’s formula) of patients 
with HbA1c < 7% and absence of episodes of severe hypoglycemia during treatment will be 
calculated for each time point. The comparison between the two study treatment arms will be 
performed by means of a Chi-square test or, if more appropriate, a Fisher’s Exact test at each time 
point. 
The proportion of patients with HbA1c <7% is calculated at timepoint level: number of events 
occurring at a specific timepoint. 
Severe hypoglycemic events are considered cumulatively and only event up to month 12 will be 
considered (condition will be evaluated by considering treatment period only).  
In particular: 
• if a subject experienced the event at a specific timepoint, it will be considered as a subject 
with the event for all subsequent timepoints.  
7.2.1.7 Events happened between month 12 and month 18 will not be considered in this 
endpoint, since they are out of treatment period. Therefore, condition of event/not event 
at month 12 will be the same as month 18.Additional Glucose Variability Indices derived 
from CGM 
Glucose AUC outside the target range of 70 – 180 mg/dL, 2-hour postprandial glucose (PPG), Mean 
Amplitude Glycemic Excursions (MAGE) considering 1 SD as threshold, continuous overall net 
glycemic action (CONGA)-n (1, 2 and 4 hours), Mean Of the Daily Differences (MODD), mean daily 
blood glucose, and SD will be compared between treatments by means of two-sample t-test or, if 
assumptions of normality is not confirmed (by Kolmogorov-Smirnov test), two-sample Mann–
Whitney U test. 
 
 
7.2.1.8 Number of self-reported episodes of severe hypoglycemia 
The effect of treatment on the cumulative number of severe hypoglycemic events will be evaluated 
by means of a Cox proportional hazards model. The Andersen-Gill intensity model with model-based 
variance will be utilized. The corresponding SAS code is provided in Appendix 12.2. 
 
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Summary statistics of blood glucose level (mg/dL) will be provided by treatment arm at each time 
point for patients reporting severe hypoglycemia. Derivation of patients reporting severe 
hypoglicemia will be the same as the one described in 7.2.1.6 section, except that in this case events 
happened between month 12 and month 18 will be considered as well.  
7.2.1.9 Average (previous 3 days) daily insulin requirement (IU/kg/day) 
Average daily insulin requirement (CRF - INSULIN REQUIREMENT form) and its change from baseline 
will be summarized at each available timepoint and comparison between treatments will be 
performed by means of two-sample t-test or, if assumptions of normality are not confirmed (by 
Kolmogorov-Smirnov test), two-sample Mann–Whitney U test. 
7.2.1.10 Estimated Glucose Disposal Rate 
eGDR comparison between treatments will be performed by means of two-sample t-test or, if 
assumptions of normality are not confirmed (by Kolmogorov-Smirnov test), two-sample Mann–
Whitney U test. 
Summary statistics by treatment will be provided along with summary of the change from baseline 
at each time point for the eGDR-related parameters: 
• 
Weight (Kg) and Height (cm),  
• 
BMI (Kg/m2) – derived from CRF,  
• 
Waist circumference (cm) and Waist-to-Hip Ratio,  
• 
Hypertension status (Yes, No). 
7.3 
MMTT over the study 
Summary statistics of C-peptide (nmol/L) during MMTT will be provided by treatment at each visit 
and time-interval (Basal1, Basal2, Average Basal, @15min, @30min, @60min, @90min, and 
@120min after the meal). In addition, for each visit, the following parameters will be summarized: 
• 
C-peptide 0-120 min AUC (nmol/L) 
• 
C-peptide 15-120 min AUC (nmol/L) 
• 
C-peptide Cmax (nmol/L) 
• 
C-peptide Tmax (min) 
 
Individual plots of the Cmax and Tmax means (±SEs) will be presented. Based on the observed 
trends, additional ad-hoc analyses might be performed. 
 
Derivation rules are reported in Table 3. 
7.4 
Analysis of 
 
 will be analyzed at each available time points by means of 
descriptive statistics. Specifically, analyses will be provided for
 
. Comparison between treatments 
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will be performed by means of 
 or, if assumptions of normality is not confirmed 
 
 
Where applicable the investigator’s interpretation (Normal, Abnormal NCS, Abnormal NC, No 
Result) will be summarized and compared by means of a 
 or, if more appropriate, a 
 at each time point 
 will not be considered for the comparison). 
 
The following results will be displayed graphically: 
 
 
 
 
 
 
 
 
 
 
 
8.  Evaluation of Safety 
8.1 
Adverse events 
Any AE which starts at or after the first administration of study treatment will be considered a 
Treatment Emergent Adverse Event (TEAE). Pre-treatment AEs and TEAEs will be presented 
separately. Pre-treatment AEs will be presented in the listings only. In case of missing or incomplete 
dates not allowing a direct allocation to any of the two categories of AEs, a worst-case allocation 
will be done according to the available parts of the onset and the end dates (see Table 5). The AE 
will be allocated to the first category allowed by the available data, according to the following order: 
• 
TEAE; 
• 
Pre-treatment AE. 
 
In case of TEAE, the event can be classified as: 
• 
On Treatment Period, or 
• 
On Follow-up period 
according to the available parts of the onset and the end dates (see Table 5). 
 
All AEs will be assigned to a Preferred Term (PT) and will be classified by primary System Organ Class 
(SOC) according to the MedDRA thesaurus. In addition, each AE will be graded according to severity 
definitions as “Mild”, “Moderate” or “Severe”.  
 
TEAEs summaries will be presented, displaying frequencies and percentages of patients reporting 
AEs. In the summaries, primary SOC will be presented alphabetically and the PT will be sorted within 
SOC in descending overall frequencies .  
Along with AEs, number of events will be reported. On each of these summaries, patients will be 
counted only once per SOC and, within each SOC, patients will be counted only once per PT. 
 
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For summaries, the drug-event relationship will be assessed as “None”, “Unlikely”, “Possible” 
“Probable” or “Highly probable”. Any TEAE reported in the study having a possible, probable or 
highly probable relationship to IMP will be defined as “Adverse Drug Reaction” (ADR). 
 
The following tables and listings will be presented by treatment group: 
• 
An overview of TEAEs including the number of patients who exhibited at least one TEAE, 
at least one severe TEAE, at least one serious TEAE, at least one non-serious TEAE, at 
least one ADR, at least one serious ADR, number of TEAEs, number of non-serious TEAEs, 
number of TESAEs, number of ADRs, number of serious ADRs, number of deaths, number 
of patients who discontinued IMP due to a TEAE; 
• 
Summary of TEAEs by primary System Organ Class and Preferred Term and by study 
period (on treatment/follow-up and overall); 
• 
Summary of TEAEs by primary System Organ Class, Preferred Term and Severity; 
• 
Summary of Serious TEAEs by Primary System Organ Class and Preferred Term and by 
study period (on treatment/follow-up and overall); 
• 
Summary of ADRs by Primary System Organ Class and Preferred Term and by study 
period (on treatment/follow-up and overall); 
• 
Summary of ADRs by Primary System Organ Class and Preferred Term and Severity; 
• 
Summary of TEAEs leading to IMP Discontinuation by Primary System Organ Class and 
Preferred Term and by study period (on treatment/follow-up and overall); 
• 
Summary of TEAEs leading to Death by Primary System Organ Class and Preferred Term 
and by study period (on treatment/follow-up and overall); 
• 
Listing of all AEs by Patient; 
• 
Listing of SAEs by Patient; 
• 
Listing of ADR by Patient; 
• 
Listing of Deaths. 
 
In addition, time-to-event methods will be used to summarize the time to onset of severe 
hypoglycemic events from first dose of treatment. Kaplan-Meier estimates and plots will be 
provided with:  
• 
the 95% confidence interval bounds calculated per the method proposed by Greenwood;  
• 
the respective number of patients at risk and Kaplan-Meier estimates at different time 
points; 
• 
the median and its 95% confidence interval; 
• 
the log-rank test p-value.  
Subjects who have discontinued/completed the study without an event will be censored at the date 
of discontinuation/completion. In case of patients still ongoing and free from event at the time of 
DB lock, they will be censored at the DB lock date. 
8.2 
Clinical laboratory evaluation 
Analysis of clinical laboratories data will be performed by treatment for Hematology and 
Biochemistry tests. In case of different units of measure considered for the same laboratory 
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parameter, all values will be converted into Standard International (SI) units (if applicable) or to the 
same unit. 
 
The following summaries will be provided: 
• 
A summary table showing for all laboratory tests the values and changes from baseline 
to each subsequent visit; 
• 
A summary table showing for all laboratory tests the frequency of patients reporting an 
abnormal (clinically or not clinically significant) laboratory value at baseline and at 
subsequent visits. 
• 
Shift tables presenting the number and the percentage of patients in each bivariate 
category (baseline versus each post-baseline visit) with regards to investigator’s 
interpretation. 
8.3 
Vital signs 
Summary statistics by treatment will be provided along with summary of the change from baseline 
at each time point for the following vital signs: 
• 
Systolic Blood Pressure (mmHg), 
• 
Diastolic Blood Pressure (mmHg), and  
• 
Heart Rate (bpm); 
8.4 
ECGs 
Summary statistics by treatment of QTcF Interval (msec) and ECG interpretation (Normal, Abnormal 
NCS, Abnormal CS, No Result) will be provided along with summary of the change/shift from 
baseline at each time point.  
 
In case of repetition of ECG evaluation (according to protocol), the repeated QTcF value will be 
considered as the only evaluation value for that visit. 
8.5 
Pregnancy test over the study 
A summary table showing test results (Negative/Positive) over the study will be produced by 
treatment group, where applicable. 
9.  Derivations and date conventions 
9.1 
Variable derivation 
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Table 3: Variable derivation rules 
Parameter 
Calculation 
HbA1c <7% and daily 
insulin requirement <0.50 
IU/Kg/day at Time point Tx 
at Time point Tx: 
• 
if HbA1c ≥7% OR daily insulin requirement ≥0.50 IU/Kg/day, then 
endpoint = ‘No’ (even in case of one missing component) 
• 
if HbA1c <7% AND daily insulin requirement <0.50 IU/Kg/day, then 
endpoint = ‘Yes’ (both component should be non-missing)  
AUC 
All AUC calculations (0-120min and 15-120min) will be based on actual 
rather than scheduled timings and will be calculated using the trapezoidal 
rule. In case of partial information collected during an assessment: 
• 
if actual time is not recorded, the scheduled time will be used 
instead; 
• 
missing values will be imputed via linear interpolation; 
• 
when C-peptide values are below the limit of detection, the limit 
value (0.2 ng/mL, any exception will be clarified) will be assumed 
in the calculation of AUC. 
Basal value to be used in the AUC calculation is the Average Basal C-peptide 
(next section). The last non-missing time of Basal #1 and Basal #2 values 
will be used to calculate the time differences in the AUC. 
C-peptide 0-120 min AUC (nmol/L) values will be calculated based on all 
Basal-120min C-peptide values. 
C-peptide 15-120 min AUC above fasting (nmol/L) will be calculated based 
on the changes from Basal in 15-120min C-peptide values.  
Unscheduled assessments will be excluded from the analysis. 
C-peptide parameters 
 
Average Basal C-peptide (nmol/L) =  
Mean (Basal #1 C-peptide; Basal #2 C-peptide);  
C-peptide Cmax (nmol/L) =  
Maximum C-peptide value between post basal values; 
C-peptide Tmax (min) =  
Time at which the C-peptide Cmax is reached 
In case both Basal #1 and Basal #2 C-peptide are missing, the Average 
Basal C-peptide will be set as missing. 
 
Time from T1D diagnosis to 
inform consent 
 
Time from T1D diagnosis to IC (days) = Date of IC signature - Date of T1D 
diagnosis +1. 
Missing/partial dates will not be imputed. Anyway, since these dates are 
crucial for enrolment, their complete presence in the final database is 
expected. 
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Parameter 
Calculation 
Time from first insulin 
administration to inform 
consent 
 
Time from first insulin admin. to IC (days) = Date of IC signature - Date of 
first insulin admin +1. 
Missing/partial dates will not be imputed. Anyway, since these dates are 
crucial for enrolment, their complete presence in the final database is 
expected. 
Date of first/last IMP 
intake 
The date of first IMP intake will be taken from the Diary form (Treatment 
Cycle No.1, Day 1). In case of missing value, the date of dispensation of 1st 
kit will be used instead (CRF - IMP DISPENSATION). 
In case of treatment discontinuation, the date of last IMP intake will be 
taken from the last available Diary form, otherwise the CRF date of visit 
reporting a Criteria for discontinuation of the IMP will be used. 
Extent of exposure 
 
Extent of exposure (days) = Date of last IMP intake - Date of first IMP intake 
+1. 
The rule for conversion from days to weeks is specified at the end of this 
table. 
CGM parameters 
See section Errore. L'origine riferimento non è stata trovata.  
Identification of severe 
hypoglycemic event 
At Baseline: CRF - SELF REPORTED SEVERE HYPOGLYCEMIA form: Did the 
patient experience any severe hypoglycemic episodes? 
At the following timepoint: 
A subject experiences a severe hypoglycemic event if there is at least one 
event in SEVHYPOD form (e-diary) or SEVHYPODP form (paper diary).  
The following rule will be applied in order to link the severe hypoglycemic 
event to the corresponding timepoint: 
-If the date of severe hypoglycemic episodes is not missing, the event will 
be considered in the subsequent closes timepoint by considering the study 
visit and the date of severe hypoglycemic episodes  
-If the date of severe hypoglycemic episodes is missing, it will be derived 
from diary data information 
Time to severe 
hypoglycemic event from 
first dose of treatment 
Time to severe hypoglycemic event = Date of onset of severe hypoglycemic 
episode - Date of first IMP intake +1. 
Date of onset of severe hypoglycemic episode will be derived according to 
the rule reported above. 
Time from randomization 
to study discontinuation 
Time from randomization to study discontinuation (days) = Date of study 
discontinuation - Date of randomization +1. 
reduction in HbA1c from 
baseline at Time point TX 
at Time point Tx: 
HbA1c reduction = HbA1c at TX - HbA1c at baseline 
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Parameter 
Calculation 
reduction in HbA1c > 0.5% 
from baseline and daily 
insulin requirement <0.50 
IU/Kg/day at Time point Tx 
at Time point Tx: 
• 
if HbA1c reduction ≤ 0.5% OR daily insulin requirement ≥ 0.50 
IU/Kg/day, then endpoint = ‘No’ (even in case of one missing 
component)  
• 
if HbA1c reduction > 0.5% AND daily insulin requirement <0.50 
IU/Kg/day, then endpoint = ‘Yes’ (both component should be non-
missing)  
Conversion of Time 
Intervals  
 
If a time interval was calculated in minutes, hours or days and needs to be 
converted into months or years the following conversion factors will be 
used:  
• 
1 week = 7 days 
• 
1 month = 30.4375 days  
• 
1 year = 365.25 days  
 
9.2 
CGM value derivation 
The Dexcom G6 Continuous Glucose Monitoring System (Dexcom G6 System) will be used to 
perform CGM during the study. Dexcom G6 System uses proprietary algorithms to create fully 
customable reports and summary measures for patients and clinicians. These reports will not be 
used during the trail given the fully customizable features. Instead, in order to standardize the 
summary statistics from each patient, the cgmanalysis package written entirely in the statistical 
programming language R (R Foundation for Statistical Computing, Vienna, Austria) will be used given 
its compatibility with raw data structure coming from Dexcom G6 System. 
Gaps in glucose data shorter or equal than 30 minutes will be imputed using linear interpolation. 
The cgmanalysis package cleandata function will be used. 
After filling eventual gaps in the glucose data, the following requirements should be met for a visit 
in order to be considered eligible for analysis: 
• a total of at least 7 days of valid CGM recordings will be required for a visit to be used for 
analysis (by study protocol, at least 10 days before each scheduled visit the CGM sensor 
should be positioned): 
o cgmanalysis: num_days_good_data >= 7; 
• the number of sensor readings as a percentage of the number of potential readings (given 
time worn) has to be greater than 80%: 
o cgmanalysis: percent_cgm_wear > 80%.  
The cgmanalysis package cgmvariables function will be used for the CGM parameters (sections 
7.2.1.4 and 7.2.1.7). The package has been modified in order to perform additional simultaneous 
analyses (see Appendix 12.1 for the entire R code). Table 5 reports the correspondence between 
required endpoint and cgmvariables outcomes.  
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For the calculation of 2h PPG, the raw data from Dexcom G6 System have to be filtered in order to 
keep only observations ≤ 120 minutes from meals, where the exact time of meals (breakfast, lunch 
and dinner) are taken from eDiary. If time of meal is missing, the adjacent CGM observations will 
not be considered. 
Table 4: Variable in cgmanalysis 
Endpoint 
Variable in cgmanalysis 
Unit 
TIR 
percent_time_70_180 
% 
Glucose AUC outside the target range of 
70/180 mg/dL 
average_auc_70 + 
average_auc_180 
mg/dL/min 
MAGE (1 SD) 
r_mage 
mg/dL 
CONGA-1, CONGA-2 and CONGA-4 
conga_1, conga_2, conga_4 
mg/dL 
MODD 
modd 
mg/dL 
Mean daily blood glucose 
average_sensor 
mg/dL 
SD 
standard_deviation 
mg/dL 
2h-PPG 
average_auc_per_day*  
mg/dL 
*raw data must be filtered with observations ≤ 120 minutes from meals 
(eDiary) 
 
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9.3 
Partial date conventions 
Table 5: Algorithm for Treatment Emergence of Adverse Events 
AE START DATE 
AE STOP DATE 
RULE for TEAE definition 
RULE for “Treatment”/”Follow-up” study 
period definition for TEAE summaries 
Known 
Known, Partial or 
Missing 
If AE start date < IMP start date, then not 
TEAE 
If AE start date >= IMP start date, then TEAE 
In case of Treatment Discontinuation:  
If start date > Date of last IMP intake, then 
Follow-up study period for TEAE occurrence. 
Otherwise, Treatment study period for TEAE 
occurrence. 
 
In case of NO Treatment Discontinuation:  
If start date ≥ Date of “Month 12 visit”, then 
Follow-up study period for TEAE occurrence. 
Otherwise, Treatment study period for TEAE 
occurrence. 
 
 
 
 
Partial, but known 
components show that it 
cannot be on or after IMP 
start date 
Known, Partial or 
Missing 
Not TEAE 
Not Applicable 
 
 
 
 
Partial, could be on or after 
IMP start date 
Known 
If AE stop date < IMP start date, then not TEAE 
If AE stop date >= IMP start date, then TEAE 
If TEAE, then Treatment study period for TEAE 
occurrence. 
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AE START DATE 
AE STOP DATE 
RULE for TEAE definition 
RULE for “Treatment”/”Follow-up” study 
period definition for TEAE summaries 
 
Partial 
Impute stop date as latest possible date (i.e. 
last day of month if day unknown or 31st 
December if day and month are unknown), 
then: 
If AE stop date < IMP start date, then not TEAE 
If AE stop date >= IMP start date, then TEAE 
 
 
Missing 
Assumed TEAE 
 
 
 
 
Missing 
Known 
If AE stop date < IMP start date, then not TEAE 
If AE stop date >= IMP start date, then TEAE 
If TEAE, then Treatment study period for TEAE 
occurrence. 
 
 
Partial 
Impute AE stop date as latest possible date 
(i.e. last day of month if day unknown or 31st 
December if day and month are unknown), 
then: 
If AE stop date < IMP start date, then not TEAE 
If AE stop date >= IMP start date, then TEAE 
 
Missing 
Assumed TEAE 
NOTE: * Assignment to “Treatment” or “Follow-up”study period is applicable only for TEAEs.  
 
 
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Table 6: Algorithm for Prior/Concomitant medications 
• 
MEDICATION 
START 
DATE 
• 
MEDICATION 
STOP DATE 
• 
RULE for prior or concomitant categorization 
Known 
Known 
If medication stop date < date of informed consent, assign as prior  
If medication stop date >= date of informed consent, assign as concomitant  
 
Partial 
Impute medication stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If medication stop date < date of informed consent, assign as prior 
If medication stop date >= date of informed consent, assign as concomitant 
 
Missing 
Assign as concomitant 
 
 
 
 
Partial or Missing 
Known 
If medication stop date < date of informed consent, assign as prior 
If medication stop date >= date of informed consent, assign as concomitant 
 
Partial 
Impute medication stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If medication stop date < date of informed consent, assign as prior 
If medication stop date >= date of informed consent, assign as concomitant 
 
Missing 
Assign as concomitant 
 
 
 
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10.  
Tables, Figures and Listings 
10.1 Output conventions 
• Each Table, Listing and Figure (TFL) should be numbered, if applicable, following the ICH E3 
guideline.  
• All tables/figures/listings will be presented in landscape format.  
• The standard font size is 9 points “Courier New” for all tables. Listings will be presented with an 8 
or 7 points Arial.  
• Titles will be center-aligned; footnotes will be left-aligned.  
• Each table/figure/listing will have 2 titles: 
• The 1st title will be the table/figure/listing number with the description of the 
table/figure/listing;  
• The 2nd title will be a description of the study set presented in the table/figure/listing. 
• Some tables will have a third title (before 2nd title) with a description of the statistical method 
used in those tables. 
• Any footnote added to explain the table/listing/figure contents will be presented in the following 
format: 
• Note 1: … 
• Note 2: … 
• Note 3: … 
• In the tables, listing and figures the treatment under comparison will be labelled as “Ladarixin” 
and “Placebo”  
• Missing descriptive statistics or p-values which cannot be estimated are reported as “-”. 
• The last two footnotes of each table/figure will be footers indicating: 
• the reference listing of the data; 
• the program name, the date and time of generation and the SAS® version used. 
• Unless otherwise stated, listings will be presented by randomised treatment, and sorted by the 
treatment group, patient number, and visit.  
• In all the listings on safety variables, a column with a flag (§) for treatment misallocation will 
identify the treatment misallocations. 
• The derived variables will be identified in the listings with a flag (*). 
• In general, dates will be presented on listings in the format ddmmmyyyy (date9.) and time in the 
format hh:mm (time5.). In case of partial dates or times, missing information will be replaced by 
dashes. 
• Numeric variables will be listed generally with the same number of decimal places as in the actual 
data; units will be presented enclosed in square brackets ([ ])., when appropriate. 
 
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11.  
Reference 
1. Study protocol, A phase 2, multicenter, randomized, double-blind, placebo-controlled study to assess the 
efficacy and safety of 400 mg twice a day oral ladarixin in patients with new-onset type 1 diabetes and preserved 
β-cell function at baseline, Protocol Version - Date: Version No. 1 final – 
. 
2. Study protocol, A phase 2, multicenter, randomized, double-blind, placebo-controlled study to assess the 
efficacy and safety of 400 mg twice a day oral ladarixin in patients with new-onset type 1 diabetes and preserved 
β-cell function at baseline, Protocol Version - Date: Version No. 2 final – 
. 
3. Communication of enrolment interruption dated 28 March 2022. 
4. (Vigers T, Chan CL, Snell-Bergeon J, Bjornstad P, Zeitler PS, Forlenza G, et al., 2019)(2019) Cgmanalysis: An R 
package for descriptive analysis of continuous glucose monitor data. PLoS ONE 14 (10): e0216851. 
https://doi.org/10.1371/journal.pone.0216851 
5. Kalbfleisch, J. D., and Prentice, R. L. (1980). The Statistical Analysis of Failure Time Data. New York: John Wiley 
& Sons. 
 
 
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(Kalbfleisch, J. D. and Prentice, R.L., 1980) 
12.  
Appendices 
12.1 R code for CGM 
R code 
Notes 
Cgmvariables_mod <- function(inputdirectory, 
                         outputdirectory = tempdir(), 
                         outputname = "Dexcom", 
                         customintervals = list(c(,)), 
                         aboveexcursionlength = 35, 
                         belowexcursionlength = 10, 
                         magedef = "1sd", 
                         congan = 1, 
                         daystart = 0, 
                         dayend = 24, 
                         id_filename = F, 
                         format = "rows", 
                         printname = F) { 
 
  # Read in data, create results dataframe. The dataframe has one column for each  
  # file in the input directory, and is designed to be uploaded to REDCap.  
  files <- base::list.files(path = inputdirectory,full.names = TRUE) 
  cgmupload <-  
    base::as.data.frame(base::matrix(nrow = 0,ncol = base::length(files))) 
  base::colnames(cgmupload) <- base::rep("Record",base::length(files)) 
  # Define the order in which lubridate parses dates.   
  dateparseorder <- c("mdy HM","mdy HMS","mdY HM","mdY HMS","dmy HM","dmy 
HMS", 
                      "dmY HM","dmY HMS","Ymd HM","Ymd HMS","ymd HM","ymd HMS", 
                      "Ydm HM","Ydm HMS","ydm HM","ydm HMS") 
  allhours <- 0:23 
  # Iterate through the input directory and calculate CGM variables for each file. 
  # The cgmvariables() function only works on CSV files that have been cleaned by  
  # cleandata(), or that have been manually edited and fit the format of 
  # cleandata() output.  
  for (f in 1:base::length(files)) {     
    # Basic variables 
    table <- utils::read.csv(files[f],stringsAsFactors = FALSE,na.strings = c("NA","")) 
    # Remove duplicates 
    if(id_filename == F) { 
      table$subjectid <- table$subjectid[1] 
    } else { 
      table$subjectid[1] <- sub("*.csv","",basename(files[f])) 
    } 
    table <- unique(table) 
    # Print name 
Minor manipulation of 
the imported files may 
be done by data 
management and 
programming in order to 
make the files readable 
by the algorithm. 
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R code 
Notes 
    if(printname == T) { 
      print(basename(files[f])) 
    } 
    # Column names to lower case 
    colnames(table) = tolower(colnames(table)) 
    cgmupload["subject_id",f] <- table$subjectid[1] 
    # Format columns.     
    table$timestamp <-  
      base::as.POSIXct(lubridate::parse_date_time(table$timestamp, 
                                                  dateparseorder,tz = "UTC")) 
    table$sensorglucose <- suppressWarnings(base::as.numeric(table$sensorglucose)) 
    interval <- pracma::Mode(base::diff(base::as.numeric(table$timestamp))) 
    interval <- base::abs(interval) 
    cgmupload["date_cgm_placement", f] <-  
      base::as.character(min(table$timestamp,na.rm = T)) 
     
    totaltime <-  
      base::as.numeric(base::difftime(base::max(table$timestamp, na.rm = T), 
                                      base::min(table$timestamp,na.rm = T), 
                                      units = "secs")) 
    cgmupload["percent_cgm_wear",f] <-  
      
base::floor(((base::length(which(!is.na(table$sensorglucose)))/(totaltime/interval))*100)) 
    cgmupload["num_days_good_data",f] <-  
      base::round(base::length(which(!is.na(table$sensorglucose)))/(86400/interval)) 
     
    table <- table[!is.na(table$timestamp) & !is.na(table$sensorglucose),] 
     
    cgmupload["total_sensor_readings",f] <-  
      base::as.numeric(base::length(base::which(!is.na(table$sensorglucose)))) 
    cgmupload["average_sensor",f] <-  
      base::mean(table$sensorglucose[base::which(!is.na(table$sensorglucose))],na.rm = 
T) 
    cgmupload["estimated_a1c",f] <-  
      base::round((46.7 + (base::mean(table$sensorglucose[ 
        base::which(!is.na(table$sensorglucose))]))) / 28.7,digits = 1) 
    cgmupload["gmi",f] <- base::round(3.31 + (0.02392 * 
base::mean(table$sensorglucose[ 
      base::which(!is.na(table$sensorglucose))])), digits = 1) 
    cgmupload["q1_sensor",f] <-  
      base::as.numeric(base::summary(table$sensorglucose[ 
        base::which(!is.na(table$sensorglucose))])[2]) 
    cgmupload["median_sensor",f] <-  
      base::as.numeric(base::summary(table$sensorglucose[ 
        base::which(!is.na(table$sensorglucose))])[3]) 
    cgmupload["q3_sensor",f] <-  
      base::as.numeric(base::summary(table$sensorglucose[ 
        base::which(!is.na(table$sensorglucose))])[5]) 
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R code 
Notes 
    cgmupload["standard_deviation",f] <-  
      stats::sd(table$sensorglucose[base::which(!is.na(table$sensorglucose))]) 
    cgmupload["cv",f] <-  
      (stats::sd(table$sensorglucose[base::which(!is.na(table$sensorglucose))]))/ 
      base::mean(table$sensorglucose[base::which(!is.na(table$sensorglucose))]) 
    cgmupload["min_sensor",f] <-  
      base::min(table$sensorglucose[base::which(!is.na(table$sensorglucose))]) 
    cgmupload["max_sensor",f] <-  
      base::max(table$sensorglucose[base::which(!is.na(table$sensorglucose))]) 
     
    # Excursions over 120 calculations. 
    BGover120 <-  
      base::as.numeric(table$sensorglucose[base::which(!is.na( 
        table$sensorglucose))],length = 1) 
    BGover120[BGover120 < 120] <- 0 
    BGover120[BGover120 >= 120] <- 1 
    BG120.rle <- base::rle(BGover120) 
    excursions120 <-  
      base::as.numeric(BG120.rle$lengths[base::which(BG120.rle$values == 1)]) 
     
    cgmupload["excursions_over_120",f] <-  
      base::length(base::which(excursions120 >  
                                 ((aboveexcursionlength * 60)/interval))) 
    cgmupload["min_spent_over_120",f] <- base::sum(BGover120) * (interval/60) 
    cgmupload["percent_time_over_120",f] <-  
      ((base::sum(BGover120) * (interval/60))/ 
         (base::length(table$sensorglucose) * (interval/60))) * 100 
     
    # Over 140. 
    BGover140 <-  
      base::as.numeric(table$sensorglucose[base::which(!is.na( 
        table$sensorglucose))],length = 1) 
    BGover140[BGover140 < 140] <- 0 
    BGover140[BGover140 >= 140] <- 1 
    BG140.rle <- base::rle(BGover140) 
    excursions140 <-  
      base::as.numeric(BG140.rle$lengths[base::which(BG140.rle$values == 1)]) 
     
    cgmupload["excursions_over_140",f] <-  
      base::length(base::which(excursions140 >  
                                 ((aboveexcursionlength * 60)/interval))) 
    cgmupload["min_spent_over_140",f] <- base::sum(BGover140) * (interval/60) 
    cgmupload["percent_time_over_140",f] <-  
      ((base::sum(BGover140) * (interval/60))/ 
         (base::length(table$sensorglucose) * (interval/60))) * 100 
     
    # Over 180. 
    BGover180 <-  
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R code 
Notes 
      base::as.numeric(table$sensorglucose[base::which(!is.na( 
        table$sensorglucose))],length = 1) 
    BGover180[BGover180 < 180] <- 0 
    BGover180[BGover180 >= 180] <- 1 
    BG180.rle <- base::rle(BGover180) 
    excursions180 <-  
      base::as.numeric(BG180.rle$lengths[base::which(BG180.rle$values == 1)]) 
     
    cgmupload["excursions_over_180",f] <-  
      base::length(base::which(excursions180 >  
                                 ((aboveexcursionlength * 60)/interval))) 
    cgmupload["min_spent_over_180",f] <- base::sum(BGover180) * (interval/60) 
    cgmupload["percent_time_over_180",f] <-  
      ((base::sum(BGover180) * (interval/60))/ 
         (base::length(table$sensorglucose) * (interval/60))) * 100 
     
    # Over 200. 
    BGover200 <-  
      base::as.numeric(table$sensorglucose[base::which(!is.na( 
        table$sensorglucose))],length = 1) 
    BGover200[BGover200 < 200] <- 0 
    BGover200[BGover200 >= 200] <- 1 
    BG200.rle <- base::rle(BGover200) 
    excursions200 <-  
      base::as.numeric(BG200.rle$lengths[base::which(BG200.rle$values == 1)]) 
     
    cgmupload["excursions_over_200",f] <-  
      base::length(base::which(excursions200 >  
                                 ((aboveexcursionlength * 60)/interval))) 
    cgmupload["min_spent_over_200",f] <- base::sum(BGover200) * (interval/60) 
    cgmupload["percent_time_over_200",f] <-  
      ((base::sum(BGover200) * (interval/60))/ 
         (base::length(table$sensorglucose) * (interval/60))) * 100 
     
    cgmupload["avg_excur_over_140_per_day",f] <-  
      as.numeric(cgmupload["excursions_over_140",f])/ 
      as.numeric(cgmupload["num_days_good_data",f]) 
    cgmupload["avg_excur_over_200_per_day",f] <-  
      as.numeric(cgmupload["excursions_over_200",f])/ 
      as.numeric(cgmupload["num_days_good_data",f]) 
     
    # Over 250. 
    BGover250 <-  
      base::as.numeric(table$sensorglucose[base::which(!is.na( 
        table$sensorglucose))],length = 1) 
    BGover250[BGover250 < 250] <- 0 
    BGover250[BGover250 >= 250] <- 1 
    BG250.rle <- base::rle(BGover250) 
PPD


 
 
Protocol Number: 
LDX0419 
Version: 3.0 
Document Date: 07 May 2024 
R code 
Notes 
    excursions250 <-  
      base::as.numeric(BG250.rle$lengths[base::which(BG250.rle$values == 1)]) 
     
    cgmupload["excursions_over_250",f] <-  
      base::length(base::which(excursions250 >  
                                 ((aboveexcursionlength * 60)/interval))) 
    cgmupload["min_spent_over_250",f] <- base::sum(BGover250) * (interval/60) 
    cgmupload["percent_time_over_250",f] <-  
      ((base::sum(BGover250) * (interval/60))/ 
         (base::length(table$sensorglucose) * (interval/60))) * 100 
     
    # Under 54. 
    BGunder54 <-  
      base::as.numeric(table$sensorglucose[base::which(!is.na( 
        table$sensorglucose))],length = 1) 
    BGunder54[BGunder54 <= 54] <- 1 
    BGunder54[BGunder54 > 54] <- 0 
    BG54.rle <- base::rle(BGunder54) 
    excursions54 <-  
      base::as.numeric(BG54.rle$lengths[base::which(BG54.rle$values == 1)]) 
     
    cgmupload["excursions_under_54",f] <-  
      base::length(base::which(excursions54 >  
                                 ((belowexcursionlength * 60)/interval))) 
    cgmupload["min_spent_under_54",f] <- base::sum(BGunder54) * (interval/60) 
    cgmupload["percent_time_under_54",f] <-  
      ((base::sum(BGunder54) * (interval/60))/ 
         (base::length(table$sensorglucose) * (interval/60))) * 100 
     
    # Under 60. 
    BGunder60 <-  
      base::as.numeric(table$sensorglucose[base::which(!is.na( 
        table$sensorglucose))],length = 1) 
    BGunder60[BGunder60 <= 60] <- 1 
    BGunder60[BGunder60 > 60] <- 0 
    BG60.rle <- base::rle(BGunder60) 
    excursions60 <-  
      base::as.numeric(BG60.rle$lengths[base::which(BG60.rle$values == 1)]) 
     
    cgmupload["excursions_under_60",f] <-  
      base::length(base::which(excursions60 >  
                                 ((belowexcursionlength * 60)/interval))) 
    cgmupload["min_spent_under_60",f] <- base::sum(BGunder60) * (interval/60) 
    cgmupload["percent_time_under_60",f] <-  
      ((base::sum(BGunder60) * (interval/60))/ 
         (base::length(table$sensorglucose) * (interval/60))) * 100 
     
    # Under 70. 
PPD


 
 
Protocol Number: 
LDX0419 
Version: 3.0 
Document Date: 07 May 2024 
R code 
Notes 
    BGunder70 <-  
      base::as.numeric(table$sensorglucose[base::which(!is.na(table$sensorglucose))], 
                       length = 1) 
    BGunder70[BGunder70 <= 70] <- 1 
    BGunder70[BGunder70 > 70] <- 0 
    BG70.rle <- base::rle(BGunder70) 
    excursions70 <-  
      base::as.numeric(BG70.rle$lengths[base::which(BG70.rle$values == 1)]) 
     
    cgmupload["excursions_under_70",f] <-  
      base::length(base::which(excursions70 >  
                                 ((belowexcursionlength * 60)/interval))) 
    cgmupload["min_spent_under_70",f] <- base::sum(BGunder70) * (interval/60) 
    cgmupload["percent_time_under_70",f] <-  
      ((base::sum(BGunder70) * (interval/60))/ 
         (base::length(table$sensorglucose) * (interval/60))) * 100 
     
    # Time in range. 
    BGinrange <-  
      base::as.numeric(table$sensorglucose[base::which(!is.na(table$sensorglucose))], 
                       length = 1) 
    BGinrange <- ifelse(BGinrange %in% 70:180, 1,0) 
    cgmupload["min_spent_70_180",f] <- base::sum(BGinrange) * (interval/60) 
    cgmupload["percent_time_70_180",f] <-  
      ((base::sum(BGinrange) * (interval/60))/ 
         (base::length(table$sensorglucose) * (interval/60))) * 100 
     
    # Custom intervals 
    if(!is.null(customintervals[[1]])) { 
      lows <- unlist(lapply(customintervals, '[[', 1)) 
      highs <- unlist(lapply(customintervals, '[[', 2)) 
      for (r in 1:length(customintervals)) { 
        # Range 
        BGinrange <- 
base::as.numeric(table$sensorglucose[base::which(!is.na(table$sensorglucose))], 
                                      length = 1) 
        BGinrange <- ifelse(BGinrange %in% lows[r]:highs[r], 1,0) 
        minname <- paste0("min_spent_",lows[r],"_",highs[r]) 
        cgmupload[minname,f] <- base::sum(BGinrange) * (interval/60) 
        percname <- paste0("percent_time_",lows[r],"_",highs[r]) 
        cgmupload[percname,f] <-  
          ((base::sum(BGinrange) * (interval/60))/ 
             (base::length(table$sensorglucose) * (interval/60))) * 100 
        # Below 
        BGunder <-  
          base::as.numeric(table$sensorglucose[base::which(!is.na(table$sensorglucose))], 
                           length = 1) 
        BGunder[BGunder <= lows[r]] <- 1 
PPD


 
 
Protocol Number: 
LDX0419 
Version: 3.0 
Document Date: 07 May 2024 
R code 
Notes 
        BGunder[BGunder > lows[r]] <- 0 
        BGunder.rle <- base::rle(BGunder) 
        excursionsunder <-  
          base::as.numeric(BGunder.rle$lengths[base::which(BGunder.rle$values == 1)]) 
         
        cgmupload[paste0("excursions_under_",lows[r]),f] <-  
          base::length(base::which(excursionsunder >  
                                     ((belowexcursionlength * 60)/interval))) 
        cgmupload[paste0("min_spent_under_",lows[r]),f] <- base::sum(BGunder) * 
(interval/60) 
        cgmupload[paste0("percent_time_under_",lows[r]),f] <-  
          ((base::sum(BGunder) * (interval/60))/ 
             (base::length(table$sensorglucose) * (interval/60))) * 100 
        # Above 
        BGover <-  
          base::as.numeric(table$sensorglucose[base::which(!is.na( 
            table$sensorglucose))],length = 1) 
        BGover[BGover < highs[r]] <- 0 
        BGover[BGover >= highs[r]] <- 1 
        BGover.rle <- base::rle(BGover) 
        excursionsover <-  
          base::as.numeric(BGover.rle$lengths[base::which(BGover.rle$values == 1)]) 
         
        cgmupload[paste0("excursions_over_",highs[r]),f] <-  
          base::length(base::which(excursionsover >  
                                     ((aboveexcursionlength * 60)/interval))) 
        cgmupload[paste0("min_spent_over_",highs[r]),f] <- base::sum(BGover) * 
(interval/60) 
        cgmupload[paste0("percent_time_over_",highs[r]),f] <-  
          ((base::sum(BGover) * (interval/60))/ 
             (base::length(table$sensorglucose) * (interval/60))) * 100 
      } 
    } 
    # Find daytime AUC. 
    if ("wake" %in% colnames(table)) { 
      daytime_indexes <-  
        base::which(table$wake == 1) 
    } else { 
      daytime_indexes <-  
        base::which(base::as.numeric(base::format(table$timestamp,"%H")) %in%  
                      daystart:dayend) 
    } 
    daytime_sensor <- table$sensorglucose[daytime_indexes] 
    xaxis <-  
      base::seq(from = 0, length.out = base::length(daytime_sensor),by =  
                  (interval / 60)) 
     
    # Remove NAs if they are present. 
PPD


 
 
Protocol Number: 
LDX0419 
Version: 3.0 
Document Date: 07 May 2024 
R code 
Notes 
    xaxis[base::which(is.na(daytime_sensor))] <- NA 
    xaxis <- xaxis[!is.na(xaxis)] 
    daytime_sensor <- daytime_sensor[!is.na(daytime_sensor)] 
    aucs <- pracma::cumtrapz(xaxis,daytime_sensor) 
    cgmupload["daytime_auc",f] <- aucs[base::length(daytime_sensor)] 
     
    # TIR variables for daytime 
    BGinrange <- ifelse(daytime_sensor %in% 70:180, 1,0) 
    cgmupload["min_spent_70_180_day",f] <- base::sum(BGinrange,na.rm = T) * 
(interval/60) 
    cgmupload["percent_time_70_180_day",f] <-  
      (base::sum(BGinrange,na.rm = T) * (interval/60))/(base::length(daytime_sensor) * 
(interval/60)) * 100 
     
    BGinrange <- ifelse(daytime_sensor < 54, 1,0) 
    cgmupload["min_spent_under_54_day",f] <- base::sum(BGinrange,na.rm = T) * 
(interval/60) 
    cgmupload["percent_time_under_54_day",f] <-  
      (base::sum(BGinrange,na.rm = T) * (interval/60))/(base::length(daytime_sensor) * 
(interval/60)) * 100 
     
    BGinrange <- ifelse(daytime_sensor < 60, 1,0) 
    cgmupload["min_spent_under_60_day",f] <- base::sum(BGinrange,na.rm = T) * 
(interval/60) 
    cgmupload["percent_time_under_60_day",f] <-  
      (base::sum(BGinrange,na.rm = T) * (interval/60))/(base::length(daytime_sensor) * 
(interval/60)) * 100 
     
    BGinrange <- ifelse(daytime_sensor < 70, 1,0) 
    cgmupload["min_spent_under_70_day",f] <- base::sum(BGinrange,na.rm = T) * 
(interval/60) 
    cgmupload["percent_time_under_70_day",f] <-  
      (base::sum(BGinrange,na.rm = T) * (interval/60))/(base::length(daytime_sensor) * 
(interval/60)) * 100 
     
    BGinrange <- ifelse(daytime_sensor > 180, 1,0) 
    cgmupload["min_spent_over_180_day",f] <- base::sum(BGinrange,na.rm = T) * 
(interval/60) 
    cgmupload["percent_time_over_180_day",f] <-  
      (base::sum(BGinrange,na.rm = T) * (interval/60))/(base::length(daytime_sensor) * 
(interval/60)) * 100 
     
    BGinrange <- ifelse(daytime_sensor > 200, 1,0) 
    cgmupload["min_spent_over_200_day",f] <- base::sum(BGinrange,na.rm = T) * 
(interval/60) 
    cgmupload["percent_time_over_200_day",f] <-  
      (base::sum(BGinrange,na.rm = T) * (interval/60))/(base::length(daytime_sensor) * 
(interval/60)) * 100 
PPD


 
 
Protocol Number: 
LDX0419 
Version: 3.0 
Document Date: 07 May 2024 
R code 
Notes 
     
    BGinrange <- ifelse(daytime_sensor > 250, 1,0) 
    cgmupload["min_spent_over_250_day",f] <- base::sum(BGinrange,na.rm = T) * 
(interval/60) 
    cgmupload["percent_time_over_250_day",f] <-  
      (base::sum(BGinrange,na.rm = T) * (interval/60))/(base::length(daytime_sensor) * 
(interval/60)) * 100 
     
    # Other daytime sensor glucose variables. 
    cgmupload["daytime_avg_sensor_glucose",f] <-  
      base::mean(stats::na.omit(daytime_sensor)) 
    cgmupload["daytime_min_sensor_glucose",f] <- base::min(daytime_sensor) 
    cgmupload["daytime_max_sensor_glucose",f] <- base::max(daytime_sensor) 
    cgmupload["daytime_sd",f] <- stats::sd(daytime_sensor) 
     
    # Nighttime AUC. 
    if ("wake" %in% colnames(table)) { 
      nighttime_indexes <- base::which(table$wake == 0) 
    } else { 
      nighttime_indexes <-  
        base::which(base::as.numeric(base::format(table$timestamp,"%H")) %in%  
                      allhours[base::which(!(0:23 %in% daystart:dayend))]) 
    } 
    if (length(nighttime_indexes) > 0) { 
      nighttime_sensor <- table$sensorglucose[nighttime_indexes] 
      xaxis <-  
        base::seq(from = 0, length.out = base::length(nighttime_indexes),by =  
                    (interval / 60)) 
       
      # Day/night ratio. 
      cgmupload["day_night_sensor_ratio",f] <-  
        base::round(base::length(daytime_sensor)/base::length(nighttime_sensor),1) 
       
      # Remove NAs if they are present. 
      xaxis[base::which(is.na(nighttime_sensor))] <- NA 
      xaxis <- xaxis[!is.na(xaxis)] 
      nighttime_sensor <- nighttime_sensor[!is.na(nighttime_sensor)] 
      aucs <- pracma::cumtrapz(xaxis,nighttime_sensor) 
      cgmupload["nighttime_auc",f] <- aucs[base::length(nighttime_sensor)] 
       
      # TIR variables for nighttime 
      BGinrange <- ifelse(nighttime_sensor %in% 70:180, 1,0) 
      cgmupload["min_spent_70_180_night",f] <- base::sum(BGinrange,na.rm = T) * 
(interval/60) 
      cgmupload["percent_time_70_180_night",f] <-  
        (base::sum(BGinrange,na.rm = T) * (interval/60))/(base::length(nighttime_sensor) * 
(interval/60)) * 100 
       
PPD


 
 
Protocol Number: 
LDX0419 
Version: 3.0 
Document Date: 07 May 2024 
R code 
Notes 
      BGinrange <- ifelse(nighttime_sensor < 54, 1,0) 
      cgmupload["min_spent_under_54_night",f] <- base::sum(BGinrange,na.rm = T) * 
(interval/60) 
      cgmupload["percent_time_under_54_night",f] <-  
        (base::sum(BGinrange,na.rm = T) * (interval/60))/(base::length(nighttime_sensor) * 
(interval/60)) * 100 
       
      BGinrange <- ifelse(nighttime_sensor < 60, 1,0) 
      cgmupload["min_spent_under_60_night",f] <- base::sum(BGinrange,na.rm = T) * 
(interval/60) 
      cgmupload["percent_time_under_60_night",f] <-  
        (base::sum(BGinrange,na.rm = T) * (interval/60))/(base::length(nighttime_sensor) * 
(interval/60)) * 100 
       
      BGinrange <- ifelse(nighttime_sensor < 70, 1,0) 
      cgmupload["min_spent_under_70_night",f] <- base::sum(BGinrange,na.rm = T) * 
(interval/60) 
      cgmupload["percent_time_under_70_night",f] <-  
        (base::sum(BGinrange,na.rm = T) * (interval/60))/(base::length(nighttime_sensor) * 
(interval/60)) * 100 
       
      BGinrange <- ifelse(nighttime_sensor > 180, 1,0) 
      cgmupload["min_spent_over_180_night",f] <- base::sum(BGinrange,na.rm = T) * 
(interval/60) 
      cgmupload["percent_time_over_180_night",f] <-  
        (base::sum(BGinrange,na.rm = T) * (interval/60))/(base::length(nighttime_sensor) * 
(interval/60)) * 100 
       
      BGinrange <- ifelse(nighttime_sensor > 200, 1,0) 
      cgmupload["min_spent_over_200_night",f] <- base::sum(BGinrange,na.rm = T) * 
(interval/60) 
      cgmupload["percent_time_over_200_night",f] <-  
        (base::sum(BGinrange,na.rm = T) * (interval/60))/(base::length(nighttime_sensor) * 
(interval/60)) * 100 
       
      BGinrange <- ifelse(nighttime_sensor > 250, 1,0) 
      cgmupload["min_spent_over_250_night",f] <- base::sum(BGinrange,na.rm = T) * 
(interval/60) 
      cgmupload["percent_time_over_250_night",f] <-  
        (base::sum(BGinrange,na.rm = T) * (interval/60))/(base::length(nighttime_sensor) * 
(interval/60)) * 100     
       
      # Other nighttime sensor glucose variables. 
      cgmupload["nighttime_avg_sens_glucose",f] <-  
        base::mean(stats::na.omit(nighttime_sensor)) 
      cgmupload["nighttime_min_sens_glucose",f] <- base::min(nighttime_sensor) 
      cgmupload["nighttime_max_sens_glucose",f] <- base::max(nighttime_sensor) 
      cgmupload["nighttime_sd",f] <- stats::sd(nighttime_sensor) 
PPD


 
 
Protocol Number: 
LDX0419 
Version: 3.0 
Document Date: 07 May 2024 
R code 
Notes 
    } 
     
    # Total AUC. 
    sensorBG <- base::as.numeric(table$sensorglucose,length = 1) 
    xaxis <-  
      base::seq(from = 0, length.out = base::length(sensorBG),by =  
                  (interval / 60)) 
     
    # Remove NAs if they are present. 
    xaxis[base::which(is.na(sensorBG))] <- NA 
    xaxis <- xaxis[!is.na(xaxis)] 
    sensorBG <- sensorBG[!is.na(sensorBG)] 
    aucs <- pracma::cumtrapz(xaxis,sensorBG) 
    cgmupload["total_auc",f] <- aucs[base::length(sensorBG)] 
     
    cgmupload["average_auc_per_day",f] <- 
      base::as.numeric(cgmupload["total_auc",f]) / 
      base::as.numeric(cgmupload["num_days_good_data",f]) 
     
    # AUC over 180. 
    sensorover180 <- table$sensorglucose 
    sensorover180 <- sensorover180[sensorover180 >= 180] 
    sensorover180 <- sensorover180[!is.na(sensorover180)] 
    xaxis <-  
      base::seq(from = 0, length.out = base::length(sensorover180),by =  
                  (interval / 60)) 
     
    # Calculate cumulative AUC, and subtract recatangle where length = 180 & 
    # width = minutes. 
    if (base::length(sensorover180) > 1) { 
      aucs <- pracma::cumtrapz(xaxis,sensorover180) 
      aucs <-  
        (aucs[base::length(sensorover180)]) - (xaxis[base::length(xaxis)] * 180) 
      cgmupload["auc_over_180",f] <- aucs 
    } else { 
      cgmupload["auc_over_180",f] <- 0 
    } 
    cgmupload["average_auc_180",f] <- 
      base::as.numeric(cgmupload["auc_over_180",f]) / 
      base::as.numeric(cgmupload["num_days_good_data",f]) 
 
    # AUC lower 70. 
    sensorlower70 <- table$sensorglucose 
    sensorlower70 <- sensorlower70[sensorlower70 < 70] 
    sensorlower70 <- sensorlower70[!is.na(sensorlower70)] 
    xaxis <-  
      base::seq(from = 0, length.out = base::length(sensorlower70),by =  
                  (interval / 60)) 
This section has been 
modified in order to 
calculate the AUC 
between 70 (upper 
limit) and the glucose 
curve (lower limit). 
PPD


 
 
Protocol Number: 
LDX0419 
Version: 3.0 
Document Date: 07 May 2024 
R code 
Notes 
     
    # Calculate cumulative AUC, and subtract recatangle where length = 70 & 
    # width = minutes. 
    if (base::length(sensorlower70) > 1) { 
      aucs <- pracma::cumtrapz(xaxis,sensorlower70) 
      aucs <-  
        -(aucs[base::length(sensorlower70)]) + (xaxis[base::length(xaxis)] * 70) 
       
      cgmupload["auc_lower_70",f] <- aucs 
    } else { 
      cgmupload["auc_lower_70",f] <- 0 
    } 
    cgmupload["average_auc_70",f] <- 
      base::as.numeric(cgmupload["auc_lower_70",f]) / 
      base::as.numeric(cgmupload["num_days_good_data",f])    
     
    cgmupload["interval (sec)",f] <- interval 
     
    # Calculate MAGE. 
    # Smooth data using an exponentially weighted moving average, calculate SD of  
    # unsmoothed data.   
    table$smoothed <-  
      base::as.numeric(zoo::rollapply(zoo::zoo(table$sensorglucose), 9,  
                                      function(x) c(1,2,4,8,16,8,4,2,1) %*%  
                                        (x / 46),fill = NA)) 
    table$smoothed[1:4] <- base::mean(stats::na.omit(table$sensorglucose[1:4])) 
    table$smoothed[(base::length(table$smoothed)-3): 
                     base::length(table$smoothed)] <-  
      base::mean(table$sensorglucose[(base::length(table$sensorglucose)-3): 
                                       base::length(table$sensorglucose)]) 
     
    sd <- stats::sd(table$sensorglucose) 
    # Identify turning points, peaks, and nadirs. 
    tpoints <- pastecs::turnpoints(table$smoothed) 
    peaks <- base::which(tpoints[["peaks"]] == TRUE) 
    pits <- base::which(tpoints[["pits"]] == TRUE) 
    # Calculate the difference between each nadir and its following peak. If the      
    # data starts on a peak, remove it. Otherwise remove the final pit to create an  
    # even number of pits and peaks. 
    if (tpoints[["firstispeak"]] == TRUE && base::length(peaks) !=  
        base::length(pits)) { 
      peaks <- peaks[2:base::length(peaks)] 
    } else if (tpoints[["firstispeak"]] == FALSE &&  
               base::length(peaks) != base::length(pits)) { 
      pits <- pits[1:(base::length(pits)-1)] 
    } 
    differences <- table$sensorglucose[peaks] - table$sensorglucose[pits] 
     
 
PPD


 
 
Protocol Number: 
LDX0419 
Version: 3.0 
Document Date: 07 May 2024 
R code 
Notes 
    # Calculate the average of the differences greater than the entire dataset  
    # SD, 2SD, etc. 
    if (magedef == "1sd") { 
      cgmupload["r_mage",f] <-  
        base::mean(stats::na.omit(differences[base::which(differences > sd)])) 
    } else if (magedef == "1.5sd") { 
      cgmupload["r_mage",f] <-  
        base::mean(stats::na.omit(differences[base::which(differences >  
                                                            (sd * 1.5))])) 
    } else if ( magedef == "2sd") { 
      cgmupload["r_mage",f] <-  
        base::mean(stats::na.omit(differences[base::which(differences >  
                                                            (sd * 2))])) 
    } else { 
      cgmupload["r_mage",f] <-  
        base::mean(stats::na.omit(differences[base::which(differences >  
                                                            magedef)])) 
    } 
     
    #J-index 
    cgmupload["j_index",f] <-  
      0.001 * (base::mean(table$sensorglucose, na.rm = T) +  
                 stats::sd(table$sensorglucose, na.rm = T))^2 
  
    # CONGA     
    #    n <- (congan * 3600) 
    #    conga.times <- table$timestamp + n 
    #    conga.times <- conga.times[!is.na(conga.times)] 
    #    conga.times <- conga.times[base::order(conga.times)] 
    #    conga.times <- conga.times[base::which(conga.times %in% table$timestamp)] 
    #    begin.times <- conga.times - n 
    #    suppressWarnings(congas <- 
table$sensorglucose[base::which(table$timestamp %in% conga.times)] -  
    #                       table$sensorglucose[base::which(table$timestamp %in% begin.times)]) 
    #    cgmupload[base::paste0("conga_",congan),f] <- stats::sd(congas,na.rm = T) 
     
    congan=1 
    n <- (congan * 3600) 
    conga.times <- table$timestamp + n 
    conga.times <- conga.times[!is.na(conga.times)] 
    conga.times <- conga.times[base::order(conga.times)] 
    conga.times <- conga.times[base::which(conga.times %in% table$timestamp)] 
    begin.times <- conga.times - n 
    suppressWarnings(congas <- table$sensorglucose[base::which(table$timestamp %in% 
conga.times)] -  
                       table$sensorglucose[base::which(table$timestamp %in% begin.times)]) 
    cgmupload[base::paste0("conga_",congan),f] <- stats::sd(congas,na.rm = T) 
         
This section has been 
modified in order to 
calculate the CONGA at 
1h, 2h and 4h 
simultaneously. 
PPD


 
 
Protocol Number: 
LDX0419 
Version: 3.0 
Document Date: 07 May 2024 
R code 
Notes 
    congan=2 
    n <- (congan * 3600) 
    conga.times <- table$timestamp + n 
    conga.times <- conga.times[!is.na(conga.times)] 
    conga.times <- conga.times[base::order(conga.times)] 
    conga.times <- conga.times[base::which(conga.times %in% table$timestamp)] 
    begin.times <- conga.times - n 
    suppressWarnings(congas <- table$sensorglucose[base::which(table$timestamp %in% 
conga.times)] -  
                       table$sensorglucose[base::which(table$timestamp %in% begin.times)]) 
    cgmupload[base::paste0("conga_",congan),f] <- stats::sd(congas,na.rm = T) 
         
    congan=4 
    n <- (congan * 3600) 
    conga.times <- table$timestamp + n 
    conga.times <- conga.times[!is.na(conga.times)] 
    conga.times <- conga.times[base::order(conga.times)] 
    conga.times <- conga.times[base::which(conga.times %in% table$timestamp)] 
    begin.times <- conga.times - n 
    suppressWarnings(congas <- table$sensorglucose[base::which(table$timestamp %in% 
conga.times)] -  
                       table$sensorglucose[base::which(table$timestamp %in% begin.times)]) 
    cgmupload[base::paste0("conga_",congan),f] <- stats::sd(congas,na.rm = T) 
     
    # MODD. 
    table$time <- lubridate::round_date(table$timestamp,"5 minutes") 
    table$time <- base::strftime(table$time, format = "%H:%M",tz = "UTC") 
    moddtable <-  
      base::data.frame(base::matrix(ncol = 2,nrow =  
                                      base::length(unique(table$time)))) 
    base::colnames(moddtable) <- c("time","mean_differences") 
    moddtable$time <- base::unique(table$time) 
    # For each time, calculate differences (absolute values) and average them.    
    for (r in 1:nrow(moddtable)) { 
      moddtable$mean_differences[r] <-  
        base::mean(base::abs(base::diff(table$sensorglucose[ 
          base::which(table$time == moddtable$time[r])]))) 
    } 
    # Average the averages. 
    cgmupload["modd",f] <-  
      base::mean(stats::na.omit(moddtable$mean_differences)) 
     
    # LBGI and HBGI (based on dc1386 appendix) 
    a <- 1.084 
    b <- 5.381 
    y <- 1.509 
    table$gluctransform <- y * ((base::log(table$sensorglucose)^a)-b) 
    table$rBG <- 10 * (table$gluctransform^2) 
 
PPD


 
 
Protocol Number: 
LDX0419 
Version: 3.0 
Document Date: 07 May 2024 
R code 
Notes 
    rl <- table$rBG[base::which(table$gluctransform < 0)] 
    rh <- table$rBG[base::which(table$gluctransform > 0)] 
    cgmupload["lbgi",f] <- base::mean(stats::na.omit(rl)) 
    cgmupload["hbgi",f] <- base::mean(stats::na.omit(rh)) 
  } 
   
  # Write file. 
  cgmupload <-  
    base::cbind("Variable / Field Name" = rownames(cgmupload),cgmupload) 
  if (format == "rows") { 
    cgmupload <- base::as.data.frame(base::t(cgmupload)) 
    cgmupload <- cgmupload[-1,] 
  } 
  filename <- base::paste(outputdirectory,"/",outputname,".csv",sep = "") 
  utils::write.csv(cgmupload, file = filename,row.names = FALSE,na = "") 
} 
 
library(cgmanalysis) 
library(stringi) 
library(base) 
 
cleandata( 
  inputdirectory = "path\\to\\data", 
  outputdirectory = "path\\to\\cleaned_data", 
           removegaps = FALSE, gapfill = TRUE, maximumgap = 30)  
 
cgmvariables_mod( 
  inputdirectory = "path\\to\\cleaned_data ", 
  outputdirectory = "path\\to\\output", 
  outputname = "Dexcom", 
  customintervals = list(c(250,400)), 
  aboveexcursionlength = 35, 
  belowexcursionlength = 10, 
  magedef = "1sd", 
  congan = 1, 
  daystart = 0, 
  dayend = 24, 
  id_filename = F, 
  format = "rows", 
  printname = F 
) 
Cleandata will fill in gaps 
shorter than 30 minutes 
but will not remove the 
24-hour chunks 
containing 
larger gaps. 
 
Parameters 
customintervals, 
aboveexcursionlength, 
belowexcursionlength, 
congan, daystart, 
dayend will not be used.  
 
 
 
 
 
PPD


 
 
Protocol Number: 
LDX0419 
Version: 3.0 
Document Date: 07 May 2024 
12.2 SAS code for Andersen-Gill intensity model 
The following SAS code will be used to implement Andersen-Gill intensity model: 
 
title 'Intensity Model'; 
proc phreg data=dataset covm ; 
      class trt01pn (ref="2"); 
      model (Tstart, Tstop) * status (0) = trt01pn;  
      hazardratio trt01pn;  
run; 
 
• The covm option specifies that the model-based covariance matrix will be used 
• In Ref option the Placebo group should be specified 
• a TStart variable to represent the (k – 1) recurrence time or the value 0 if k = 1 
• a TStop variable to represent the kth recurrence time or the follow-up time if k = K + 1 
• a Status variable indicating whether the TStop time is a recurrence time or a censored time; 
for example, Status=1 for a recurrence time and Status=0 for censored time 
 
 
 
 
 
PPD


 
 
Protocol Number: 
LDX0419 
Version: 3.0 
Document Date: 07 May 2024 
12.3 List of Tables, Listings and Figures 
Mock shells and index for tables, listings and figures are reported provided in the file “LDX0419 Mock 
shells - Version 3.0_2024-05-07.docx” attached to this document. 
PPD