An Exploratory Maintenance Trial Evaluating the Effect of BI 655064 in Lupus Nephritis Patients Who Have Achieved a Meaningful Response Either at the End of 1293.10 or After an Induction Treatment Outside of 1293.10
Phase: PHASE2
Conditions: Lupus Nephritis
Sponsor: Boehringer Ingelheim

0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct o ber 2 0 1 6
C li nic al Tri al Pr ot oc ol
TI T L E P A G E
D oc u me nt N u m ber:
c 1 37 9 5 0 1 3 - 0 4
E u dr a C T N o.:
E U Tri al N o:
   2 0 1 7- 0 0 3 1 0 1- 1 7
BI Tri al N o.:
1 2 9 3- 0 0 1 3
BI I n vesti g ati o n al 
Pr o d uct:
BI 6 5 5 0 6 4
Title:
A n ex pl orat or y  mai nte na nce trial e val uati n g t he effect of BI 
6 5 5 0 6 4 i n L u p us Ne p hritis patie nts w h o ha v e ac hie ve d a 
mea ni n gf ul res p o nse eit her at t he e n d of 1 2 9 3. 1 0 or after a n
i n d ucti o n treat me nt o utsi de of 1 2 9 3. 1 0
L a y Title :
A n ex pl orat or y  mai nte na nce trial of BI 6 5 5 0 6 4 i n patie nts wit h 
lu p us ne p hritis
Cli nic al P h ase:
II
Tri al Cli nic al 
M o nit or:
P h o ne:
Fa x:    
C o or di n ati n g 
I n vesti g at or:
P h o ne: 
Fa x:     
St at us:
Fi nal Pr ot oc ol ( Re vise d Pr ot oc ol ( base d o n gl o bal a me n d me nt 2 ))
Versi o n a n d D ate: 
Versi o n: 3 . 0
D ate: 2 1 Dec 2 0 2 0
P a ge 1 of 8 5
Pr o priet ar y c o nfi de nti al i nf or m ati o n .
2 0 2 0 B oe hri n ger I n gel hei m I nter n ati o n al G m b H or o ne or m ore of its affili ate d c o m p a nies. All ri g hts reser ve d.
T his d oc u me nt ma y n ot - i n f ull or i n part - be passe d o n, re pr o d uce d, p u blis he d or ot her wise use d wit h o ut pri or writte n per missi o n.

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 2 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
C LI NI C A L T RI A L P R O T O C O L S Y N O P SI S
C o m p a n y n a me
B oe hri n ger I n gel hei m 
Fi nis he d pr o d uct n a me
N ot a p plica ble
Acti ve i n gre die nt n a me
BI 6 5 5 0 6 4
Pr ot oc ol d ate
1 4 Se pte m ber 2 0 1 7
Re visi o n d ate
2 1 Dec 2 0 2 0
Tri al n u m ber
1 2 9 3 -0 0 1 3
Title of tri al:
A n e x pl orat or y mai nte na nce trial e val uati n g t he effect of BI 6 5 5 0 6 4 i n L u p us 
Ne p hritis patie nts w h o ha ve ac hie ve d a mea ni n gf ul res p o nse eit her at t he e n d of 
1 2 9 3. 1 0 or after a n i n d ucti o n treat me nt o utsi de of 1 2 9 3. 1 0
C o or di n ati n g 
I n vesti g at or:
Tri al sites:
M ulti -ce ntre trial
Cli nic al p h ase:
II
O bjecti ve s:
T o e val uate l o n g ter m efficac y a n d safet y of differe nt d oses of BI 6 5 5 0 6 4 vers us 
place b o as a d d -o n t hera p y t o sta n dar d of care d uri n g mai nte na nce treat me nt f or 
l u p us ne p hritis.
T o s t u d y t he effect of ster oi d ta peri n g a n d ster oi d wit h dra w al d uri n g mai nte na nce 
treat me nt.
M e t h o d ol o g y:
D o u ble bli n d, place b o -c o ntr olle d, parallel desi g n c o m paris o n of differe nt d ose 
gr o u ps o ver 5 2 w ee ks of mai nte na nce treat me nt.
N u m ber of p atie nt s
e ntere d: 
Gr o u p 1: a p pr o xi matel y 6 0 patie nts t o r oll o ver fr o m 1 2 9 3. 1 0 .
N u m ber of p atie nt s per
tre at me nt a r m :
Gr o u p 1 : the n u m ber of patie nts i n eac h treat me nt ar m will var y de pe n d i n g o n t he 
t otal n u m ber of eli gi ble patie nts r olli n g o ver fr o m 1 2 9 3. 1 0 . 
Di a g n osis:
Patie nts wit h Class III or I V l u p us ne p hritis base d o n I S N/ R P S 2 0 0 3 classificati o n.
Test pr o d uct
BI 6 5 5 0 6 4
D ose:
Gr o u p 1 – r oll-o ver patie nts will c o nti n ue t o recei ve t he sa me treat me nt all ocati o n
as pre vi o usl y assi g ne d i n 1 2 9 3. 1 0 .
M o de of a d m i nistr ati o n:
S u bc uta ne o us i njecti o n
C o m p ar at or pr o d ucts
Place b o
D ose:
N ot a p plica ble

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 3 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
C o m p a n y n a me
B oe hri n ger I n gel hei m 
Fi nis he d pr o d uct n a me
N ot a p plica ble
Acti ve i n gre die nt n a me
BI 6 5 5 0 6 4
Pr ot oc ol d ate
1 4 Se pte m ber 2 0 1 7
Re visi o n d ate
2 1 Dec 2 0 2 0
Tri al n u m ber
1 2 9 3 -0 0 1 3
M ai n i n - a n d e xcl usi o n
M ai n i n- a n d e xcl usi o n
criteri a
 
Males or fe males, a ge 1 8 – 7 0 years (i ncl usi ve)
 
Males or fe males, a ge 1 8 – 7 0 years (i ncl usi ve)
 
Dia g n osis of S L E acc or di n g t o 1 9 9 7 A C R classificati o n wit h at least 4 
d oc u me nte d criteria, o ne of w hic h m ust eit her be a p ositi ve A N A or a p ositi ve
a nti -ds D N A a nti b o d y c o nfir me d at t he start of i n d ucti o n t hera p y ( hist orical data)
 
e G F R ≥ 3 0 ml/ mi n/ 1. 7 3 m 2 at scree ni n g
 
Gr o u p 1: a c hie ve d eit her a C R R or a P R R or pr otei n uria ≤ 1 g/ d ( or U P/ U C ≤1)
at t he e n d of 1 2 9 3. 1 0.
M o de of a d m i nistr ati o n:
S u bc uta ne o us i njecti o n
D ur ati o n of tre at m e nt
5 2 we e ks
E n d p oi nts
Pri mar y e n d p oi nt: 
- Pr o p orti o n of patie nts wit h C R R a n d wit h o ut a n y re nal flares at wee k 5 2 .
Sec o n dar y e n d p oi nts:
- Pr o p orti o n of patie nts wit h C R R at wee k 5 2
- Pr o p orti o n of patie nts wit h pr otei n uria < 0. 8 g/ d a n d wit h o ut a n y re nal flares at 
wee k 5 2 .
- Pr o p orti o n of patie nts wit h C R R at wee k 5 2 a n d s ustai ne d ster oi d re d ucti o n t o ≤5 
m g / d fr o m wee k 2 6 t o wee k 5 2 .
- Pr o p orti o n of patie nts e x perie nci n g at least o ne re nal flare d uri n g 5 2 we e ks.
- Ti m e t o first re nal flare o ver t he c o urse of 5 2 wee ks .
- Pr o p orti o n of patie nts wit h c o nfir me d C R R ( defi ne d as C R R at b ot h wee k 4 2 a n d 
wee k 5 2 usi n g U P/ U C fr o m s p ot uri ne)
- C ha n ge fr o m baseli ne i n S L E D AI at wee ks 1 2, 2 6, 4 2 a n d 5 2 .
S afet y criteri a:
A ssess me nts i ncl u de p h ysical e xa mi nati o n, vital si g ns, E C G, safet y la b orat or y tests 
a n d a d verse e ve nts.
St a tistic al met h o ds:
Descri pti ve statistics, Ka pla n -Meier a nal ysis or ot her statistical met h o ds a p pr o priate 
f or e x pl orat or y a nal yses.

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 4 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
F L O W C H A R T 1 – R O L L -O V E R P A TI E N T S F R O M 1 2 9 3. 1 0 ( G R O U P 1)
Tri al Peri o ds
B aseli ne 
Tre at me nt
E n d of 
tre at me nt
F oll o w -u p 
E n d of St u d y
Visit
1 1
2
3  
4  
5
6  
7  
8 
E O T 3
F U p
E O S
W e e k
0
4
8 
1 2  
1 8  
2 6  
3 4  
4 2  
5 2 
E O T + 4 
E O T + 1 2
D a y ( ± t i me wi n d o w) 2
1
2 9 ± 3  
5 7 ± 3  
8 5 ± 5 
1 2 7 ± 5  
1 8 3 ± 5  
2 3 9 ± 5  
2 9 5 ± 5  
3 6 5 ± 5  
3 9 3 ± 5  
4 4 9 ± 5
I nf or me d c o nse nt4
X
De m o gra p hics / Me dical hist or y 5
X
Re vie w i ncl usi o n/e xcl usi o n criteria
X
P h ysical e xa mi nati o n 6
  X c 1
X t
X t
X t
X t
X c
X t
X t
X c
X t
X t
1 2 -lea d E C G
X 1
X
X
X
L u p us P R O, S F- 3 6, F A CI T -F, S L E D AI 7
X 1
X
X
X   
X
2 x 2 4 hr uri ne c ollecti o n 8
X 1
X
Pre g na nc y test 9
X 1
X   
X   
X   
X   
X   
X   
X   
X
X
X
Safet y l a b orat or y tests 1 0
X 1
X   
X   
X   
X   
X   
X   
X   
X
X
X
I nfecti o n scree ni n g1 1
X
I m m u n ol og y tests 1 2
X 1
X
X
X   
X
X
E x pl orat or y bi o mar ker sa m pli n g 1 4
X 1
X
X
X
X
m R N A per i p heral bl o o d sa m pli n g1 4
X 1
X
X
mi R N A uri ne sa m pli n g 1 4
X 1
X
X
Dis pe nse trial me dicati o n a n d pr o vi de i nstr ucti o ns f or 
h o me a d mi nistrati o n
X
X   
X   
X   
X   
X   
X   
X
A d mi nist er trial me dicati o n
X
X   
X   
X   
X   
X   
X   
X
C o nti n ue S O C ( M M F or A Z A)
Gl uc oc or tic oi ds ta peri n g1 5
C o m plia nce C hec k 
X 1
X   
X   
X   
X   
X   
X   
X   
X
Dis pe nse ne w diar y at baseli ne a n d re vie w c o m plia nce of 
diar y use
X
X   
X   
X   
X   
X   
X   
X   
X
A d verse e ve nts
X 1 6
X   
X   
X   
X   
X   
X   
X   
X
X
X
C o nc o mita nt T hera p y 1 7
X 1 6
X   
X   
X   
X   
X   
X   
X   
X
X
X

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 5 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
F L O W C H A R T 1 – R O L L- O V E R Patie nts fr o m 1 2 9 3. 1 0 ( Gr o u p 1) ( C O N T)
Vital stat us c ollecti o n 1 8
X
C o m ple tio n of patie nt partici pati o n
X
1. 
V isit 1 m ust be perf or me d o n t he sa me da y as t he 1 2 9 3. 1 0 e n d of treat me nt ( E O T) visit. All assess me nts perf or me d at t he 1 2 9 3. 1 0 E O T visit will be use d as baseli ne f or t his trial a n d s h o ul d 
n ot be re peate d. See Secti o n 6. 2. 1 .
2. 
A n y de viati o n fr o m t he visit sc he d ule is str o n gl y disc o ura ge d a n d ca n o nl y occ ur wit h t he a p pr o val of C T L/ C T M . See Secti o n 6. 1 .
3. 
F or pre mat urel y disc o nti n ue d p atie nts, a n E O T visit s h o ul d be perf or me d wit hi n 7 da ys of st o p pi n g t he trial me dicati o n a n d t hese patie nts will be i n vite d t o atte n d a s u bset of f oll o w-u p 
visits. See Secti o n 6. 2. 3. 3
4. 
Re -c o nse nti n g ma y be necessar y w he n ne w rele va nt i nf or mati o n bec o m es a vaila ble a n d s h o ul d be c o n d ucte d acc or di n g t o t he s p o ns or’s i nstr ucti o ns.
5. 
Pre vi o usl y re p orte d m e dical hist or y data fr o m 1 2 9 3. 1 0 will ha ve t o be be tra nscri be d i nt o 1 2 9 3-0 0 1 3 e C R F. I nf or mati o n o n s m o ki n g a n d alc o h ol hist or y will als o be c ollected if stat us 
c ha n ge d si nce Visit 1 of 1 2 9 3. 1 0 trial.
6. 
I ncl u des hei g ht (at scree ni n g o nl y), wei g ht a n d vital si g ns. Xc is a c o m plete p h ysical e xa mi nati o n. Xt is a tar gete d p h ysical e xa mi nati o n. See Secti o n 5. 2 . 1.
7. 
Q uesti o n naires t o be c o m plete d at t he trial site b y t he patie nts bef ore a n y trial relate d i n vesti gati o ns or disc ussi o ns. See Secti o n 5. 1 . 2.
8. 
See Secti o n 5. 1. 1 f or details o n t he 2 4-h o ur uri ne c ollecti o n. 
9. 
P re g na nc y test will be perf or me d at Baseli ne a n d t he n e ver y 4 wee ks i n w o me n of c hil d beari n g p ote ntial. See Secti o n 5. 2 . 3.
1 0. R o uti ne safet y la b orat or y tests i ncl u de hae mat ol o g y, c he mistr y, c oa g ulati o n a n d uri nal ysis. See Secti o n 5. 2 . 3.
1 1. I nfecti o us scree ni n g will o nl y be d o ne i n case of s us pici o n of a (re -) i nfecti o n as t his has bee n teste d at scree ni n g i n cli nical trial 1 2 9 3 . 1 0. If s o, bl o o d sa m ples will be c ollecte d f or assessi n g 
t he prese nce of HI V, H B V a n d H C V. T he Q ua nti F E R O N -T B G ol d test will be als o perf or me d t o assess t he prese nce of T B i nfecti o n. See Secti o n 5. 2. 3 .
1 2. I m m u n ol o g y tests: Bl o o d sa m ples f or a nti- ds D N A, a nti-C 1 q a nti b o dies, C 3 a n d C 4 c o m ple me nts will be c ollecte d at ti me -p oi nt s i n dicate d i n t he a b o ve Fl o w C hart . F or A N A a n d A nti-
p h os p h oli pi d a nti b o dies , t hese sa m ples will be c ollecte d at visits 1 a n d E O T o nl y. F or C 3/ C 4 a n d A nti -ds D N A t hese will be teste d i n a d diti o n at wee k 4 2 d ue t o t he S L E D AI q uesti o n naire 
bei n g c o m plete d. Refer t o Ta ble 5. 2. 3: 1 f or m ore i nf or mati o n.
1 3.
1 4. See Secti o n 5. 4. 1 for details o n e x pl orat or y bi o mar ker, m R N A peri p heral bl o o d a n d mi R N A uri ne sa m pli n g re q uire me nts.
1 5. F or gl uc oc ortic oi ds ta peri n g sc he d ule, see Secti o n 4. 2. 1 . 
1 6. All ne w a n d o n g oi n g A d v erse E ve nts/ C o nc o mita nt T hera p y at t he E O T of 1 2 9 3. 1 0 will nee d t o be e ntere d i nt o t he e C R F f or 1 2 9 3 -0 0 1 3 at Visit 1.
1 7. C o m plia nce t o l u p us ne p hritis -co nc o mita nt t hera p y will be rec or de d b y patie nts i n e- diar y pr o vi de d a n d assesse d b y trial staff at e ver y visit.
1 8. F or pre mat urel y disc o nti n ue d patie nts w h o are u na ble t o atte n d a s u bset of f oll o w-u p visits , t heir vital stat us s h o ul d be assesse d at Wee k 5 2, see Secti o n 6. 2. 3 . 3. All patie nts t o c o m plete t he 
trial u ntil Wee k 5 2 a n d are n ot ret ur ni n g f or F U p will ha ve at least a vital stat us c ollecti o n at Wee k 6 4 .

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 6 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
T A B L E O F C O N T E N T S
TI T L E P A G E ...........................................................................................................................1
C LI NI C A L T RI A L P R O T O C O L S Y N O P SI S .....................................................................2
F L O W C H A R T 1 – R O L L -O V E R P A TI E N T S F R O M 1 2 9 3. 1 0 ( G R O U P 1) ...................4
T A B L E O F C O N T E N T S ........................................................................................................6
A B B R E VI A TI O N S ..................................................................................................................9
1. 3 
R A TI O N A L E F O R P E R F O R MI N G T H E T RI A L .........................................1 5
2. 
T RI A L O B J E C TI V E S A N D E N D P OI N T S ......................................................1 9
2. 1 
M AI N O B J E C TI V E S, P RI M A R Y A N D S E C O N D A R Y E N D P OI N T S ........1 9
2. 1. 1 
M ai n o bjecti ves ....................................................................................................1 9
2. 1. 2 
Pri m ar y e n d p oi nt ................................................................................................1 9
2. 1. 3 
Sec o n d ar y e n d p oi nts ...........................................................................................1 9
3.   
D E S C RI P TI O N O F D E SI G N A N D T RI A L P O P U L A TI O N .........................2 1
3. 1 
O V E R A L L T RI A L D E SI G N A N D P L A N .......................................................2 1
3. 2   
DI S C U S SI O N O F T RI A L D E SI G N, I N C L U DI N G T H E C H OI C E O F 
C O N T R O L G R O U P ...........................................................................................2 2
3. 3 
S E L E C TI O N O F T RI A L P O P U L A TI O N .......................................................2 3
3. 3. 1 
M ai n di a g n osis f or tri al e ntr y
............................................................................2 3
3. 3. 2  
I ncl usi o n criteri a .................................................................................................2 3
3. 3. 3 
E xcl usi o n criteri a ................................................................................................2 4
3. 3. 4   
Wit h dr a w al of p atie nts fr o m t her a p y or assess me nts..................................... 2 5
3. 3. 4. 1 
Wit h dra wal fr o m trial treat me nt
...........................................................................2 5
3. 3. 4. 2 
Wit h dra wal of c o nse nt f or trial partici pati o n ........................................................2 6
3. 3. 4. 3 
Disc o nti n uati o n of t he trial b y  t he s p o ns or...........................................................2 6
4. 
T R E A T M E N T S ...................................................................................................2 7
4. 1 
I N V E S TI G A TI O N A L T R E AT M E N T S ...........................................................2 7
4. 1. 1 
I de ntit y of t he I n vesti g ati o n al Me dici n al Pr o d ucts..........................................2 7
4. 1. 2 
Selecti o n of d oses i n t he tri al ..............................................................................2 7
4. 1. 3 
Met h o d of assi g ni n g p atie nts t o tre at me nt gr o u ps ...........................................2 8
4. 1. 4 
Dr u g assi g n me nt a n d a d mi nistr ati o n of d oses f or e ac h p atie nt ......................2 8
4. 1. 5 
Bli n di n g a n d pr oce d ures f or u n bli n di n g ...........................................................2 9
4. 1. 5. 1  
Bli n di n g................................ .................................................................................2 9
4. 1. 5. 2 
U n bli n di n g a n d brea ki n g t he c o de ........................................................................3 0
4. 1. 6  
P ac k a gi n g, l a belli n g, a n d re- s u p pl y...................................................................3 0

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 7 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
4. 1. 7 
St or a ge c o n diti o ns ...............................................................................................3 0
4. 1. 8 
Dr u g acc o u nt a bilit y .............................................................................................3 0
4. 2 
O T H E R T R E A T M E N T S, E M E R G E N C Y P R O C E D U R E S, 
R E S T RI C TI O N S ................................................................................................3 1
4. 2. 1 
Ot her tre at me nts a n d e mer ge nc y pr oce d ures ..................................................3 1
4. 2. 2   
M a n a ge me nt of A d verse E ve nts........................................................................ 3 3
4. 2. 3 
Restricti o ns ..........................................................................................................3 4
4. 2. 3. 1 
Restricti o ns re gar di n g c o nc o mita nt treat me nt ......................................................3 4
4. 2. 3. 2 
Restricti o ns o n diet a n d lifest y le...........................................................................3 4
4. 3 
T R E A T M E N T C O M P LI A N C E ........................................................................3 5
5. 
A S S E S S M E N T S ..................................................................................................3 6
5. 1 
A S S E S S M E N T O F E F FI C A C Y ........................................................................3 6
5. 1. 1 
Assess me nt of re n al res p o nse .............................................................................3 6
5. 1. 2   
Assess me nt of p atie nt re p orte d o utc o mes......................................................... 3 7
5. 1. 3 
Assess me nt of S L E D AI: ......................................................................................3 7
5. 2 
A S S E S S M E N T O F S A F E T Y .............................................................................3 7
5. 2. 1 
P h ysic al e x a mi n ati o n ..........................................................................................3 7
5. 2. 2 
Vit al si g ns .............................................................................................................3 8
5. 2. 3 
S afet y a n d i m m u n ol o g y l a b or at or y p ar a meters ..............................................3 8
5. 2. 4 
Electr oc ar di o gr a m ..............................................................................................4 1
5. 2. 5 
Assess me nt of a d verse e ve nts .............................................................................4 1
5. 2. 5. 1 
Defi niti o ns of A Es ................................................................................................4 1
5. 2. 5. 2   
A d verse e ve nt c ollecti o n a n d re p orti n g ................................................................ 4 5
 
5. 5 
A P P R O P RI A T E N E S S O F M E A S U R E M E N T S ..............................................5 0
6. 
I N V E S TI G A TI O N A L P L A N.............................................................................5 2
6. 1 
VI SI T S C H E D U L E .............................................................................................5 2
6. 2 
D E T AI L S O F T RI A L P R O C E D U R E S A T S E L E C T E D VI SI T S .................5 3
6. 2. 1 
B aseli ne ( Gr o u p 1) ..............................................................................................5 3
6. 2. 2 
Tre at me nt peri o d ................................................................................................5 4
6. 2. 3 
F oll o w u p peri o d a n d tri al c o m pleti o n ..............................................................5 4
6. 2. 3. 1  
E n d of Treat me nt ( E O T) Visit.............................................................................. 5 4

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 8 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
6. 2. 3. 2 
F oll o w - U p ( F U p) a n d E n d of St u d y  ( E O S) Visits................................................5 5
6. 2. 3. 3 
A d diti o nal f oll o w -u p f or pre mat urel y disc o nti n ue d patie nts ................................5 5
7. 
S T A TI S TI C A L M E T H O D S A N D D E T E R MI N A TI O N O F S A M P L E SI Z E
...............................................................................................................................5 6
7. 1  
S T A TI S TI C A L D E SI G N – M O D E L
................................................................5 6
7. 2 
N U L L A N D A L T E R N A TI V E H Y P O T H E S E S ...............................................5 6
7. 3 
P L A N N E D A N A L Y S E S .....................................................................................5 6
7. 3. 1 
Pri m ar y e n d p oi nt a n al yses .................................................................................5 7
7. 3. 2 
Sec o n d ar y e n d p oi nt a n al yses .............................................................................5 7
7. 3. 4 
S afet y a n al yses .....................................................................................................5 7
7. 4  
I N T E RI M A N A L Y S E S...................................................................................... 5 8
7. 5 
H A N D LI N G O F MI S SI N G D A T A ...................................................................5 8
7. 6 
R A N D O MI S A TI O N ...........................................................................................5 8
7. 7 
D E T E R MI N A TI O N O F S A M P L E SI Z E .........................................................5 9
8. 
I N F O R M E D C O N S E N T, T RI A L R E C O R D S, D A T A P RO T E C TI O N, 
P U B LI C A TI O N P O LI C Y, A N D A D MI NI S T R A TI V E S T R U C T U R E ........6 0
8. 1 
T RI A L A P P R O V A L, P A TI E N T I N F O R M A TI O N, I N F O R M E D 
C O N S E N T ...........................................................................................................6 0
8. 2 
D A T A Q U A LI T Y A S S U R A N C E ......................................................................6 1
8. 3 
R E C O R D S ...........................................................................................................6 1
8. 3. 1 
S o urce d oc u me nts ...............................................................................................6 1
8. 3. 2   
Direct access t o s o urce d at a a n d d oc u me nts..................................................... 6 2
8. 3. 3  
St or a ge peri o d of rec or ds................................ ...................................................6 2
8. 4  
E X P E DI T E D R E P O R TI N G O F  A D V E R S E E V E N T S ..................................6 3
8. 5 
S T A T E M E N T O F C O N FI D E N TI A LI T Y A N D P A TI E N T P RI V A C Y ........6 3
8. 5. 1 
C ollecti o n, st or a ge a n d f ut ure use of bi ol o gic al s a m ples a n d c orres p o n di n g 
d at a .......................................................................................................................6 3
8. 6 
T RI A L MI L E S T O N E S .......................................................................................6 3
8. 7   
A D MI NI S T R A TI V E S T R U C T U R E O F T H E T RI A L................................... 6 4
9. 
R E F E R E N C E S ....................................................................................................6 6
9. 1 
P U B LI S H E D R E F E R E N C E S ............................................................................6 6
9. 2 
U N P U B LI S H E D R E F E R E N C E S ......................................................................6 9
1 0. 
A P P E N DI C E S .....................................................................................................7 0
1 1. 
D E S C RI P TI O N O F G L O B A L A M E N D M E N T( S) .........................................7 1
1 1. 1 
G L O B A L A M E N D M E N T 1 ..............................................................................7 1
1 1. 2 
G L O B A L A M E N D M E N T 2 ..............................................................................7 6

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 9 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
A B B R E VI A TI O N S
A C R
A merica n C olle ge of R he u mat ol o g y
A E
A d verse E ve nt
A E SI
A d verse E ve nt of S pecial I nterest
A N A
A nti n uclear A nti b o d y
A L T
A S T
A U C
Ala ni ne A mi n otra nsferase
As partate A mi n otra nsferase
Area u n der t he C ur ve
A Z A
BI
Azat hi o pri ne
B oe hri n ger I n gel hei m
C A
C D
C o m pete nt A ut h orit y
Cl uster of Differe nt iati o n
CI
C o nfi de nce I nter val
C K
Creati ni ne Ki nase
C T M
Cli nical Trial Ma na ger
C R A
Cli nical Researc h Ass ociate
C R O
C o ntract Researc h Or ga nisati o n
C R R
C o m plete re nal Res p o nse
C T C A E 
C o m m o n Ter mi n ol o g y  Criteria f or A d verse E ve nts
C Y C
C y cl o p h os p ha mi de
D B L
DI LI
D M C
D ata base L oc k
Dr u g -I n d uce d Li ver I nj ur y
Data M o nit ori n g C o m mittee
ds D N A 
d o u ble stra n d De o x y ri b o N ucleic Aci d
E C G
Electr o car di o gra m
e C R F
Electr o nic Case Re p ort F or m
E D C
E D T A
e G F R
E M A
E O S
E O T
e P R O
Electr o nic Data Ca pt ure
E t h yle n dia mi netetraacetic aci d
Esti mate d Gl o mer ular Filtrati o n Rate
E ur o pea n Me dici nes A ge nc y
E n d of St u d y
E n d of Treat me nt
Electr o nic Patie nt Re p orte d O utc o me
E S R
E S R D
Er y t hr oc yte se di me ntati o n rate
E n d Sta ge Re nal Disease
E u dra C T 
E ur o pea n Cli nical Trials Data base
F A CI T - F 
F u ncti o nal Assess me nt C hr o nic Ill ness T hera p y- Fati g ue
F A S
F ull A nal ys is Set
F C
F U p
Fl o w C hart
F oll o w U p
G C 
Gl uc oc ortic oi ds
G C P
G o o d Cli nical Practice

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 1 0 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
H A 
H ealt h A ut h orities
H P F
Hi g h P o wer Fiel d
H R Q o L 
Healt h Relate d Q ualit y  of Life
H V
Healt h y V ol u nteer
I B
I n vesti gat or’s Br oc h ure
I C
I C H
I E C
I n hi bit or y c o nce ntrati o n
I nter nati o nal C o nfere nce o n Har m o nisati o n
I n de pe n de nt Et hics C o m mittee
I RB
I nstit uti o nal Re vie w B oar d
I R T
I nteracti ve Res p o nse Tec h n ol o g y
I SF
I n vesti gat or Site File
I S N/ R P S
I T P
I nter nati o nal S ociety of Ne p hr ol o g y / Re nal Pat h ol o g y  S ociety
I m m u ne t hr o m b oc yt o pe nia
I T T
I nte nti o n T o Treat
i. v.
L N
i ntra ve n o us
L u p us Ne p hritis
L P D D
L u p us P R O
M C P 1
Last Patie nt Dr u g Disc o nti n uati o n
L u p us patie nt -re p orte d o utc o me
M o n oc y te C he m oattracta nt Pr otei n- 1
Me d D R A 
Me dical Dicti o nar y  f or Dr u g Re g ulat or y Acti vities
M M F
M y c op h e n olate m ofetil
M R D
M ulti ple Risi n g D ose
M R R
Maj or Re nal Res p o nse
M T X
Met h otre xate
N O A E L 
N o O bser ve d A d verse Effect Le vel
O P U
O perati ve U nit
P R R
Partial R e nal Res p o nse
q 1 w
O nce a wee k
q 2 w
R A
E ver y  2 wee ks
R h eu mat oi d Art hritis
R B C
Re d Bl o o d Cell
R E P
Resi d ual Effect P eri o d 
R N A
R O 
Ri b o n ucleic Aci d
Rece pt or Occ u pa nc y
S A E.
Seri o us A d verse E ve nt 
s.c
s u bc uta ne o us
S F - 3 6
Me dical O utc o mes St u d y 3 6 -Ite m S h ort-F or m Healt h S ur ve y
S L E
S y ste mic L u p us Er y t he mat os us
S L E D AI 
S L E Disease Acti vit y I nde x
S O C
Sta n dar d of Care
S O P
S P C
Sta n dar d O perati n g Pr oce d ure
S u m mar y  of Pr o d uct C haracteristics
S R D
Si n gle Risi n g D ose

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 1 1 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
S U S A R
C T L
S us pecte d U ne x pecte d Seri o us A d verse Reacti o n
Cli nical Trial L ea der
T D M A P 
Trial Data Ma na ge me nt a n d A nal ys is Pla n
T M F
Trial Master File
T S A P
U L N
U P/ U C
W B C
Trial Statistical A nal y sis Pla n
U p per Li mit of N or mal
Uri ne pr otei n/ uri ne creati ni ne (rati o i n m g/ m g)
W hite Bl o o d Cell

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 1 2 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 1 3 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 1 4 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 1 5 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
1. 3 
R A TI O N A L E F O R P E R F O R MI N G T H E T RI A L
Patie nts wit h L N class III -V are at hi g h ris k f or irre versi ble ki d ne y  da ma ge lea di n g t o E S R D, 
dial y sis a n d deat h. Alt h o u g h n ot yet a p pr o ve d i n m ost c o u ntries f or t he treat me nt of L N, t he 
c o m bi nati o n of eit her C Y C or M M F wit h gl uc oc ortic oi ds is c o nsi dere d as c urre nt sta n dar d of 
care ( S O C) f or i n d ucti o n t hera p y i n L N. T he c urre nt S O C f or mai nte na nce t hera p y  is a 
c o m bi nati o n of l o w d ose M M F or azat hi o pri ne ( A Z A) wit h l o w d ose gl uc oc ortic oi ds.
H o we ver , o nl y 2 0-3 0 % of L N patie nts treate d wit h i n d ucti o n t hera p y  ac hie ve d a c o m plete 
re nal res p o nse ( C R R) wit hi n 1 y ear a n d a n o t her 2 0-3 0 % wit h a partial re nal res p o nse ( P R R). 
Patie nts wit h a C R R, or P R R wit h pr otei n uria < 0. 8 g/ d at 1 ye ar after t he start of i n d ucti o n 
t hera py ha ve t he best l o n g ter m pr o g n osis ( R 1 5 -4 2 9 4 ). T heref ore, t he tar get f or l o n ger 
treat me nt of L N is t o re d uce pr otei n uria t o < 0. 8 g/ d. Wit h t he c urre nt mai nte na nce t hera p y, 
there is a rele va nt ris k of rela psi n g w hic h j ustifies l o n g-ter m mai nte na nce t hera p y (R 1 5 - 3 7 2 4).
F urt her m ore, a lar ge n u m ber of patie nts w h o ac hie ve d a re nal res p o nse b y  i n d ucti o n t hera py 
still re q uire treat me nt wit h ster oi ds at d oses > 5 m g/ d. T he E ur o pea n Me dici nes A ge nc y  
( E M A) gui deli ne rec o m me n ds at least o ne ye ar mai nte na nce treat me nt after c o m pleti o n of 
i n d ucti o n t hera py f or L N (R 1 5 - 3 7 1 6). As a res ult, ster oi d-relate d si de effects are fre q ue ntly 

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 1 6 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
o bser ve d i n L N patie nts, t heref ore re d uci n g ster oi d d osa ge is a critical tar get i n mai nte na nce 
t hera py f or L N (P 1 5 -0 1 9 1 6 ).
I n a d diti o n, b ot h i m m u n os u p pressa nts use d f or mai nte na nce t hera py of L N ha ve ass ociate d 
si de-effects, s.a. gastr oi ntesti nal relate d si de effects a n d le uc oc yt o pe nia f or b ot h M M F a n d 
A Z A; a me n orr h oea f or M M F a n d li ver da ma ge f or A Z A. T h us, alter nati ve 
i m m u n os u p pressa nt wit h a better safety a n d efficac y pr ofile for L N mai nte na nce t hera p y wit h 
t he ai m t o re d uce ster oi d d oses s h o ul d be e x pl ore d.
Bl oc ki n g t he C D 4 0 -C D 4 0 L  pat h wa ys will i m pact m ulti ple mec ha nis ms w hic h i n v ol ve d i n 
pat h ol o g y  of L N b y i n hi biti n g B-cell a n d T- cell res p o nses as well as directl y i nfl ue nce t he 
i nfla m mati o n i n t he ki d ne y b y decreasi n g C D 4 0 L i n d uce d M C P 1
secreti o n of e n d ot helial 
cells, mesa n gial cells a n d C D 4 0 L  i n d uce d I L-6 secreti o n b y  pr o xi mal t u b ular e pit helial cells. 
T heref ore, tar geti n g t he C D 4 0- C D 4 0 L  pat h wa y is c o nsi dere d a p ote ntial effecti ve a p pr oac h 
f or t he treat me nt of t his disease.
T he t hera pe utic be nefit or s pecific a d verse e ve nts i n patie nts ca n n ot al wa ys be a ntici pate d 
d uri n g t he trial set u p. Later o n t here ma y  be ne w scie ntific k n o wle d ge a b o ut bi o mar kers a n d 
ot her fact ors c o ntri b uti n g t o diseases or t he acti o n of a dr u g. I n or der t o be a ble t o a d dress 
f ut ure scie ntific q uesti o ns, patie nts will be as ke d t o v ol u ntaril y d o nate bi os peci me ns f or 
ba n ki n g. If t he patie nt a grees, ba n ke d sa m ples ma y be use d f or f ut ure dr u g de vel o p me nt 
pr ojects, e. g. t o i de ntif y  patie nts t hat are m ore li kel y t o be nefit fr o m a treat me nt or e x perie nce 
a n a d verse e ve nt, a n d t here b y better matc h patie nts wit h t hera pies.

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 1 7 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 1 8 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 1 9 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
2. 
T RI A L O B J E C TI V E S A N D E N D P OI N T S
2. 1   
M AI N O B J E C TI V E S , P RI M A R Y A N D S E C O N D A R Y E N D P OI N T S
2. 1. 1 
M ai n o bje cti ves
T he mai n o bjecti ves of t h is trial are t o e val uate t he l o n g-ter m efficac y a n d safety of differe nt 
d oses of BI  6 5 5 0 6 4 vers us place b o as a d d-o n t hera p y  t o S O C d uri n g mai nte na nce t hera p y f or 
l u p us ne p hritis. Si nce patie nts are ra n d o mize d at t he start of 1 2 9 3. 1 0 a n d o n t he sa me 
treat me nt i n 1 2 9 3- 0 0 1 3, t he baseli ne of trial 1 2 9 3. 1 0 will be use d as baseli ne f or all 
assess me nts of c ha n ge fr o m baseli ne if n ot s pecifie d ot her wise.
2. 1. 2 
Pri m ar y en d p oi nt
T he pri mar y  e n d p oi nt is t he pr o p orti o n of patie nts wit h c o m plete re nal re p o nse (C R R ) a n d 
wit h o ut a n y  re nal flares at wee k 5 2.
2. 1. 3  
Sec o n d ar y e n d p oi nts
- Pr o p orti o n of patie nts wit h C R R at wee k 5 2
- Pr o p orti o n of patie nts wit h pr otei n uria < 0. 8 g/ d a n d wit h o ut a n y re nal flares at wee k 5 2.
- Pr o p orti o n of patie nts wit h C R R at wee k 5 2 a n d s ustai ne d ster oi d re d ucti o n t o ≤5 m g/ d fr o m 
wee k 2 6 t o wee k 5 2.
- Pr o p orti o n of patie nts e x perie nci n g at least o ne re nal flare d uri n g 5 2 wee ks.
- Ti me t o first re nal flare o ver t he c o urse of 5 2 wee ks.
- Pr o p orti o n of patie nts wit h c o nfir me d C R R ( defi ne d as C R R at b ot h wee k 4 2 a n d wee k 5 2 
usi n g U P/ U C fr o m s p ot uri ne)
- C ha n ge fr o m baseli ne i n S L E D AI at wee ks 1 2, 2 6, 4 2 a n d 5 2.

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 2 0 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
S afet y e n d p oi nts: 
• P h ysical e xa mi nati o n 
• Vital si g ns 
• Safet y la b orat or y tests 
• Electr ocar di o gra m 
• A d verse e ve nts (i ncl u di n g dr u g-relate d A Es) 
• A d verse e ve nts of s pecial i nterest ( A E SI) 
• Seri o us a d verse e ve nts 

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 2 1 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
3. 
D E S C RI P TI O N O F D E SI G N A N D T RI A L P O P U L A TI O N
3. 1 
O V E R A L L T RI A L D E SI G N A N D P L A N
T his is a p hase II, d o u ble -bli n d , parallel -desi g n, d ose -ra n gi n g, place b o-c o ntr olle d, 
e x pl orat or y mai nte na nce trial. T he trial is desi g ne d t o e val uate t he l o n g ter m efficac y a n d
safety of differe nt d oses of BI 6 5 5 0 6 4 i n patie nts wit h L N; a n d t o st u d y t he effect of ster oi d 
ta peri n g a n d ster oi d wit h dra wal d uri n g 5 2 wee ks of mai nte na nce treat me nt.
T h is trial is ha d bee n pla n ne d t o i ncl u de u p t o t w o gr o u ps of patie nts :
- 
Gr o u p 1 are r oll-o ver patie nts t hat ha ve ac hie ve d eit her a C R R or a P R R or pr otei n uria 
≤1. 0 g/ d ( or U P/ U C ≤ 1) at t he e n d of 1 2 9 3. 1 0.
- 
Gr o u p 2 was n ot starte d as t he pre defi ne d criteria t o start t he gr o u p was n ot met (cf. C h 
1. 2)
I n a d diti o n t o recei vi n g eit her BI 6 5 5 0 6 4 or place b o, all e ntere d patie nts will c o nti n ue t o 
recei ve S O C treat me nt, a n d ster oi ds ta peri n g will be perf or me d. Refer t o Fi g ure 3. 1 : 1 bel o w 
a n d secti o n 4. 2. 1 f or m ore i nf or mati o n. T his trial c o nsists, a n d of a 5 2- wee k treat me nt peri o d; 
f oll o we d by safet y assess me nts at F U p a n d E O S visits ( Fl o w C harts ). T he pri mar y  a nalys is 
will be perf or me d i n all treate d patie nts t o assess t he pr o p orti o n of patie nts wit h C R R after 5 2  
wee ks of treat me nt a n d wit h o ut a n y re nal flares.
St u d y  Desi g n: Patie nts fr o m 1 2 9 3. 1 0 ( Gr o u p 1)
* F or patie nts wit h C R R or pr otei n uria < 0. 8 g/ d: ster oi ds ta peri n g s h o ul d start i m me diatel y at Visit 1 a n d ster oi ds 
s h o ul d be st o p pe d at Wee k 1 2.
* * F or patie nts wit h pr otei n uria ≥0. 8 g/ d : ster oi ds s h o ul d be ta pere d d o w n t o ≤7. 5 m g/ d at Wee k 2 6 a n d t he n t o 
≤5 m g/ d at Wee k 5 2.
Fi g ure 3. 1: 1 O utli ne of trial desi g n – Gr o u p 1
E O S
E O T
5 2
6 4
     0
2 6
1 2
Wee k s
Visits     1
  4
   6
BI 6 5 5 0 6 4 ( 1 2 0 m g / 1 8 0 m g / 2 4 0 m g) a n d S O C
P atie nts will c o nti n ue t o recei v e t he s a me tre at me nt ar m as pre vi o usl y assi g ne d i n 1 2 9 3. 1 0
Pl ace b o a n d S O C
T a per ster oi ds t o ≤7. 5 m g/ d at  W k 2 6 * *
T a per ster oi ds t o ≤5 m g / d at  W k 5 2 * *
St o p ster oi ds at  W k 1 2 *
5 6

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 2 2 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
3. 2 
DI S C U S SI O N O F T RI A L D E SI G N, I N C L U DI N G T H E C H OI C E O F 
C O N T R O L G R O U P
T he desi g n of t his trial t o get her wit h t he 1 2 9 3. 1 0 ( d ose -fi n di n g, efficac y a n d safety of BI 
6 5 5 0 6 4 i n patie nts wit h acti ve L N) is i nte n de d t o facilitate t he selecti o n of a ppr o priate d ose 
re gi mens f or f urt her c o nfir mati o n i n t he P hase III trials.
T he treat me nt d urati o n of 5 2 wee ks was selecte d base d o n fee d bac k fr o m e xter nal e x perts 
a n d rec o m me n dati o n i n t he c urre ntl y a vaila ble E M A g ui deli ne f or at least o ne ye ar
mai nte na nce treat me nt f oll o wi n g i n d ucti o n t hera p y f or L N (R 1 5 -3 7 1 6 ).
Gr o u p 1 are patie nt s t hat ha ve ac hie ve d a re nal res p o nse or pr otei n uria ≤1. 0 g/ d ( or U P/ U C 
≤1) at t he e n d of 1 2 9 3. 1 0; it is t heref ore j ustifia ble f or t hese patie nts t o c o nti n ue recei vi n g t he 
sa me treat me nt ar m as pre vi o usl y  assi g ne d i n 1 2 9 3. 1 0 d uri n g t he mai nte na nce p hase . T his is 
t o e ns ure b ot h patie nts a n d i n vesti gat ors re mai n bli n de d i n or der t o all o w c o m paris o ns of 
efficac y a n d safety of differe nt d oses i n a p o p ulati o n t hat a p pears t o be a ble t o safely recei ve 
t he sa me d ose as i n t he 1 2 9 3. 1 0 i n d ucti o n st u d y. The patie nts will c o nti n ue t o recei ve o ne 
i njecti o n per wee k at Visit 1 of eit her BI 6 5 5 0 6 4 (1 2 0 m g/ 1 8 0 m g/) or Place b o f or u p t o 5 2 
wee ks ( 1 2 m o nt hs). Patie nts o n 2 4 0 m g recei ve o ne i njecti o n of 1 2 0 m g e ver y  wee k.
After t o pli ne data fr o m trial 1 2 9 3. 1 0 beca me a vaila ble, a n i n de pe n de nt D M C re vie we d t hese 
t o pli ne data a n d u n bli n de d safety a n d efficac y data of Gr o u p 1 patie nts i n trial 1 2 9 3 - 0 0 1 3. 
T he D M C rec o m me n de d t o c o nti n ue trial 1 2 9 3 - 0 0 1 3 as pla n ne d.  
T he B oe hri n ger I ngel hei m Be nefit Ris k C o m mittee ( B R C) assesse d t he be nefit -ris k of BI 
6 5 5 0 6 4 f or patie nts i n Gr o u p 1 of trial 1 2 9 3 1 3 (res p o n ders fr o m trial 1 2 9 3. 1 0). T he B R C 
t o o k i nt o c o nsi derati o n t he reco m me n dati o n t o c o nti n ue t he trial gi ve n b y  t he D M C a n d 
c o ncl u de d t hat t he be nefit-ris k f or patie nts i n Gr o u p 1 of trial 1 2 9 3 0 0 1 3 is u nc ha n ge d f or 
res p o n ders b ut deci de d t hat i n vesti gat ors s h o ul d be i nf or me d a b o ut t o pli ne data a n d s h o ul d 
recei ve treat me nt inf or mati o n f or t h ose patie nts re mai ni n g i n Gr o u p 1 of trials 1 2 9 3 - 0 0 1 3. 
T he i n vesti gat or a n d t he patie nt s h o ul d t h or o u g hl y disc uss treat me nt o pti o ns a n d t he patie nt’s 
c o nti n ui n g partici pati o n i n 1 2 9 3- 0 0 1 3. F oll o wi n g t his decisi o n, a t otal of 2 9 patie nts ( 2 0 o n 
treat me nt, 9 i n f oll o w-u p) were u n bli n de d. 
As t he maj orit y  of efficac y e n d p oi nts are base d o n la b orat or y para meters (ser u m creati ni ne, 
uri ne pr otei n a n d uri ne creati ni ne) w hic h s h o ul d n ot be i nfl ue nce d b y t he k n o wle d ge of t he 
treat me nt, t he u n bli n de d patie nts will be a nal yz e d. F urt her details o n a nal ys is will be 
pr o vi de d i n t he Trial Statistical A nal y sis Pla n. 
It was pla n ne d t o i nitiate a sec o n d patie nt gr o u p de pe n di n g o n t he fi nal a nal ysis of 1 2 9 3. 1 0, 
h o we ver as t he pri mar y  e n d p oi nt i n trial 1 2 9 3. 1 0 was n ot met, it was deci de d n ot t o pr ocee d 
wit h gr o u p 2. T heref ore, all secti o ns i n t he cli nical trial pr ot oc ol referri n g t o gr o u p 2 were 
delete d.
Base d o n literat ure, patie nts w h o reac he d C R R ha ve a g o o d l o n g ter m pr o g n osis o n re nal 
o utc o me t h us re d uci n g ster oi d d osa ge is a maj or tar get t o re d uce si de effects (R 1 5 -4 2 9 4 ). 
Patie nts wit h pr otei n uria < 0. 8 g/ d will als o ha ve a g o o d l o n g t er m pr o g n osis (R 1 5 - 4 9 2 0); it is 
t heref ore j ustifia ble t o als o start ster oi d ta peri n g i n t hese patie nts. Ta peri n g of ster oi ds ma y 

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 2 3 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
i ncrease t he ris k of re nal flares a n d t his ris k mi g ht e ve n be hi g her i n t h ose patie nts o n 
Place b o. F or ster oi d -relate d si de effects, e xce pt effects o n b o ne, a d ose of 7. 5 m g / d
pre d nis o ne -e q ui vale nt is l o o ke d u p o n as t hres h ol d. F or ster oi d-relate d effects o n b o ne, it is 
ar g ua ble t hat e ve n a d ose < 7. 5 m g/ d will ha ve a n effect if a d mi nistere d f or a l o n g peri o d. 
T heref ore, ster oi ds s h o ul d be ta pere d t o as l o w as p ossi ble a n d i deall y  s h o ul d be st o p pe d.
I n a d diti o n, o nce t he 1 2 9 3. 1 0 trial res ults are a vaila ble, BI 6 5 5 0 6 4 d oses mi g ht p ote ntiall y be 
a dj uste d d urin g 1 2 9 3- 0 0 1 3 trial peri o d a n d treat me nt ar ms mi g ht be m o difie d acc or di n gl y via 
a n a me n d me nt .
T he pri mar y  e n d p oi nt selecte d f or t his trial is t he pr o p orti o n of patie nts wit h C R R after o ne 
ye ar of mai nte na nce treat me nt wit h o ut a n y  re nal flares. T he trial a nal ys is will be e x pl orat or y . 
Patie nts wit h C R R a n d wit h ster oi ds d ose of ≤5 m g/ d pre d nis o ne e q ui vale nt after o ne ye ar of 
mai nte na nce treat me nt will be c o nsi dere d t o ha ve a n o pti mal pr o g n osis as t hese patie nts will 
ha ve hi g her c ha nce f or a g o o d l o n g ter m re nal o utc o me a n d a re d uce d ris k of ster oi d -relate d 
si de effects (R 1 5 -3 1 5 7 ).
3. 3 
S E L E C TI O N O F T RI A L P O P U L A TI O N
T his e xte nsi o n trial is desi g ne d t o offer c o nti n u o us treat me nt t o all eligi ble patie nts r olli n g 
o ver fr o m 1 2 9 3. 1 0 ( Gr o u p 1). 
It is esti mate d t hat a p pr o xi matel y 6 0 patie nts fr o m 1 2 9 3. 1 0 will r oll o ver i nt o t his 
m ulti nati o nal trial .
All sites r olli n g o ver patie nts fr o m partici pat i n g i n t he f or mer trial, 1 2 9 3. 1 0, will be eli gi ble 
t o c o nti n ue t heir partici pati o n i n t his st u d y.
A l o g of all patie nts e nr olle d i nt o t he trial (i.e. w h o ha ve si g ne d i nf or me d c o nse nt) will be 
mai ntai ne d i n t he I S F at t he i n vesti gati o nal site irres pecti ve of w het her t he y  ha ve bee n treate d 
wit h t he i n vesti gati o nal dr u g or n ot.
3. 3. 1 
M ai n di a g n osis f or tri al e ntr y
Patie nts wit h lu p us ne p hritis w h o ha ve ac hie ve d a re nal res p o nse or reac he d a pre-defi ne d 
pr otei n uria le vel ; a n d met all eli gi bilit y criteria ma y q ualif y f or i ncl usi o n i n t he trial.
P lease refer t o secti o n 8. 3. 1 ( S o urce D oc u me nts) f or t he d oc u me ntati o n re q uire me nts 
p ertai ni n g t o t he i n cl usi o n a n d e xcl usi o n criteria.
3. 3. 2  
I ncl usi o n criteri a
1. 
Male or fe male patie nt s.
- W o me n of c hil d beari n g p ote ntial * m ust be rea d y a n d a ble t o use t w o relia ble met h o ds 
of birt h c o ntr ol si m ulta ne o usl y, o ne of w hic h m ust be hi g hl y effecti ve. Hi g hl y effecti ve 
birt h c o ntr ol per I C H M 3( R 2) is a met h o d t hat res ult i n a l o w fail ure rate of less t ha n 1 % 
per year w he n use d c o nsiste ntl y  a n d c orrectl y. T he relia ble met h o ds of birt h c o ntr ol m ust 
be use d bef ore starti n g M M F / A Z A a n d t he trial dr u g; t he n c o nti n ue d uri n g t he trial 

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 2 4 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
peri o d ; a n d f or at least 5 0 da ys after t he last d ose of M M F a n d trial me dicati o n. I n case a 
fe male patie nt is treate d wit h A Z A t he c o ntrace pti o n s hall c o nti n ue f or 9 0 da ys after 
treat me nt wit h A Z A. A list of c o ntrace pti o n met h o ds meeti n g t hese criteria is pr o vi de d i n 
t he patie nt i nf or mati o n.
- Se x uall y  acti ve me n m ust be rea d y t o use c o n d o ms * * d uri n g treat me nt wit h M M F /A Z A
a n d f or at least 9 0 da ys after cessati o n of M M F/A Z A .
* A w o m an is c o nsi dere d of c hil d beari n g p ote ntial , i.e. fertile, f oll o wi n g me narc he a n d u ntil bec o mi n g 
p ost me n o pa usal u nless per ma ne ntl y sterile.
- Per ma ne nt sterili sati o n met h o ds i ncl u de h ysterect o m y, bilateral o o p h orect o m y a n d bilateral 
sal pi n gect o m y.
- T u bal li gati o n is N O T a met h o d of per ma ne nt steri lisati o n.
- A p ost me n o pa usal state is defi ne d as n o me n ses f or 1 2 m o nt hs wit h o ut a n alter nati ve me dical ca use.
* * C o n d o ms are a p plie d f or b ot h re pr o d ucti vel y c o m pete nt a n d vasect o mise d me n, beca use t he ris ks 
ass ociate d wit h t he tra nsfer of se mi nal fl ui d als o a p pl y t o me n w h o ha ve ha d a vasect o m y. I n a d diti o n, 
fe male part ners of male patie nts treate d wit h M M F are rec o m me n de d t o use hi g hl y effecti ve 
c o ntrace pti o n d uri n g treat me nt a n d f or a t otal of 9 0 da ys after t he last d ose of M M F.
Defi niti o n of hi g hl y effecti ve c o ntrace pti ves:
• 
T he use of h or m o nal met h o ds of c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n 
(eit her c o m bi ne d oestr o ge n a n d pr o gest o ge n c o ntai ni n g h or m o nal c o ntrace pti o n, or 
pr o gest o ge n - o nly h or m o nal c o ntrace pti o n)
•  
Place me nt of i ntra uteri ne de vice (I U D) or i ntra uteri ne h or m o ne-releasi n g s yste m
(I U S)
• 
Bilateral t u bal occl usi o n
• 
Vasect o mise d se x ual part ner 
• 
C o m plete se x ual a bsti ne nce 
Se x ual a bsti ne nce is c o nsi dere d a hi g hl y effecti ve met h o d o nl y  if defi ne d as refrai ni n g fr o m 
heter ose x ual i nterc o urse d uri n g t he e ntire peri o d of ris k ass ociate d wit h t he st u d y  treat me nts. 
T he relia bilit y  of se x ual a bsti ne nce nee ds t o be e val uate d i n relati o n t o t he d urati o n of t he 
cli nical trial a n d t he preferre d a n d us ual lifest yl e of t he s u bject.
2. 
Si g ne d a n d date d writte n i nf or me d c o nse nt i n acc or da nce wit h I CH- G C P a n d l ocal 
le gislati o n pri or t o a d missi o n t o t he trial.
F or Gr o u p 1 patie nts o nl y:
3. 
Ac hie ve d eit her a C R R or a P R R or pr otei n uria ≤ 1 g/ d ( or U P/ U C ≤ 1) at t he e n d of 
1 2 9 3. 1 0.
3. 3. 3 
E xcl usi o n criteri a
1. 
E vi de nce of c urre nt or pre vi o us cli nicall y  si g nifica nt diseases or me dical c o n diti o ns 
ot her t ha n l u p us, or fi n di n g s of t he me dical e xa mi nati o n (i ncl u di n g vital si g ns a n d E C G) 
t hat, i n t he o pi ni o n of t he i n vesti gat or, w o ul d c o m pr o mise t he safety of t he patie nt or t he 
q ualit y  of t he data. T his criteri o n pr o vi des a n o p p ort u nit y f or t he i n vesti gat or t o e xcl u de 
patie nts base d o n cli nical j u d g me nt, e ve n if ot her eli gi bilit y  criteria are satisfie d.
2. 
Si g nifica nt ce ntral ner v o us s y ste m sy m pt o ms relate d t o S L E base d o n i n vesti gat ors 
assess me nt.

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 2 5 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
3. 
Cli nicall y  i m p orta nt ac ute or c hr o nic i nfecti o ns i ncl u di n g b ut n ot li mite d t o HI V, 
he patitis B or C.
4. 
I m paire d he patic f u ncti o n defi ne d as ser u m A S T/ A LT, bilir u bi n or al kali ne p h os p hatase 
> 2 x U L N.
5. 
Esti mate d gl o mer ular filtrati o n rate (e G F R) < 3 0 ml/ mi n/ 1. 7 3 m 2 at scree ni n g ( usi n g 
C K D -E PI  f or m ula).
6. 
K n o w n h y perse nsiti vit y  t o a n y c o nstit ue nts of t he trial me dicati o n; a n d/ or
c o ntrai n dicati o ns t o M M F or A Z A or gl uc oc ortic oi ds.
7. 
T he use of a n y restricte d me dicati o ns (see secti o n 4. 2.3. 1 ) or a ny dr u g c o nsi dere d li kel y 
t o i nterfere wit h t he safe c o n d uct of t he trial.
8. 
U na ble t o c o m pl y wit h t he pr ot oc ol i n t he i n vesti gat or’s o pi ni o n.
9. 
C hr o nic alc o h ol or dr u g a b use or a n y c o n diti o n t hat, i n t he i n vesti gat or’s o pi ni o n , ma kes
t he m a n u nrelia ble trial patie nt or u nli kel y  t o c o m plete t he trial.
1 0.
W o me n w h o are pre g na nt, n ursi n g, or w h o pla n t o bec o me pre g na nt w hile i n t he trial.
3. 3. 4 
Wit h dr a w al
of p atie nt s fr o m t her a p y or assess me nts
Patie nts ma y p ote ntiall y be wit h dra w n fr o m trial treat me nt or fr o m t he trial as a w h ole
(“ wit h dra wal of c o nse nt”) wit h ver y  differe nt i m plicati o ns, please see secti o ns 3. 3. 4. 1 a n d 
3. 3. 4. 2 bel o w.
E ver y  eff ort s h o ul d be ma de t o kee p patie nts i n t he trial if p ossi ble, o n treat me nt or at least t o 
c ollect i m p orta nt trial data. Meas ures t o c o ntr ol t he wit h dra wal rate i ncl u de c aref ul patie nt
selecti o n, a p pr o priate e x pla nati o n of t he trial re q uire me nts as well as t he e x pla natio n of t he 
safety f oll o w u p after a p ote ntial wit h dra wal.
It s h o ul d be a v oi de d t hat wit h dra w n patie nts w o ul d bec o me l ost t o f oll o w u p, t heref ore safety 
visits or at least p h o ne calls s hall be c o n d ucte d u ntil 5 2 wee ks after st u d y start ( V 1 f or gr o u p 1 
a n d V 2 f or gr o u p 2). See als o 6. 2. 3. 3.
3. 3. 4. 1 
Wit h dra wal fr o m trial treat me nt
A n i n di vi d ual patie nt is t o be wit h dra w n fr o m trial treat me nt if:

T he patie nt wa nts t o wit h dra w fr o m trial treat me nt, wit h o ut t he nee d t o j ustif y t he 
decisi o n.

T he patie nt nee ds t o ta ke c o nc o mita nt dr u gs t hat i nterfere with t he i n vesti gati o nal pr o d uct 
or ot her trial me dicati o n (see secti o n 4. 2).

T he patie nt ca n n o l o n ger be treate d wit h trial me dicati o n f or ot her me dical reas o ns (s uc h 
as s ur ger y, a d verse e ve nts, ot her diseases, or pre g na nc y).

T he patie nt has re peate dl y s h o w n t o be n o n-c o m plia nt wit h i m p orta nt trial pr oce d ures 
a n d, i n t he o pi ni o n of b ot h, t he i n vesti gat or a n d s p o ns or re prese ntati ve , is n ot willi n g or 
a ble t o a d here t o t he trial re q uire me nts i n t he f ut ure.

T he patie nt de vel o ps a n a na p h y lactic reacti o n (see secti o n 4. 2.2 ).

In case of w orse ni n g or flare, if dee me d a p pr o priate b y  t he i n vesti gat or, t he patie nt will 
be disc o nti n ue d fr o m t he trial treat me nt t o recei ve resc ue t hera py as per t he a vaila ble 
g ui deli nes f or t he treat me nt of L N .

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 2 6 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6

T he patie nt e x perie nces a n i nfecti o n wit h S A R S- C o V -2 (as c o nfir me d b y l ocal P C R test). 
T he patie nt ma y  res u me trial treat me nt f oll o wi n g rec o ver y fr o m S A R S-C o V -2 i nfecti o n if 
a ne gati ve test f or S A R S- C o V 2 was ta ke n a n d t he patie nt is e x pecte d t o deri ve cli nical 
be nefit, as a gree d bet wee n t he i n vesti gat or a n d s p o ns or.
Please n ote t hat wit h dra wal fr o m trial treat me nt s h o ul d n ot necessaril y lea d t o wit h dra wal 
fr o m t he st u d y. Gi ve n t he patie nt ’s a gree me nt, t he patie nt will u n der g o t he pr oce d ures f or 
earl y treat me nt disc o nti n uati o n a n d f oll o w u p as o utli ne d i n t he Fl o w C hart s a n d secti o n 
6. 2. 3 .
F or all patie nt s, t he decisi o n t o wit h dra w fr o m trial treat me nt (e. g. a d verse e ve nts) or fr o m 
t he w h ole trial as well as t he reas o n m ust be d oc u me nte d i n t he patie nt files a n d rec or de d i n 
t he eC R F . T hese data will be i ncl u de d i n t he trial data base a n d re p orte d.
3. 3. 4. 2   
W it h dra wal of c o nse nt f or trial partici pati o n
P atie nts ma y  wit h dra w t heir c o nse nt f or trial partici pati o n at a n y ti me wit h o ut t he nee d t o 
j ustif y t he decisi o n. T his will h o we ver mea n t hat n o f urt her i nf or mati o n ma y be c ollecte d f or 
t he p ur p ose of t he trial a n d ne gati ve i m plicati o ns f or t he scie ntific val ue m a y be t he 
c o nse q ue nce. F urt her m ore, it ma y mea n t hat f urt her patie nt f oll o w- u p o n safet y ca n n ot occ ur.
If a patie nt wa nts t o wit h dra w c o nse nt, t he i n vesti gat or s h o ul d e x plai n t he differe nce bet wee n 
treat me nt wit h dra wal a n d wit h dra wal of c o nse nt t o trial partici pati o n a n d e x plai n t he o pti o ns 
f or c o nti n ue d f oll o w u p after wit h dra wal fr o m trial treat me nt, please see secti o n 3. 3. 4. 1
a b o ve.
3. 3. 4. 3 
Disc o nti n uati o n of t he trial b y  t he sp o ns or
B oe hri n ger I n gel hei m reser ves t he ri g ht t o disc o nti n ue t he trial o verall or at a partic ular trial
site at a n y ti me f or t he f oll o wi n g reas o ns:
1.
Fail ure t o meet e x pecte d e nr ol me nt g oals o veral l or at a partic ular trial site.
2.
E mer ge nce of a n y efficac y/safety i nf or mati o n i n vali dati n g t he earlier p ositi ve be nefit-ris k
assess me nt t hat c o ul d si g nifica ntl y affect t he c o nti n uati o n of t he trial.
3.
Vi olati o n of G C P, t he trial pr ot oc ol, or t he c o ntract i m pairi n g t he ap pr o priate c o n d uct of 
t he trial.
4.
T he s p o ns or deci des t o disc o nti n ue f urt her de vel o p me nt of BI 6 5 5 0 6 4.
T he i n vesti gat or / t he trial site will be rei m b urse d f or reas o na ble e x pe nses i nc urre d i n case of 
trial ter mi nati o n (e xce pt i n case of t he t hir d reas o n).

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 2 7 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
4. 
T R E A T M E N T S
4. 1  
I N V E S TI G A TI O N A L T R E A T M E N T S
T he trial me dicat i o n will be pr o vi de d by B oe hri n ger I n gel hei m P har ma G m b H & C o K G, 
Bi berac h, Ger ma n y.
4. 1. 1 
I de ntit y of t he I n vesti g ati o n al Me dici n al Pr o d ucts
Details of t he trial me dicati o n are pr o vi de d bel o w.
Ta ble 4. 1. 1: 1
I n vesti gati o nal Me dici nal Pr o d uct 1
S u bsta nce:
BI 6 5 5 0 6 4
P har mace utical f or m ulati o n:
S ol uti o n f or i njecti o n
S o urce:
B oe hri n ger I n gel hei m P har ma G m b H & C o. K G 
U nit stre n gt h:
1 2 0 m g/ pre -fille d syri n ge a n d 1 8 0 m g/ pre -fille d syri n ge
P os ol o g y
Gr o u p 1 patie nts: 1 i njecti o n per wee k .
R o ute of a d mi nistrati o n: 
s.c. 
Ta ble 4. 1. 1: 2
I n vesti gati o nal Me dici nal Pr o d uct 2
S u bsta nce:
Place b o
P har mace utical f or m ulati o n:
S ol uti o n f or i njecti o n
S o urce:
B oe hri n ger -I ngel hei m P har ma G m b H & C o. K G 
U nit stre n gt h:
Place b o t o matc h 1 2 0 m g BI 6 5 5 0 6 4
Place b o t o matc h 1 8 0 m g BI 6 5 5 0 6 4
P os ol o g y :
Gr o u p 1 patie nts: 1 i njecti o n per wee k.
R o ute of a d mi nistrati o n: 
s.c. 
4. 1. 2  
Selecti o n of d oses i n t he tri al
T he differe nt d oses of BI 6 5 5 0 6 4 use d i n t he i n d ucti o n trial, 1 2 9 3. 1 0, were selecte d 
b ase d o n t he res ults of precli nical st u dies , t he 1 2 9 3. 1 Ca ucasia n S R D st u d y, 1 2 9 3. 8 
Asia n S R D st u d y a n d 1 2 9 3. 2 M R D st u d y as well as t he res ults fr o m m o delli n g of 
e x p os ure i n c hr o nic treat me nt of L N . Treat me nt wit h BI 6 5 5 0 6 4 has bee n well t olerate d 
wit h n o d os e-de pe n de nt safet y c o ncer ns i de ntifie d s o far (see s e cti o n 1. 3). Refer t o t he 
In vesti gat or’s Br oc h ure (U 1 1 - 1 9 2 5) a n d secti o n 4. 1. 3 bel o w f or f urt her i nf or mati o n o n 
d osi n g i n 1 2 9 3 - 0 01 3 trial .

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 2 8 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
4. 1. 3 
Met h o d of assi g ni n g p atie nt s t o tre at me nt gr o u ps
Gr o u p 1 patie nts w ill c o nti n ue t o recei ve t he sa me treat me nt all ocati o n as pre vi o usl y  assi g ne d
i n t he 1 2 9 3. 1 0 trial (i.e., eit her 1 2 0 m g or 18 0 m g or 2 4 0 m g or Place b o) at Visit 1.
T he assi g n me nt will occ ur i n a bli n de d fas hi o n via I nteracti ve Res p o nse Tec h n ol o g y (I R T).
Details re gar di n g t he use of I R T are descri be d i n t he site I R T user ma n ual a vaila ble i n t he 
I SF.
4. 1. 4 
Dr u g assi g n me nt a n d a d mi nistr ati o n of d oses f or e ac h p atie nt
Eac h pre -fille d syri n ge of trial me dicati o n will be la b elle d wit h t he trial c o de a n d a u ni q ue 
me dicati o n i de ntificati o n n u m ber. At eac h a p plica ble visit w here trial me dicati o n is t o be 
prescri be d, t he trial sites will be re q uire d t o c o m plete t he me dicati o n (re)s u p ply m o d ule i n 
I R T. The I R T will t he n a de q uately assi g n e n o u g h me dicati o n kits f or t he wee kl y s.c 
i njecti o ns a d mi nistere d b y t he patie nt at h o me u ntil t he ne xt o nsite visit .
BI 6 5 5 0 6 4 / Place b o will be pr o vi de d i n sterile, preser vati v e-free, n o n-p y r o ge nic, si n gle-
use pre- fille d glass syr in ge s f or s u bc uta ne o us i njecti o n. A n y u n use d pr o d uct or waste 
material will be dis p ose d of i n acc or da nce wit h l ocal re q uire me nts.
T he first d ose of trial me dicati o n will be a d mi nistere d at t he trial site f or all eli gi ble 
patie nts b y t he i n vesti gat or ( or a s uita bly q ualifie d desi g nee).
All s u bse q ue nt d oses s hall be d o ne b y  self-i njecti o n at t he patie nt’s h o me.
F or gr o u p 1 patie nts is it acce pta ble t o d o t he first st u d y dr u g a d mi nistrati o n at h o me, as it 
is n ot c o nsi dere d t o be a safet y or c o m plia nce iss ue beca use t hese patie nts ha ve i njecte d 
t he msel ves i n t he pre vi o us trial f or o ne year alrea d y
After pr o per trai ni n g o n t he a d mi nistrati o n tec h ni q ue f or self-i njecti o n a n d if t he 
i n vesti gat or deter mi nes t hat it is a p pr o priate wit h me dical f oll ow- u p as necessar y, t he 
patie nts will be i nstr ucte d t o self-i nject t he trial me dicati o n at h o me i n bet wee n o nsite 
visits o n t he sa me d a y of eac h wee k ( +/- 1 d a y ). F urt her i nf or mati o n o n sel f-i njecti o n 
tec h ni q ue a n d i nstr ucti o ns f or use will be a vaila ble i n t he IS F f or pr o vi di n g t o patie nts.
In case of misse d d ose, t he patie nt s h o ul d i m me diatel y  c o ntact t he st u d y i n vesti gat or f or 
g ui da nce o n f urt h er d osi n g.
Ta ble 4. 1. 4: 1
D osa ge a n d treat me nt s c he d ule f or patie nts i n Gr o u ps 1 a n d 2
Patie nt 
Gr o u p
Treat me nt ar m & 
D ose re gi me n
BI 6 5 5 0 6 4 1 2 0 m g 
BI 6 5 5 0 6 4 1 8 0 m g  
BI 6 5 5 0 6 4 2 4 0 m g 
Place b o
Gr o u p 1 
Baseli ne t o E O T 
1 2 0 m g q 2 w
1 8 0 m g q 2 w
1 2 0 m g q 1 w 
  Pl ace b o
S y ri n ges t o be 
a d mi nistere d 
wee k l y
1 x 1 2 0 m g BI 6 5 5 0 6 4 
s yri n ge alter nati n g wit h 1
x Place b o s yri n ge 
1 x 1 8 0 m g BI 6 5 5 0 6 4
s yri n ge alter nati n g wit h 1
x Place b o s yri n ge
1 x 1 2 0 m g BI 
6 5 5 0 6 4 s yri n ge
1 x Place b o
s yri n ge

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 2 9 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
D ose m o dificati o n is n ot per mitte d d uri n g t he treat me nt peri o d . I n a d diti o n, dil uti o n of t he 
trial me dicati o n or t he use of ot her syri n ges or ot her nee dles t ha n t h ose s pecifically pr o vi de d 
b y  t he s p o ns or is pr o hi bite d .
Gr o u p 1 patie nts o nl y : I n case a patie nt ca n n ot be r olle d o ver ( o nly f or a d mi nistrati ve iss ues) 
wit hi n t he ti mefra me defi ne d i n secti o n 6. 2. 1, b ut f or et hical reas o ns t he patie nt s hall still be 
gi ve n t he c ha nce t o c o nti n ue i nt o 1 2 9 3 -0 0 1 3, a p pr o val m ust be o btai n fr o m C T L/ T M M. It 
will be deci de d o n a case b y case basis h o w t o o verc o me t he pr ol o n ge d treat me nt i nterr u pti o n 
bet wee n t he trials, w hic h ma y  i ncl u de c ha n gi n g t he or der i n w hic h t he i nitial i njecti o ns are 
gi ve n t o t he patie nt or w hic h ma y  i ncl u de a d di n g a l oa di n g d ose at t he be gi n ni n g of t he trial.
  
D uri n g t he C O VI D -1 9 pa n de mic, p h y sical visits t o t he sites ma y nee d t o be restricte d t o 
e ns ure patie nt safet y. Base d o n a t h or o u g h assess me nt of t he be nefits a n d ris ks, t he 
i n vesti gat or ma y still deci de t o c o nti n ue t he trial treat me nt a n d trial me dicati o n ma y be 
s hi p pe d t o t he patie nt’s h o me if acce pta ble acc or di n g t o l ocal la w a n d re g ulati o ns (f or m ore 
details see secti o n 6. 2. 2).
4. 1. 5 
Bli n di n g a n d pr oce d ures f or u n bli n di n g
4. 1. 5. 1  
Bli n di n g
I n t his d o u ble -bli n d trial, all patie nts, i n vesti gat ors a n d s p o ns or staff ( e xce pt t h ose BI 
me m bers i n de pe n de nt of t he trial tea m t hat will perf or m t he pri mar y  a nal ys is) will re mai n 
bli n de d wit h re gar d t o t he ra n d o mi se d treat me nt assi g n me nts.
After t he fi nal a nal ys is of t he precee di n g trial 1 2 9 3. 1 0 it was re veale d t hat t he pri mar y 
e n d p oi nt was n ot reac he d. A n i n de pe n de nt D M C re vie we d t he t o pli ne res ults of 1 2 9 3. 1 0 a n d 
u n bli n de d efficac y  a n d safety res ults of t he o n g oi n g Gr o u p 1 i n trial 1 2 9 3 -0 0 1 3 a n d 
rec o m me n de d t o c o nti n ue trial 1 2 9 3. 0 0 1 3. Ta ki n g t his rec o m me n dati o n i nt o c o nsi derati o n, a 
Be nefit Ris k C o m mittee c o ncl u de d t hat t he be nefit-ris k f or patie nts i n Gr o u p 1 of trial 1 2 9 3-
0 0 1 3 is u nc ha n ge d b ut deci de d t hat treat me nt of patie nts re mai ni n g i n t he trial s h o ul d be 
u n bli n de d. 
T he u n bli n di n g ste p was ta ke n o n 2 0 Oct 2 0 2 0 a n d c o m m u nicate d t o t he a p plica ble 
i n vesti gat ors. All ot her patie nts w h o ha d alrea dy c o m plete d or earl y disc o nti n ue d t he trial at 
t hat ti me p oi nt a n d were n o l o n ger i n f oll o w u p re mai n bli n de d.
F or t he re mai ni n g patie nts w h o were n ot u n bli n de d,  a li mite d n u m ber of s p o ns or pers o n nel 
will ha ve t he p ote ntial t o be u n bli n de d a li mite d n u m ber of s p o ns or pers o n ne l will ha ve t he 
p ote ntial t o be u n bli n de d; h o we ver, s p o ns or pers o n nel i n v ol ve d i n t he c o n d uct of 1 2 9 3- 0 0 1 3 
(e. g.trial m o nit or a n d l ocal m o nit ors) will re mai n bli n de d u ntil c o m pleti o n of 1 2 9 3- 0 0 1 3. 
T hese i n vesti gat ors a n d patie nts will als o re mai n bli n de d u ntil c o m pleti o n of t he trial.
F or Gr o u p 1 I RT will use d i n 1 2 9 3. 1 0 f or t he assi g n me nt of patie nts t o treat me nt gr o u ps a n d 
t he ra n d o misati o n se q ue nce ge nerate d usi n g vali date d s oft ware a n d verifie d b y  a n 
i n de pe n de nt BI statisticia n w h o is was n ot i n v ol ve d i n t he pla n ni n g or perf or ma nce of t he 
trial. T he ra n d o misati o n c o de will be ke pt c o nfi de ntial b y  Cli nical Trial S u p p ort u p t o D B L .
F or Gr o u p 1.

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 3 0 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
T he ra n d o mi sati o n c o des will be pr o vi de d t o bi oa nal y tics pri or t o last patie nt o ut t o all o w f or 
t he e xcl usi o n fr o m t he a nal yses of p har mac o ki netic ( P K) sa m ples ta ke n fr o m place b o 
patie nts. Bi oa nal yt ics will n ot discl ose t he ra n d o misati o n c o de or t he res ults of t heir 
meas ure me nts u ntil t he trial is officiall y  u n bli n de d.
4. 1. 5. 2 
U n bli n di n g a n d brea ki n g t he c o de
E mer ge nc y  u nbli n di n g will be a vaila ble t o t he i n vesti gat or via I R T . It m ust o nl y be use d i n
a n e mer ge nc y sit uati o n w he n t he i de ntit y of t he trial dr u g m ust be k n o w n t o t he i n vesti gat or
i n or der t o pr o vi de a p pr o priate me dical treat me nt or ot her wise t o ass ure t he safety of trial
partici pa nts . T he reas o n f or u n bli n di n g m ust be d oc u me nte d i n t he s o urce d oc u me nts a n d/or 
o n a p pr o priate e C R F pa ge al o n g wit h t he date a n d t he i nitials of t he pers o n w h o br o ke t he 
c o de; a n d t he S p o ns or m ust be i nf or me d i m me diatel y .
D ue t o t he re q uire me nts t o re p ort S us pecte d U ne x pecte d Seri o us A d verse Reacti o ns 
( S U S A Rs), it ma y be necessar y f or a re prese ntati ve fr o m BI ’s P har mac o vi gila nce gr o u p t o 
access t he ra n d o misati o n c o de f or i n di vi d ual patie nt s d uri n g trial c o n d uct. T he access t o t he 
c o de will o nl y be gi ve n t o a ut h orise d P har mac o vi gila nce re prese ntati ves a n d n ot be s hare d 
f urt her.
4. 1. 6 
P ac k a gi n g, l a belli n g, a n d re-s u p pl y
BI 6 5 5 0 6 4 a n d Place b o s u p plies will be pr o vi de d b y  BI or a desi g nate d C R O. Eac h prefille d 
s yri n ge of trial me dicat i o n will be pac ka ge d i n i n di vi d ual cart o n a n d la belle d i n acc or da nce 
wit h t he pri nci ples of G o o d Ma n ufact uri n g Practice. Refer t o t he I SF f or details of pac ka gi n g 
a n d descri pti o n of t he la bel .
Re -s u p pl y t o t he sites will be ma na ge d via a n I R T s yste m, w hic h will als o m o nit or e x pir y  
dates of trial me dicati o n s u p plies a vaila ble at t he sites.
4. 1. 7 
St or a ge c o n diti o ns
Eac h prefille d s yri n ge will be ke pt i n its ori gi nal pac ka gi n g u ntil a d mi nistrati o n i n or der t o 
pr otect fr o m li g ht a n d st ore d acc or di n g t o t he rec o m me n de d st ora ge c o n diti o ns o n t he 
me dica ti o n la bel at 2-8° C ( 3 6 - 4 6oF). It ca n n ot be fr oze n. A te m perat ure l o g m ust be 
mai ntai ne d f or d oc u me ntati o n.
If t he st ora ge c o n diti o ns are f o u n d t o be o utsi de t he s pecifie d ran ge, t he l ocal cli nical m o nit or 
m ust be c o ntacte d i m me diatel y . F or te m perat ure de viati o ns d uri n g s hi p pi n g t o sites a n d 
de p ots, refer t o t he I S F f or i nstr ucti o ns.
4. 1. 8 
Dr u g acc o u nt a bilit y
T he i n vesti gat or, phar macist , or i n vesti gati o nal dr u g st ora ge ma na ger will recei ve t he 
i n vesti gati o nal dr u gs deli vere d by t he s p o ns or w he n t he f oll o wi n g re q uire me nts are f ulfille d:

A p pr o val of t he cli nical trial pr ot oc o l b y t he I R B / et hics c o m mittee,

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 3 1 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6

A vaila bilit y  of a si g ne d a n d date d cli nical trial c o ntract bet wee n t he s p o ns or a n d t he 
i n vesti gati o nal site,

A p pr o val/ n otificati o n of t he re g ulat or y  a ut h orit y, e. g. c o m pete nt a ut h ority,

A vaila bilit y  of t he c urric ul u m vitae of t he Pri nci pal I nvesti gat or ,

A vaila bilit y  of a si g ne d a n d date d cli nical trial pr ot oc ol ,

A vaila bilit y  of t he pr o of of a me dical lice nse f or t he P ri nci pal I n vesti gat or if a p plica ble,

A vaila bilit y  of F D A F or m 1 5 7 2 (f or U S A o nly).
I n vesti gati o nal dr u gs are n ot all o we d t o be use d o utsi de t he c o nte xt of t his pr ot oc ol. T he y  
m ust n ot be f or war de d t o ot her i n vesti gat ors or cli nics. Patie nts s h o ul d be i nstr ucte d t o ret ur n 
u n use d i n vesti gati o nal dr u g.
T he i n vesti gat or, p har macist , or i n vesti gati o nal dr u g st ora ge ma na ger m ust mai ntai n rec or ds 
of t he pr o d uct’s deli ver y  t o t he trial site, t he i n ve nt or y at t he site, t he use by eac h patie nt , a n d 
t he ret ur n t o t he s p o ns or or ware h o use / dr u g distri b uti o n ce ntre or alter nati ve dis p os al of 
u n use d pr o d ucts. If a p plica ble, t he s p o ns or or ware h o use / dr u g distri b uti o n ce ntre will 
mai ntai n rec or ds of t he dis p osal.
T hese rec or ds will i ncl u de dates, q ua ntities, batc h / serial n u m bers, e x pir y (‘ use- b y ’) dates, 
a n d t he u ni q ue c o de n u m bers assi g ne d t o t he i n vesti gati o nal pr o d uct a n d trial patie nt s. T he 
i n vesti gat or / phar macist / i n vesti gati o nal dr u g st ora ge ma na ger wi ll mai ntai n rec or ds 
d oc u me nt a de q uatel y t hat t he patie nt s were pr o vi de d t he d oses s pecifie d by t he pr ot oc ol a n d 
rec o ncile all i n vesti gati o nal pr o d ucts recei ve d fr o m t he s p o ns or. At t he ti me of ret ur n t o t he 
s p o ns or or a p p oi nte d C R O, t he i n vesti gat or / p har macist / i n vesti gati o nal dr u g st ora ge 
ma na ger m ust verif y  t hat all u n use d or partially use d dr u g s u p plies ha ve bee n ret ur ne d b y t he 
cli nical trial patie nt a n d t hat n o re mai ni n g s u p plies are i n t he i n vesti gat or’s p ossessi o n.
4. 2   
O T H E R T R E A T M E N T S , E M E R G E N C Y P R O C E D U R E S , 
R E S T RI C TI O N S
4. 2. 1 
Ot her tre at me nts a n d e mer ge nc y pr oce d ures
Sta n dar d of care ( S O C) treat me nt
All patie nts will c o nti n ue t o recei ve S O C treat me nt f or L N of eit her M M F or A Z A i n 
c o m bi nati o n wit h gl uc oc ortic oi ds (if n ot ta pere d d o w n t o 0 m g).
It is accepta ble t o s witc h a patie nt fr o m m yc o p he n olate m ofetil t o m y c o p he n olate s o di u m as 
l o n g as t he d ose is d oc u me nte d as t o m yc o p he n olate m ofetil e q ui vale nt i n t he C R F. F or 
si m plicit y reas o ns t he e ntire pr ot oc ol refers t o M M F o nl y.
T he S O C treat me nt ( M M F a n d/ or A Z A) will be pr oc ure d l ocall y  a n d prescri be d at t he trial 
site b y t he i n vesti gat or. T he s p o ns or will rei m b urse t he c osts f or S O C treat me nt d uri n g t he 
trial peri o d i n acc or da nce wit h l ocal re g ulati o ns.

M M F a n d A Z A will be c o nsi dere d a u xiliar y me dici nal pr o d uct ( A M P) i n t his trial. M M F:
a sta ble d ose of 1 t o 2 g/ d . It is rec o m me n de d n ot t o i ncrease M M F a b o ve 2 g/ d t o re d uce 
t he ris k of M M F relate d
se vere si de effects. I n case of si de effects, M M F d ose ma y be 
re d uce d t o 1 g/ d; or i n case of i nt olera nce, s witc h t o A Z A at 2 m g/ k g/ da y .

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 3 2 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
- 
Patie nts de viati n g fr o m t he a b o ve me nti o ne d d ose ra n ges s hall be pre-a p pr o ve d b y 
t he C T L/ T M M w het her t he y ca n be e nr olle d i n t he trial or n ot. 
-
Patie nts o n less t ha n 1 g/ d M M F bef ore e nteri n g t he trial ma y  be eli gi ble, if it is 
d oc u me nte d t hat t he patie nt di d n ot t olerate hi g her d oses.
-
Patie nts o n m ore t ha n 2 g/ d M M F bef ore e nteri n g t he trial ma y  be eli gi ble o nl y if 
t he patie nt di d n ot s uffer fr o m a ny si de effects c o nsi dere d p ossi bl y relate d t o 
M M F i n t he past.

A Z A: 2 m g/ k g/ da y . I n case of i nt olera nce or t he b o d y  wei g ht < 5 0 k g, d ose ma y be re d uce d 
t o 1 m g/ k g/ da y  or t he d osa ge s h o ul d be r o u n de d t o t he nearest 5 0 m g. I n re gi o ns w here 
o nl y  a fi xe d si n gle d osa ge is a vaila ble o n t he mar ket, t he r o u n di n g s h o ul d be d o ne 
acc or di n g t o t he i n ves ti gat ors j u d g me nt, n ot e xcee di n g 2 m g/ k g/ da y. 

Gl uc oc ortic oi ds: At Visit 1 rec o m me n de d ≤1 0 m g/ d pre d nis o ne -e q ui vale nt f or gr o u p 1 
patie nts ( de pe n di n g o n act ual d ose at t he e n d of 1 2 9 3. 1 0) . The ta peri n g of ster oi ds s h o ul d 
be perf or me d as f oll o ws:

Gr o u p 1:
-
Pa tie nts wit h a C R R or pr otei n uria of < 0. 8 g/ d at t he e n d of 1 2 9 3. 1 0 s h o ul d start 
ster oi d ta peri n g i m me diatel y at Visit 1. If necessar y, patie nts ma y re mai n o n a certai n 
le vel of ster oi ds d ue t o ot her sy m pt o ms of S L E base d o n i n vesti gat or’s j u d ge me nt.
Alt h o u g h t he ta peri n g sc he d ule will all o w s o me fle xi bilit y , h o we ver ster oi ds s h o ul d 
be st o p pe d at 3 m o nt hs ( Wee k 1 2) after r oll o ver. If t his is n ot p ossi ble d ue t o t he 
patie nt’s me dical c o n diti o n, t he patie nt ca n sta y o n t he l o west p ossi ble d ose wit h t he
best be nefit . 
-
Patie nts wit h pr otei n uria of ≥0. 8 g/ d at t he e n d of 1 2 9 3. 1 0 s h o ul d ta per ster oi ds d o w n 
t o ≤7. 5 m g/ d at wee k 2 6 a n d t he n t o ≤5 m g/ d at wee k 5 2.
I n case of w orse ni n g or re nal flare occ urs at a n y ti me p oi nt , patie nts will be all o we d 
treatme nt wit h hi g her d ose of ster oi ds; alter nati vel y, t he i n vesti gat or ma y all o w patie nts t o 
recei ve resc ue t hera py i n acc or di n g t o t he a vaila ble g ui deli nes f or L N treat me nt. F or t he
st u d y a nal ys is, t hese patie nts will be c o nsi dere d treat me nt fail ures.
H o we ver, i n a n y case, de viati n g fr o m t he ta peri n g sc he me d ue t o me dical reas o ns will n ot 
e xcl u de t he patie nt fr o m t he trial.
A dj u ncti ve treat me nts
All patie nts s h o ul d c o nti n ue ta ki n g a dj u ncti ve treat me nts if starte d bef ore scree ni n g s uc h as:
 
H y dr o x y c hl or o q ui ne at 2 0 0 – 4 0 0 m g/ da y  or ot her a nti-malarial (s uc h as c hl or o q ui ne).
 
A n gi ote nsi n -c o n verti n g e nz yme i n hi bit or or a n gi ote nsi n rece pt or bl oc ker ,
 
Ss tati ns.
It is rec o m me n de d t hat patie nts t o re mai n o n sta ble d oses f or t hese treat me nts d uri n g t he 
d urati o n of t he st u d y .
T here are n o s pecial e mer ge nc y  pr oce d ures t o be f oll o we d.

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 3 3 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
4. 2. 2   
M a n a ge me nt of A d verse E ve nts
I n case of e mer ge nc y s ur ger y or if patie nt de vel o ps a seri o us i nfecti o n , o p p ort u nistic or 
m y c o bacteri u m t u berc ul osis i nfecti o ns treat me nt of t he i nfecti o n s h o ul d be i nitiate d pr o m ptl y 
acc or di n g t o l ocal sta n dar d of care , d uri n g t he treat me nt peri o d, treat me nt wit h BI 6 5 5 0 6 4 
a n d S O C will be te m p oraril y i nterr u pte d a n d t o be restarte d o nce t he patie nt has rec o vere d as 
per t he i n vesti gat or’s j u d ge me nt. I n a d diti o n, patie nts w h o de vel o p rec urre nt i nfecti o ns 
s h o ul d ha ve t heir ser u m I g M a n d I g G meas ure d acc or di n g t o i n vesti gat or’s assess me nt .
I n case patie nt de vel o ps a t hr o m b osis s us pecte d t o be relate d t o i m m u n os u p pressi o n d uri n g 
t he treat me nt peri o d , treat me nt wit h BI 6 5 50 6 4 a n d S O C will be te m p oraril y i nterr u pte d a n d
a nti-t hr o m b otic t hera py will be starte d. Treat me nt wit h BI 6 5 5 0 6 4 a n d/ or S O C ma y  be
restarte d o nce t he patie nt has rec o vere d acc or di n g t o i n vesti gat or’s assess me nt.
I n case of s us pecte d he patic i nj ur y (as defi ne d i n secti o n 5. 2. 5. 1) d uri n g t he treat me nt peri o d , 
treat me nt wit h BI 6 5 5 0 6 4 has t o be st o p pe d. If t he f oll o w– u p i de ntifies a c o nf o u n der (e. g. 
hi g h d ose of paraceta m ol) a n d t he li ver f u ncti o n has rec o vere d, treat me nt wit h BI 6 5 5 0 6 4 
ma y  be restarte d acc or di n g t o t he i n vesti gat or’s assess me nt after disc ussi o n wit h t he s p o ns or.
I n case of se vere i njecti o n reacti o ns, a na p h ylactic reacti o ns, c yt o ki ne release s yn dr o me , or 
occ urre nce of l y m p h o pr oliferati ve diseases , treat me nt wit h BI 6 5 5 0 6 4 a n d S O C will be
per ma ne ntl y disc o nti n ue d a n d m ust n ot be re-i ntr o d uce d.
F or si de effects k n o w n t o be relate d t o hi g her d oses of M M F or A Z A , d ose re d ucti o n of
M M F or A Z A s h o ul d be c o nsi dere d a n d ha n dle d as per t he i n vesti gat or’s j u d ge me nt.
Mali g na ncies
I n case of occ urre nce of mali g na nt ne o plas m ot her t ha n a p pr o priately treate d basal cell 
carci n o ma or s q ua m o us cell carci n o ma of t he s ki n or i n sit u carci n o ma of uteri ne cer vi x, t he 
i n vesti gat or s h o ul d disc o nti n ue treat me nt wit h BI 6 5 5 0 6 4. Dia g n ostics a n d treat me nt ha ve t o 
be i nitiate d acc or di n g t o l ocal sta n dar d of care.
-i n case a patie nt de vel o ps ne utr o pe nia ( < 1 0 0 0 cells/ µl) c o nfir me d b y a sec o n d meas ure me nt 
c o nsi der t o re d uce or s us pe n d M M F, i n case t he ne utr o pe nia w orse ns
- I n case of e mer ge nc y s ur ger y d uri n g treat me nt i n t he st u d y, treat me nt wit h BI 6 5 5 0 6 4 a n d 
M M F (res pecti vel y azat hi o pri ne) will be i nterr u pte d. Treat me nt wit h BI 6 5 5 0 6 4 a n d S O C 
will be restarte d w he n t he patie nt has rec o vere d acc or di n g t o i n vesti gat or’s assess me nt.
- I n case of se vere i njecti o n reacti o ns, a na p hyl actic reacti o ns or c yt o ki ne release sy n dr o me, 
treat me nt wit h BI 6 5 5 0 6 4 a n d S O C has t o be st o p pe d a n d m ust n ot be i ntr o d uce d a gai n.
- I n case of occ urre nce of l ym p h o pr oliferati ve diseases, treat me nt wit h BI 6 5 5 0 6 4 a n d S O C 
has t o be st o p pe d a n d m ust n ot be i ntr o d uce d a gai n.

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 3 4 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
4. 2. 3   
Restricti o ns
4. 2. 3. 1 
Restricti o ns re gar di n g c o nc o mita nt treat me nt
C o nc o mita nt me dicati o ns ( or t hera p y)  t o pr o vi de a de q uate care ma y be gi ve n as cli nically 
necessar y . If a restricte d c o nc o mita nt t hera p y is re q uire d, treat me nt wit h trial me dicati o n 
s h o ul d be per ma ne ntly disc o nti n ue d.
Ta ble 4. 2. 3 . 1: 1    Per mitte d a n d restricte d me dicati o ns
T her a p y
Tre at m e nt P e ri o d
F oll o w u p
Peri o d
M M F
Per mitte d if d ose
< 1 - 2 g/ d *
P er mitte d
Az at hi o pri ne
Per mitte d if 
d ose ≤ 2 m g/ k g
Per mitte d
A b at ace pt or
C ycl o p h os p h a mi de
N ot per mitte d 
N ot Per mitte d
C ycl os p ori ne /
T acr oli m us / 
Miz ori bi ne 
N ot per mitte d 
Per m itte d if re q uire d 
as per i n vesti gat or’s 
de cisi o n
B eli m u m a b o r 
ot her “ a nt i- B L y S ”
or a n ot her 
i n vesti g ati o n al dr u g
N ot per mitte d   
N ot per mitte d
Bi ol o gic B- cell 
de pleti n g t her a p y 
(e. g. a nt i-C D 2 0)
N ot per mitte d   
N ot per mitte d
I V gl uc oc ortic oi ds
N ot Per m itte d
Per mitte d
1: f or gr o u p 1 patie nts, t he d oses f or M M F a n d A Z A are gi ve n i n 1 2 9 3. 1 0 are acce pta ble t o be 
c o nti n ue d t hr o u g h o ut 1 2 9 3-0 0 1 3 as l o n g as t he patie nt ot her wise q ualifies f or r oll o ver.
*e xce pti o n see secti o n 4. 2. 1.
4. 2. 3. 2  
Restricti o ns o n diet a n d lifest yle
Patie nts s h o ul d n ot d o nate bl o o d d uri n g M M F treat me nt a n d f or at least 6 we e ks after t he last 
d ose of M M F.
I n a d diti o n, me n s h o ul d n ot d o nate se me n d uri n g M M F/ A Z A treat me nt a n d f or at least 9 0 
da y s after t he last d ose of M M F/ A Z A.

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 3 5 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
D uri n g t he trial, all patie nts s h o ul d a v oi d i nte nsi ve p h y sical acti vity a n d u n pr otecte d 
e x p os ure t o direct s u nli g ht. I nte nsi ve p h ys ical acti vit y is a n acti vit y t hat is c o nsi dere d as a 
hi g her i nte nsit y t ha n us uall y perf or me d b y t he i n di vi d ual. T he use of ta n ni n g b o ot hs is 
f or bi d de n.
4. 3  
T R E A T M E N T C O M P LI A N C E
P atie nts m ust ta ke all d oses of trial me dicati o n a n d S O C bac k gr o u n d t hera p y  acc or di n g t o t he 
trial pr ot oc ol u nless me dicall y i n dicate d. A n y te m p orar y i nterr u pti o n s h o ul d be disc usse d 
wit h t he S p o ns or a n d all patie nts are t o be a d vise d of t he i m p orta nce i n a d heri n g t o t he d osi n g 
sc he d ule.
Eac h patie nt will be pr o vi de d wit h a me dicati o n ba g t o st ore u n use d a n d e m pt y  cart o ns of 
trial me dicati o n a n d a s har p bi n t o st ore all use d s yri n ges. Patie nts are re q ueste d t o bri n g all
re mai ni n g trial me dicati o n i ncl u di n g e m pt y cart o ns wit h t he m w he n atte n di n g o nsite visit s f or 
c o m plia nce c hec k s. At t he E O T visit, patie nts m ust ret ur n t he s har p bi n t o t he trial site f or 
dis p osal i n acc or da nce wit h l ocal re q uire me nts.
At eac h o nsite visit, a c o m plia nce c hec k of t he trial me dicati o n will be perf or me d t o e ns ure 
t he wee kly i njecti o n s are bei n g a d mi nistere d c orrectl y  at b ot h t he trial site a n d b y t he patie nt 
at h o me. In case of n o n -c o m plia nce, t he site staff will e x plai n t o patie nt t he i m p orta nce of 
treat me nt c o m plia nce a n d retrai n patie nt o n t he i njecti o n t ec h ni q ue f or self -a d mi nistrati o n at 
h o me .
I n a d diti o n, M M F d osi n g le vel will als o be c hec ke d at t he ti me p oi nts i n dicate d i n t he Fl o w 
C harts t o assess c o m plia nce. T he last t w o i nta kes dates a n d ti me of M M F ta ke n bef ore t he 
bl o o d sa m pli n g will be rec or de d i n e C R F, base d o n patie nt’s i nter vie w.
A n y  discre pa ncies s h o ul d be d oc u me nte d a n d e x plai ne d i n t he e C R F b y t he i n vesti gat or or 
t he desi g nee. P atie nts will als o be pr o vi de d wit h a n e- diar y  t o rec or d t he i nta ke of trial 
me dicati o n a n d S O C bac k gr o u n d t hera p y.
T he e diar y is c o nsi dere d t o be t he pri mar y  t o ol f or c ollecti n g c o m plia nce i nf or mati o n t o t he 
trial me dicati o n. 
Patie nts will be as ke d t o e nter date a n d ti me of i njecti o n as well as t he kit n u m ber of a n y d ose 
ta ke n. If a d ose was n ot i njecte d t he kit s hall still be rec or de d i n t he e diar y  
S O C me dicati o n is trac ke d b y  res p o n di n g w het her t he dail y me dicati o n was ta ke n.
I n case t he patie nt di d n ot e nter a d ose i n t he e diar y, t he i njecti o n s hall be e ntere d i n t he 
e C R F b y t he site st aff. Pr o per s o urce d oc u me ntati o n will be re q uire d f or t his data e ntr y .
E ver y  kit of i n vesti gati o nal pr o d uct dis pe nse d t o a patie nt s h o ul d be acc o u nte d f or (i njecte d 
or n ot i njecte d).

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 3 6 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
5. 
A S S E S S M E N T S
5. 1   
A S S E S S M E N T O F E F FI C A C Y
5. 1. 1
Assess me nt of r e n al res p o nse
F or pri mar y , sec o n dar y a n d f urt her efficac y e n d p oi nts assesse d at baseli ne a n d at wee k 5 2, 
t he 2 4 hr uri ne c ollecti o ns will be perf or me d i n d u plicate ( 2 x 2 4 hr c ollecti o n). A detaile d
descri pti o n f or 2 4 hr uri ne c ollecti o n will be pr o vi de d i n t he la b orat or y  ma n ual a n d f urt her
i nstr ucti o ns will be pr o vi de d t o t he patie nts. F or ot her ti me p oi nts, pr otei n uria will be 
assesse d b y s p ot uri ne.
C o m plete a n d partial re nal res p o nses are defi ne d as f oll o ws:

C o m plete re nal res p o nse ( C R R) is defi ne d as U pr ot < 0. 5 g/ da y a n d eit her e G F R wit hi n 
n or mal ra n ge or decrease i n e G F R < 2 0 % fr o m baseli ne if bel o w n or mal ra n ge .

Partial re nal res p o nse ( P R R) is defi ne d as 5 0 % re d ucti o n of pr otei n uria fr o m baseli ne a n d 
eit her e G F R wit hi n n or mal ra n ge or decrease i n e G F R < 2 0 % fr o m baseli ne if bel o w 
n or mal ra n ge .
A n alter nati ve wa y  t o calc ulate C R R a n d P R R will be t o use U P/ U C fr o m 2 4 hr uri ne 
c ollecti o ns, w hic h c o ul d c o m pe nsate f or i nc o m plete uri ne c ollecti o ns. T he decisi o ns w hic h 
calc ulati o n a p pr oac h is selecte d f or t he pri mar y  e n d p oi nt will be base d o n re vie w of bli n de d 
data bef ore fi nalizati o n of t he T S A P.
A re nal flare is defi ne d as f oll o ws:
 
If pr otei n uria ≤0. 5 g/ d at baseli ne: if i ncrease t o > 1g/ d (or U P/ U C > 1) at a n yti me d uri n g 
t he treat me nt peri o d as c o nfir me d b y a re peat test wit hi n 2 wee k s a n d if w orse ni n g of 
pr otei n uria ca n n ot be e x plai ne d b y  a n y ot her reas o ns 
Or
 
If pr otei n uria > 0. 5 g/ d at baseli ne : if i m pr o vi n g t o ≤ 0. 5 g/ d (res pecti vel y U P/ U C ≤ 0. 5) 
d uri n g t he treat me nt peri o d i n at least 2 c o nsec uti ve visits b ut s u bse q ue ntl y i ncrease t o > 
1 g/ d ( or U P/ U C > 1) as c o nfir me d b y a re peat test wit hi n 2 wee ks a n d if w orse ni n g of 
pr otei n uria ca n n ot be e x plai ne d b y  a n y ot her reas o ns 
Or
 
If pr otei n uria > 0. 5 g/ d at baseli ne: if i ncrease t o d o u bl e (res pecti vely U P/ U C > 2 x 
baseli ne) as c o nfir me d b y a re peat test wit hi n 2 wee k s a n d if w orse ni n g of pr otei n uria 
ca n n ot be e x plai ne d b y a n y ot her reas o n s
Or
 
Decrease i n e G F R b y > 2 0 % fr o m baseli ne a n d e G F R < 9 0 ml/ mi n as c o nfir me d b y a 
re peat test wit hi n 2 wee ks a n d if w orse ni n g of e G F R ca n n ot be e x plai ne d b y  a ny ot her 
reas o ns e g, i nfecti o n or i nj ur y.
T he pri mar y  e n d p oi nt is t he pr o p orti o n of patie nts wit h c o m plete re nal re p o nse ( C R R) a n d 
wit h o ut a n y  re nal flares at wee k 5 2.

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 3 7 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
5. 1. 2 
Assess me nt of p atie nt re p orte d o utc o mes
Patie nts s h o ul d c o m plete all st u d y q uesti o n naires i n t he f oll o wi n g or der : L u p us P R O, S F - 3 6, 
F A CI T -F at t he trial site at eac h ti me p oi nt i n dicate d i n t he Fl o w C harts i n a q uiet area/r o o m 
pri or t o a n y assess me nts or treat me nts a n d, if p ossi ble, bef ore a ny i nteracti o ns wit h t he 
i n vesti gat or or a n y me m ber of t he st u d y tea m. T he trial site staff /i n vesti gat or ma y  rec or d t he 
st u d y q uesti o n naires o n be half of t he patie nt o nl y  if t he patie nt has diffic ult y i n writi n g or 
u na ble t o rea d. T his m ust be clearl y  d oc u me nte d i n t he patie nt me dical n otes.
T he q uesti o n naires ge nerall y  ta ke a b o ut 5-1 0 mi n utes t o c o m plete. Refer t o t he I S F f or a c o p y  
of t he q uesti o n naire s. T he S F -3 6 versi o n 2 will be use d i n t his trial.
5. 1. 3 
Assess me nt of S L E D AI:
T he S L E D AI assess me nt s h o ul d ta ke a p pr o xi matel y  1 0 mi n utes t o c o m plete. T he i n vesti gat or 
will c o m plete t he S L E D AI assess me nts (versi o n S E L E N A -S L E D AI) base d o n e xa mi nati o n 
of t he patie nt, t heir me dical hist or y  i ncl u di n g s ym pt o ms o ver t he last 1 0 da y s a n d t heir 
la b orat or y res ults.
La b orat or y  tests ma y be c o nsi dere d f or use i n sc ori n g t he S L E D AI if t he y are dra w n -1 0 t o 
+ 7 da y s fr o m t he date of assess me nt a n d ca n n ot be use d t o c o m plete m ore t ha n o ne 
assess me nt.
5. 2   
A S S E S S M E N T O F S A F E T Y
Safet y  will be assesse d descri pti vel y base d o n:

P h y sical e xa mi nati o n 

Vital si g ns 

Safet y  la b orat or y tests 

Electr ocar di o gra m

A d verse e ve nts (i ncl u di n g dr u g- relate d A Es)

A d verse e ve nts of s pecial i nterest ( A E SI)

Seri o us a d verse e ve nts
5. 2. 1 
P h ysic al e x a mi n ati o n
P h ysical e xa mi nati o ns will be perf or me d at t he ti me p oi nts s pecifie d i n t he fl o w c harts.
C o m plete p h y sical e xa mi nati o n will i ncl u de ge neral a p peara nce, vital si g ns assess me nt a n d 
e val uati o n of or ga n s yste ms (ey es, ears, n ose, m o ut h, t h r oat, nec k a n d res pirat or y, 
car di o vasc ular, c hest, gastr oi ntesti nal, l ym p hatic, m usc ul os keletal, s ki n, ne ur ol o gic a n d 
ps yc hi atric). Hei g ht (at scree ni n g o n ly) a n d b o d y wei g ht will als o be meas ure d .
Tar gete d p h y sical e xa mi nati o n will i ncl u de wei g ht, vital si g n assess me nt a n d 
e val uati o n of or ga n s yste ms ass ociate d wit h A E(s) s ym pt o ms or la b orat or y
a b n or malities.

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 3 8 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
All a b n or mal fi n di n gs at baseli ne will be rec or de d o n t he Me dical Hist or y / C o nc o mita nt 
Dia g n osis e C R F p a ge. Ne w a b n or mal fi n di n gs or w orse ni n g of baseli ne c o n diti o ns detecte d 
at t he s u bse q ue nt p h ys ical e xa mi nati o ns will be rec or de d as a d verse e ve nts o n t he a p pr o priate 
e C R F pa ge.
5. 2. 2 
Vit al si g ns
Vital si g n s e val uati o n i ncl u des te m perat ure, p ulse rate a n d s ys t olic/ diast olic bl o o d press ure 
will be perf or me d at t he ti me p oi nts s pecifie d i n t he Fl o w C harts . P ulse rate a n d bl o o d 
press ure will be meas ure d after patie nts ha ve bee n sitti n g c o mf orta bl y f or at least fi ve 
mi n utes. Meas ure me nt of vital si g ns s h o ul d prece de bl o o d sa m pli n g t o a v oi d p ote ntial i m pact 
o n vital meas ure me nts.
A n y  a b n or mal fi n di n gs s hall be e val uate d b y t he i n vesti gat or a n d c o nfir me d w het her t he y 
q ualif y  t o be d oc u me nte d as a d verse e ve nt.
5. 2. 3  
S afet y a n d i m m u n ol o g y l a b or at or y p ar a meters
T he safet y a n d i m m u n ol o g y la b orat or y para meters t o be assesse d are liste d i n Ta ble 5. 2 . 3: 1.
Patie nts d o n ot ha ve t o be faste d f or t he bl o o d sa m pli n g. Refer  t o t he fl o wc harts f or bl o o d
sa m pli n g ti me p oi nts. 
Ta ble 5. 2. 3: 1  
Safet y a n d i m m u n ol o g y la b orat or y tests
C ate g or y 
Test n a me
Fre q ue nc y
Hae m at ol o g y 
Hae m at ocrit
Hae m o gl o bi n 
Re d Bl o o d Cell C o u nt / Er y t hr oc ytes 
W hite
Bl o o d Cells / Le u k oc ytes Platelet
C o u nt / T hr o m b oc ytes
At e ve r y visit u ntil E O T (i ncl usi ve), re peat after
E O T o nl y if cli nicall y si g nifica nt fi n di n gs at t he 
discreti o n of i n vesti gat or.
Er yt hr oc yte se di me ntati o n rate
A nal yse d l ocally at b as eli n e, we e ks 1 2 , 2 6 a n d 5 2.
Retic ul oc yte C o u nt
At b as eli n e, wee k s 1 2 , 2 6 a n d 5 2.
Diff. A ut o matic 
Relati ve c o u nt:
Ne utr o p hils, E osi n o p hils, Bas o p hils,
M o n oc ytes, L y m p h oc ytes
At e ve r y visit u ntil E O T (i ncl usi ve), re peat after
E O T o nl y if cli nicall y si g nifica nt fi n di n gs at t he 
discreti o n of i n vesti gat or.
Diff. Ma n ual   
Ne utr o p hils,
ba n ds ( Sta bs) 
Ne utr o p hils, p ol y m or p h o n uclear 
E osi n o p hils, Bas o p hils, 
M o n oc ytes, L y m p h oc ytes
O nl y if D iff. A ut o matic is a b n or mal (refle x test).

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 3 9 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
Ta ble 5. 2. 3: 1 Safet y  a n d i m m u n ol o g y la b orat or y tests ( C o nt.)
C oa g ulati o n 
Partial T hr o m b o plasti n Ti m e
Pr ot hr o m bi n ti me ( Q uic k a n d I N R)
At e ve r y visit u ntil E O T (i ncl usi ve), re peat after
E O T o nl y if cli nicall y si g nifica nt fi n di n gs at t he 
discreti o n of i n vesti gat or.
Fi bri n o ge n
At baseli ne, wee k s 1 2 , 2 6 a n d 5 2 . Re peat after
E O T o nl y if cli nicall y si g nifica nt fi n di n gs.
E nz y mes 
A S T( G O T) , A L T( G P T) 
Al kali ne P h os p hatase Creati ne
Ki nase ( C K)
C K- M B
(o nl y if C K is ele vate d)
Ga m m a-Gl uta m yl Tra nsferase
Lactate De h y dr o ge nase
At e ve r y visit u ntil E O T (i ncl usi ve), re peat
after E O T o nl y if cli nicall y si g nifica nt
fi n di n gs at t he discreti o n of i n vesti gat or.
Li pase, A m ylase
At b as eli n e, w e e k s 1 2 , 2 6 a n d 5 2.
Electr ol ytes 
Calci u m, S o di u m , P otassi u m, 
C hl ori de
At e ve r y visit u ntil E O T (i ncl usi ve), re peat
after E O T o nl y if cli nical si g nifica nt fi n di n gs
at t he discreti o n of i n vesti gat or.
S u bstrates 
Plas ma Gl uc ose,
Creati ni ne a n d calc ulate d Creati ni ne
Cleara nce (C K D -E PI ),
Bilir u bi n T otal, Bilir u bi n Direct a n d 
I n direct
Al b u mi n, Uric Aci d, Urea Nitr o ge n
At e ve r y visit u ntil E O T (i ncl usi ve), re peat
after E O T o nl y if cli nicall y si g nifica nt
fi n di n gs at t he discreti o n of i n vesti gat or.
C h olester ol, tri gl yceri des
At b aseli ne, wee k s 1 2, 2 6 a n d 5 2 .
hs C -Reacti ve Pr otei n
At baseli ne , we e ks 1 2, 2 6 a n d 5 2
Ha pt o gl o bi n
At baseli ne , we e ks 1 2, 2 6 a n d 5 2
Ser u m Pre g na nc y
test *
H u ma n Ser u m C h ori o nic
G o na d otr o pi n
At scree ni n ga n d a n yti me if uri nar y test is
p ositi ve .
Uri ne Pre g na nc y
test *
H u ma n C h ori o nic G o na d otr o pi n i n t he
uri ne
At scree ni n g, baseli ne a n d t he n e ver y 4 
we e ks t hereafter.
Uri nal ysis -
di pstic k
Uri ne: Nitrite, Pr otei n, Gl uc ose, Ket o ne,
Bilir u bi n, R B C/ Er yt hr oc ytes, W B C/
Le u k oc ytes, p H, creati ni ne
Ur o bili n o ge n
At e ve r y visit u ntil E O T (i ncl usi ve), re peat
after E O T o nl y if cli nicall y si g nifica nt
fi n di n gs at t he discreti o n of i n vesti gat or.
Uri ne
S p ot pr otei n/creati ni ne rati o
At e ver y visit f or safet y/efficac y meas ure me nt.

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 4 0 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
Ta ble 5. 2. 3: 1  
Safet y  a n d i m m u n ol o g y la b orat or y tests ° ( C o nt.)
Uri n e-Se di me nt
( micr osc o pic 
e xa mi nati o n)
Uri ne: Se di me nt Bacteria, Cast i n 
Se di me nt, S q ua m o us E pit helial Cells, 
Se d. Cr ys., U ns pecifie d, Se di me nt R B C/
Er yt hr oc ytes, Se di me nt W B C/ 
Le uc oc ytes
At e ver y visit or if uri ne a nal ysis is a b n or mal 
acc or di n g t o i n vesti gat or (refle x test) .
I nfecti o ns
scree ni ng * *
He patitis B S urface A nti ge n ( q ualitati ve)
He patitis B c ore A nti b o d y
He patitis C A nti b o dies ( q ualitati ve)
HI V -1 a n d HI V -2 A nti b o d y ( q ualitati ve)
Q ua nti F E R O N- T B G ol d * * *
At scree ni n g o nl y f or gr o u p 2 patie nts.
F or gr o u p 1 patie nts o nl y d o ne if s us pici o n 
f or a n i nfecti o n
I m m u n o gl o b uli n 
I g G, I g M
At b aseli ne, wee k s 1 2 , 2 6 a n d 5 2.
I m m u n ol o g y
testi n g
A N A
A nt i-p h os p h oli pi d a nti b o dies
At scree ni n g f or Gr o u p 2 o nl y.
At baseli ne f or Gr o u p 1 o nl y 
F or b ot h gr o u ps: we e k 5 2.
A nti -ds D N A,
At scree ni n g f or Gr o u p 2 o nl y.
At baseli ne f or Gr o u p 1 o nl y
F or b ot h gr o u ps: we e ks 1 2 , 2 6 , 5 2 a n d E O S. 
C o m ple me nt s C 3, C 4 , a nti-C 1 q 
a nti b o dies
At baseli ne f or Gr o u p 1 
a n d we e ks 1 2 , 2 6 , 4 2( o nl y c o m ple me nts C 3 a n d 
4), 5 2 a n d E O S.
° B aseli ne is referri n g t o visit 1 of gr o u p 1 -patie nts a n d visit 2 of gr o u p 2 patie nts. F or gr o u p 1 patie nts 
a n y la b para meters f or visit 1 are alrea d y ta ke n d uri n g t he e n d of treat me nt visit of cli nical trial 1 2 9 3-
0 0 1 0 a n d w ill n ot be re peate d.
* Uri ne ( di pstic k) pre g na nc y test will be perf or me d pri or t o st u d y e ntr y a n d t he n e ver y 4 wee ks i n 
w o me n of c hil d beari n g p ote ntial. If vi sit i nter vals are > 4 wee ks, di pstic k s will be pr o vi de d t o patie nts 
t o perf or m t he pre g na nc y test at h o me. A ser u m pre g na nc y test will als o be perf or me d at Scree ni n g 
visit. T hr o u g h o ut t he trial, if a n y di pstic k test is p ositi ve or u ncertai n, a ser u m pre g na n c y test m ust be 
c ollecte d o n t he sa me da y f or c o nfir mati o n. O nl y patie nts wit h a ne gati ve pre g na nc y test will be 
eli gi ble a n d will c o nti n ue wit h trial me dicati o n a d mi nistrati o n. 
* * Res ults of i nfecti o ns scree ni n g will n ot be ca pt ure d i n t he s p o ns or’s data base. I n case H B C p ositi ve 
b ut H Bs a nti ge n ne gati ve t he n meas ure He p atitis B D N A . If res ult p ositi ve, e xcl u de patie nt ; if res ult 
ne gati ve , patie nt ca n be i ncl u de d.
* * * In case of a n i n deter mi nate res ult, test s h o ul d be re peate d ; i n case t he res ult is in deter mi nate a gai n, 
a P P D s ki n test s h o ul d be perf or me d .
1 I n case H Bc p ositi ve b ut H Bs a nti ge n ne gati ve t he n meas ure He patitis B D N A: if p ositi ve e xcl u de patie nt, if 
ne gati ve patie nt ca n be i ncl u de d.
If patie nt is p ositi ve f or a nti-H C V d uri n g t he trial, t he H C V-R N A test ca n be perf or me d l ocall y t o e xcl u de false 
p ositi ve res ults. If H C V -R N A test is ne gati ve, patie nt ma y c o nti n ue (t he res ult m ust be d oc u me nte d i n e C R F).
All bl o o d sa m ples will be a nal ys e d at a desi g nate d ce ntral la b orat or y, a n d if necessar y , b y  
a d diti o nal s pecialist la b orat ories, e xce pt er yt hr oc yte se di me ntati o n rate (E S R ) w hic h will be 
perf or me d o nsite or at a l ocal accre dite d la b . T he ce ntral la b orat or y  will pr o vi de materials f or 

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 4 1 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
all bl o o d sa m pli n g i ncl u di n g E S R . I nstr ucti o ns f or sa m ple c ollecti o n, ha n dli n g , pr ocessi n g 
a n d s hi p pi n g are pr o vi de d i n t he La b orat or y Ma n ual i n t he I S F.
T he ce ntral la b ora t or y will se n d re p orts t o t he i n vesti gat or a n d will tra nsfer t he res ults of t he 
a nal ys is t o t he s p o ns or. It is t he res p o nsi bilit y of t he i n vesti gat or t o e val uate t he la b orat or y 
re p orts. Cli nicall y rele va nt a b n or mal fi n di n gs as j u d ge d by t he i n vesti gat or will be re p orte d 
as a d verse e ve nts (refer t o Secti o n 5. 2. 5 ); a n d s h o ul d be re peate d usi n g a n u nsc he d ule d visit 
la b kit u ntil n or malisati o n or sta bilisati o n or u ntil a n alter na ti ve e x pla nati o n has bee n 
esta blis he d.
M yc o p he n olate bl o o d le vels will be c ollecte d at all ti me p oi nts i n dicate d i n t he Fl o w 
C harts . Sa m ples will be a nal yse d f or e x pl ora t or y p ur p oses after trial c o m pleti o n.
I n case t he criteria f or he patic i nj ur y are f ulfille d, a n u m ber of a d ditio nal meas ures will be 
perf or me d ( please see Secti o n 5. 2. 5. 1 a n d t he DI LI C hec klist pr o vi de d i n t he I S F ). T he 
a m o u nt of bl o o d ta ke n fr o m t he patie nt c o ncer ne d will be i ncrease d d ue t o t his a d diti o nal 
sa m pli n g.
5. 2. 4 
Electr oc ar di o gr a m
T he 1 2- lea d E C Gs will be rec or de d acc or di n g t o l ocal sta n dar d pr oce d ures at t he visits 
i n dicate d i n t he Fl o w C harts . A ut o maticall y ge nerate d i nter val data ( P R, Q R S, Q T) a n d 
heart rate o n t he pri nte d E C G will be c ollecte d o n t he e C R F. Q Tc B a n d Q Tc F will be 
calc ulate d wit h H R a n d Q T i nter val.
Rate, r h y t h m a n d re p olarisati o n c ha n ges ha ve t o be e val uate d, c o m pare d t o pre vi o us 
c harts, a n d assesse d f or cli nical rele va nce. C li nically rele va nt a b n or mal fi n di n gs will be 
re p orte d eit her as baseli ne c o n diti o ns ( if i de ntifie d at t he scree ni n g visit) or ot her wise as 
ad verse e ve nts a n d will be f oll o we d u p a n d/ or treate d as me dicall y a p pr o priate. I f 
necessar y , a d diti o nal E C Gs ma y be re peate d f or q ualit y or safety reas o ns a n d t he 
re peate d E C G will be use d f or a nalys is.
Date d a n d si g ne d pri nt o uts of E C G wit h fi n di n gs s h o ul d be d oc u me nte d i n patie nt’s me dical 
rec or d.
5. 2. 5 
Assess me nt of a d verse e ve nts
5. 2. 5. 1 
Defi niti o ns of A Es 
A d verse e ve nt
A n a d verse e ve nt ( A E) is defi ne d as a n y  u nt o war d me dical occ urre nce i n a patie nt or cli nical 
i n vesti gati o n s u bject a d mi nistere d a me dici nal pr o d uct a n d w hic h d oes n ot necessaril y  ha ve 
t o ha ve a ca usal relati o ns hi p wit h t his treat me nt.
A n A E ca n t heref ore be a n y  u nfa v o ura ble a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal 
la b orat or y fi n di n g), sy m pt o m, or disease te m p orall y  ass ociate d wit h t he use of a me dici nal 
pr o d uct, w het her or n ot c o nsi dere d relate d t o t he me dici nal pr o d uct.

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Seri o us a d verse e ve nt
A seri o us a d verse e ve nt ( S A E) is defi ne d as a ny A E w hic h f ulfils at least o ne of t he 
f oll o wi n g criteria:
-
res ults i n deat h
-
is life-t hreate ni n g, w hic h refers t o a n e ve nt i n w hic h t he patie nt was at ris k of deat h at 
t he ti me of t he e ve nt; it d oes n ot refer t o a n e ve nt t hat h yp ot heticall y mi g ht ha ve 
ca use d deat h if m ore se vere
-
re q uires i npatie nt h os pitalisati o n or pr ol o n gati o n of e xisti n g h os pitalis ati o n
-
res ults i n persiste nt or si g nifica nt disa bilit y or i nca pacit y, or
-
is a co n ge nital a n o mal y / birt h defect, or
-
is dee me d seri o us f or a n y ot her reas o n if it is a n i m p orta nt me dical e ve nt w he n base d 
o n a p pr o priate me dical j u d g eme nt w hic h ma y  je o par dise t he patie nt a n d ma y re q uire 
me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he ot her o utc o mes liste d i n t he 
a b o ve defi niti o ns.
E xa m ples of s uc h e ve nts are i nte nsi ve treat me nt i n a n e mer ge nc y  r o o m or at h o me f or 
aller gic br o nc h os pas m, bl o o d d y scrasias or c o n v ulsi o ns t hat d o n ot res ult i n h os pitalisati o n or 
de vel o p me nt of de pe n de nc y  or a b use. 
F or J a p a n o nly: the f oll o wi n g e ve nts will be ha n dle d as “ dee me d seri o us f or a n y ot her 
reas o n”. A Es w hic h p ossi bl y  lea d t o disa bilit y will be re p orte d as S A Es.
A Es c o nsi dere d “ Al w a ys Seri o us ”
Ca ncers of ne w hist ol o g y a n d e xacer bati o ns of e xisti n g ca ncer m ust be classifie d as a seri o us 
e ve nt re gar dless of t he d urati o n bet wee n disc o nti n uati o n of t he dr u g a n d m ust be re p orte d as 
descri be d i n Secti o n 5. 2. 5. 2 , s u bsecti o ns “ A E C ollecti o n” a n d “A E re p orti n g t o s p o ns or a n d 
ti meli nes”.
I n acc or da nce wit h t he E M A i nitiati ve o n Im p orta nt Me dical E ve nts, B oe hri n ger I ngel hei m 
has set u p a list of f urt her A Es, w hic h b y t heir nat ure, ca n al wa ys be c o nsi dere d t o be 
“seri o us” e ve n t h o u g h t he y m a y n ot ha ve met t he criteria of a n S A E as defi ne d a bo ve.
T he latest list of “ Al wa y s Seri o us A Es” ca n be f o u n d i n t he electr o nic data ca pt ure (e D C )
s yste m. T hese e ve nts s h o ul d al wa ys be re p orte d as S A Es as descri be d a b o ve.
A d verse e ve nts of s peci al i nterest ( A E SIs)
T he ter m A E SI relates t o a n y  s pecific A E t hat has bee n i de ntifie d at t he pr oject le vel as bei n g 
of partic ular c o ncer n f or pr os pecti ve safet y m o nit ori n g a n d safet y assess me nt wit hi n t his trial, 
e. g. t he p ote ntial f or A Es base d o n k n o wle d ge fr o m ot her c o m p o u n ds i n t he sa me class. 
A E SI s nee d t o be re p orte d t o t he s p o ns or’s P har mac o vi gila nce De part me nt wit hi n t he sa me 
ti mefra me t hat a p plies t o S A Es, please see a b o ve.
T he f ol l o wi n g are c o nsi dere d as A E SIs:

He patic i nj ur y
A he patic i nj ur y  is defi ne d b y t he f oll o wi n g alterati o ns of he patic la b orat or y para meters: 

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
a n ele vati o n of A S T a n d/ or A L T ≥3 f ol d U L N c o m bi ne d wit h a n ele vati o n of t otal 
bilir u bi n ≥2 f ol d U LN meas ure d i n t he sa me bl o o d dra w sa m ple, a n d/ or

a mi n otra nsferase ( A L T, a n d/or A S T) ele vati o ns ≥1 0 f ol d U L N
T hese la b fi n di n gs c o nstit ute a he patic i nj ur y  alert a n d t he patie nt s s h o wi n g t hese la b 
a b n or malities nee d t o be f oll o we d u p acc or di n g t o t he “ DI LI c hec klist” pr o vi de d via t he 
e D C s yste m. I n case of cli nical s ym pt o ms of he patic i nj ur y  (icter us, u ne x plai ne d 
e nce p hal o pat h y, u ne x plai ne d c oa g ul o pat h y, ri g ht u p per q ua dra nt a b d o mi nal pai n, etc.) 
wit h o ut la b res ults ( A L T, A S T, t otal bilir u bi n) a vaila ble, t he i n vesti gat or s h o ul d ma ke 
s ure t hese para meters are a nal ys e d, if necessar y i n a n u nsc he d ule d bl o o d test. S h o ul d t he 
res ults meet t he criteria of he patic i nj ur y alert, t he pr oce d ures descri be d i n t he DI LI 
c hec klist s h o ul d be f oll o we d .

I njecti o n reacti o ns i ncl u di n g a na p hyl actic reacti o n
A n y  s us pici o n of se vere i njecti o n reacti o n a n d a n y p ote ntial cases of a na p h yla xis s h o ul d 
be defi ne d a n d assesse d usi n g t he criteria disc usse d i n t he state me nt pa per fr o m Sa m ps o n 
H A ( R 1 1 - 4 8 9 0).

C y t o ki ne release sy n dr o me
A c y t o ki ne release sy n dr o me ma nifests w he n a lar ge n u m ber of i m m u ne cells bec o mes 
acti vate d a n d releases i nfla m mat or y  c yt o ki nes. It is c o nsiste ntl y ass ociate d wit h ele vate d 
T N F α, I F Nγ, a n d I L-6 le vels. T he c y t o ki ne-release s yn dr o me is cli nicall y c haracteri se d 
b y  fe ver, c hills, ri g or a n d ras h. Ot her sy m pt o ms are na usea, d ys p n oea, tac h y car dia a n d 
h y p ote nsi o n. P ote ntiall y  life-t hreate ni n g c o m plicati o ns of a c yt o ki ne release s yn dr o me 
i ncl u de car diac dys f u ncti o n, res pirat or y distress sy n dr o me, ne ur ol o gic t o xicit y , re nal 
a n d/ or he patic fail ure, a n d disse mi nate d i ntra vasc ular c oa g ulati o n. I n case of s us pici o n of 
a c yt o ki ne release sy n dr o me, it is rec o m me n de d t o meas ure I L -6 le vels i n t he l ocal 
la b orat or y if t he assa y is a vaila ble.
I n ge neral t hera py wit h BI 6 5 5 0 6 4 is i m m u n os u p pres si ve a n d p ote ntially c o ul d i ncrease 
t he ris k f or i nfecti o ns or l y m p h o pr oliferati ve diseases.

O p p ort u nistic i nfecti o ns a n d/ or se vere i nfecti o ns
O p p ort u nistic i nfecti o ns i ncl u de p ne u m oc y stis p ne u m o nia, t o x o plas m osa g o n dii 
e nce p halitis, cr ypt os p ori di osis; micr os p ori di osis, m y c o bacteri u m t u berc ul osis, 
m y c o bacteri u m a vi u m; bacterial res pirat or y  disease, bacterial e nteric i nfecti o n, 
m uc oc uta ne o us ca n di diasis, i n vasi ve m y c oses, C M V, E B V, her pes si m ple x (i n vasi ve 
o nl y ), varicella z oster, h u ma n her pes vir us 8, J C vir us i nfecti o n. 
A n y  se vere i nfecti o n s h o ul d als o be re p orte d as A E SI.
W he ne ver a patie nt c o mes t o a visit a n d re p orts of a n ( S) A E relate d t o i nfecti o ns w hic h 
occ urre d i n t he i nter val si nce t he last visit, t he n he/s he is r o uti nel y  as ke d w het her t he y 
ha ve bee n see n/treate d b y  a p h ysicia n a n d w het her bl o o d sa m ples ha d bee n ta ke n i n t hat 
c o nte xt. S h o ul d t his be a ns were d i n t he affir mati ve t he n eff orts s h o ul d be u n derta ke n t o 
c ollect t he res pecti ve i nf or mati o n.

L y m p h o pr oliferati ve dis or ders (e. g. B- a n d T-cell l ym p h o ma, N o n - H o d g ki n 
l ym p h o ma a n d H o d g ki n l y m p h o ma, he pat os ple nic T -cell l ym p h o ma)
I n case of a de n o pat hy, he pat o - or s ple n o me gal y, fe ver of u nclear ori gi n, ni g ht s weats or 
l oss of wei g ht, occ urre nce of l ym p h o pr oliferati ve diseases s h o ul d be e val uate d. A s t he 

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occ urre nce of l y m p h o pr oliferati ve dis or ders is ass ociate d wit h acti ve E B V- i nfecti o n, 
patie nts s ufferi n g fr o m acti ve E B V i nfecti o n s h o ul d be caref ull y e val uate d f or t he 
occ urre nce of l y m p h o pr oliferati ve diseases.

T hr o m b osis a n d a dj u nct i m m u n os u p press i o n
I m m u n os u p pressi o n ma y fa v o ur a pr ot hr o m b otic state. T heref ore, patie nts s h o ul d be 
caref ull y f oll o we d f or earl y si g ns of peri p heral or ce ntral t hr o m b osis or t hr o m b oe m b olic 
e ve nts.
F or c o u nter meas ures a n d ma na ge me nt of t he a b o ve me nti o ne d A d verse E ve nts please refer t o 
secti o n 4. 2. 2 of t he pr ot oc ol.
T he s pecific t hera p y of t he liste d A E SI s will be acc or di n g t o i nstit uti o nal sta n dar ds.
Ot her a d verse e ve nts
I n case d uri n g t he c o urse of t he trial a patie nt de vel o ps a ne utr o pe nia wit h a se verit y gra de 
hi g her t ha n 3, it is rec o m me ne d t o first decrease or st o p M M F, t he n t o c hec k la b val ues a n d 
deci de o n t he p ossi ble r o ot ca use of t he ne utr o pe nia.
I nte nsit y (se verit y) of A Es
T he i nte nsit y  (se verity) of a d verse e ve nts s h o ul d be class ifie d a n d rec or de d i n t he eC R F
acc or di n g t o t he R he u mat ol o g y  C o m m o n Ter mi n ol o g y  Criteria f or A d verse E ve nts ( R C T C)
V ersi o n 2. 0 de vel o pe d b y  
(R 1 3 - 3 5 1 5). Refer t o t he I SF f or R C T C 
i nte nsit y/se verity classificati o n .
I nte nsity o pti o ns are:
Gra de 1  
mil d
Gra de 2 
m o derate
Gra de 3  
se vere
Gra de 4  
life-t hreate ni n g
C a us al rel ati o ns hi p of A Es
Me dical j u d g e me nt s h o ul d be use d t o deter mi ne t he relati o ns hi p, c o nsi deri n g all rele va nt 
fact ors, i ncl u di n g patter n of reacti o n, te m p oral relati o ns hi p, de-c halle n ge or re -c halle n ge, 
c o nf o u n di n g fact ors s uc h as c o nc o mita nt me dicati o n, c o nc o mita nt diseases a n d rele va nt 
h ist or y. 
Ar g u me nts t hat ma y  s u g gest t hat t here is a reas o na ble p ossi bilit y of a ca usal relati o ns hi p 
c o ul d be:

T he e ve nt is c o nsiste nt wit h t he k n o w n p har mac ol o g y  of t he dr u g.

T he e ve nt is k n o w n t o be ca use d b y or attri b ute d t o t he dr u g class.

A pla usi ble ti me t o o nset of t he e ve nt relati ve t o t he ti me of dr u g e x p os ure.

E vi de nce t hat t he e ve nt is re pr o d uci ble w he n t he dr u g is re- i ntr o d uce d.

N o me dicall y s o u n d alter nati ve aeti ol o gies t hat c o ul d e x plai n t he e ve nt (e. g. pre -
e xisti n g or c o nc o mita nt diseases, o r c o-me dicati o ns).

T he e ve nt is t y picall y dr u g -relate d a n d i nfre q ue nt i n t he ge neral p o p ulati o n n ot 
e x p ose d t o dr u gs (e. g. Ste ve ns -J o h ns o n s yn dr o me).

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
A n i n dicati o n of d ose -res p o nse (i.e. greater effect size if t he d ose is i ncrease d, s maller 
effect size if d ose is di mi nis he d).
Ar g u me nts t hat ma y  s u g gest t hat t here is n o reas o na ble p ossi bilit y of a ca usal relati o ns hi p 
c o ul d be:

N o pla usi ble ti me t o o nset of t he e ve nt relati ve t o t he ti me of dr u g e x p os ure is e vi de nt 
(e. g. pre-treat me nt cases, dia g n osis of ca ncer or c hr o nic disease wit hi n da ys / wee ks 
of dr u g a d mi nistrati o n; a n aller gic reacti o n wee ks after disc o nti n uati o n of t he dr u g 
c o ncer ne d).

C o nti n uati o n of t he e ve nt des pite t he wit h dra wal of t he me dicati o n, ta ki n g i nt o 
acc o u nt t he p har mac ol o gical pr o perti es of t he c o m p o u n d (e. g. after 5 half- li ves).
Of n ote, t his criteri o n ma y n ot be a p plica ble t o e ve nts w h ose ti me c o urse is pr ol o n ge d 
des pite re m o vi n g t he ori gi nal tri g ger.

A d diti o nal ar g u me nts a m o n gst t h ose state d bef ore, li ke alter nati ve e x pla nati o n (e. g.
sit uati o ns w here ot her dr u gs or u n derlyi n g diseases a p pear t o pr o vi de a m ore li kel y  
e x pla nati o n f or t he o bser ve d e ve nt t ha n t he dr u g c o ncer ne d).

Disa p peara nce of t he e ve nt e ve n t h o u g h t he trial dr u g treat me nt c o nti n ues or re mai ns 
u nc ha n ge d.
5. 2. 5. 2 
A d verse e ve nt c ollecti o n a n d re p orti n g
A E C ollecti o n
T he i n vesti gat or s hall mai ntai n a n d kee p detaile d rec or ds of all A Es i n t he patie nt files.
T he f oll o wi n g m ust be c ollecte d a n d d oc u me nte d o n t he a p pr o priate eC R F(s) b y  t he 
i n vesti gat or:
• 
Fr o m si g ni n g t he i nf or me d c o nse nt o n war ds u ntil t he i n di vi d ual patie nt’s e n d of st u d y:
- 
All A Es (seri o us a n d n o n-seri o us) a n d all A E SIs.
•
Patie nts w h o disc o nti n ue trial me dicati o n pre mat urel y  a n d a gree t o be c o ntacte d f urt her, 
s h o ul d be f oll o we d u p as descri be d i n secti o n 3. 3. 4. 1. Fr o m t he n o n u ntil t he i n di vi d ual 
patie nt’s e n d of t he trial:
- 
T he i n vesti gat or m ust re p ort all deat hs/fatal A Es re gar dless of relati o ns hi p; relate d 
S A Es a n d relate d A E SI s t hat t he i n vesti gat or bec o mes a ware of.
• 
After t he i n di vi d ual patie nt’s e n d of st u d y:
- 
The in vesti gat or d oes n ot nee d t o acti vel y m o nit or t he patie nt f or A Es b ut s h o ul d 
re p ort relate d S A Es a n d relat e d A E SIs of w hic h t he i n vesti gat or ma y  bec o me a ware of b y  
a n y mea ns of c o m m u nicati o n, e. g. p h o ne call. T h ose A Es s h o ul d, h o we ver, n ot be 
re p orte d i n t he eC R F .

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Fi g ure 5. 2. 5 . 2: 1 
A E C ollecti o n
T he R E P is defi ne d as 5 0 da y s after t he last trial dr u g a d mi nistrati o n. All A Es t hat occ ur 
d uri n g t he treat me nt p hase a n d t hr o u g h o ut t he R E P will be c o nsi dere d as o n treat me nt (see 
secti o n 7. 3. 4). E ve nts t hat occ ur after t he R E P will be c o nsi dere d as p ost treat me nt e ve nts.
A E re p orti n g t o s p o ns or a n d ti meli nes
T he i n vesti gat or m ust re p ort S A Es, A E SI s, a n d n o n-seri o us A Es w hic h are rele va nt f or t he 
re p orte d S A E or A E SI, o n t he BI S A E f or m i m me diatel y ( wit hi n 2 4 h o urs) to t he s p o ns or’s 
u ni q ue e ntr y p oi nt (c o u ntr y  s pecific re p orti n g pr ocess will be pr o vi de d i n t he I S F). T he sa me 
ti meli ne a p plies if f oll o w-u p i nf or mati o n bec o mes a vaila ble. I n s pecific occasi o ns t he 
i n vesti gat or c o ul d i nf or m t he s p o ns or u pfr o nt via tele p h o ne. T his d oes n ot re place t he 
re q uire me nt t o c o m plete a n d se n d t he BI S A E f or m.
Wit h recei pt of a n y f urt her i nf or mati o n t o t hese e ve nts, a f oll o w -u p S A E f or m has t o be 
pr o vi de d. F or f oll o w -u p i nf or mati o n t he sa me r ules a n d ti meli ne a p pl y  as f or i nitial 
i nf or mati o n.
I nf or m ati o n re q uire d
F or eac h A E, t he i n vesti gat or s h o ul d pr o vi de t he i nf or mati o n re q ueste d o n t he ap pr o priate 
eC R F pa ges a n d t he BI S A E f or m, if a p plica ble. T he i n vesti gat or s h o ul d deter mi ne t he ca usal 
relati o ns hi p t o t he trial me dicati o n a n d a n y p ossi ble i nteracti o ns bet wee n t he trial me dicati o n
a n d an A u xiliar y  Me dici nal Pr o d uct ( A M P).
T he f oll o wi n g s h o ul d als o be rec or de d as a n ( S) A E i n t he C R F a n d BI S A E f or m (if 
a p plica ble):

W orse ni n g of t he u n derl y i n g disease or of ot her pre-e xisti n g c o n diti o ns

C ha n ges i n vital si g ns, E C G, p h y sical e xa mi nati o n a n d la b orat or y test res ults, if t he y 
are j u d ge d cli nicall y rele va nt b y t he i n vesti gat or.
If s uc h a b n or malities alrea d y pre-e xist pri or t o trial i ncl usi o n t he y will be c o nsi dere d as 
baseli ne c o n diti o ns a n d s h o ul d be c ollecte d i n t he e C R F o nl y .
All ( S) A Es, i ncl u di n g t h ose persisti n g after i n di vi d ual patie nt ’s e n d of st u d y m ust be 
f oll o we d u p u ntil t he y ha ve res ol ve d, ha ve bee n as sesse d as “c hr o nic” or “sta ble” or n o 
f urt her i nf or mati o n ca n be o btai ne d.
I C
Scree ni n g / Tre at me nt Peri o d
E n d of 
Tre at m e nt
R E P
E xte n de d F U p
All A Es a n d A E SIs
All de at hs/f at al A E s, 
rel ate d S A Es a n d A E SIs
Rele v a nt S A Es a n d A E SIs t h at 
i n vesti g at or m a y s u bse q ue ntl y 
bec o me a w are of
E n d of St u d y

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 4 7 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
Pre g n a nc y
I n rare cases, pre g na nc y mi g ht occ ur i n a cli nical trial. O nce a patie nt has bee n e nr olle d i n t he 
cli nical trial a n d has ta ke n trial me dicati o n, t he i n vesti gat or m ust re p ort a n y dr u g e x p os ure 
d uri n g pre g na nc y  i n a trial p artici pa nt i m me diatel y ( wit hi n 2 4 h o urs) b y mea ns of Part A of 
t he Pre g na nc y M o nit ori n g F or m t o t he s p o ns or’s u ni q ue e ntr y p oi nt. Si milarl y , p ote ntial dr u g 
e x p os ure d uri n g pre g na nc y m ust be re p orte d if a part ner of a male trial partici pa nt bec o mes 
pre g na nt. T his re q uires a writte n c o nse nt of t he pre g na nt part ner.
T he o utc o me of t he pre g na nc y  ass ociate d wit h t he dr u g e x p os ure d uri n g pre g na nc y  m ust be 
foll o we d u p a n d re p orte d t o t he s p o ns or’s u ni q ue e ntr y  p oi nt o n t he Pre g na nc y M o nit ori n g 
F or m f or Cli nical Trial s ( Part B). T he I S F will c o ntai n t he Pre g na nc y  M o nit ori n g F or m f or 
Cli nical Trial s ( Parts A a n d B) as well as i nf or mati o n a n d c o nse nt f or m f or t he pre g na nt 
part ner .
As pre g na nc y  itself is n ot t o be re p orte d as a n A E, i n t he a bse nce of a n acc o m pa n yi n g S A E 
a n d/ or A E SI, o nl y t he Pre g na nc y M o nit ori n g F or m f or Cli nical Trial s a n d n ot t he S A E f or m 
is t o be c o m plete d. If t here is a n S A E a n d/ or A E SI ass ociate d wit h t he pre g na nc y a n S A E 
f or m m ust be c o m plete d i n a d diti o n.

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 4 8 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 4 9 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 5 0 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
5. 5 
A P P R O P RI A T E N E S S O F M E A S U R E M E N T S
S ta n dar d met h o ds will be use d as meas ures c o n d ucte d f or b ot h pri mar y  a n d sec o n dar y 
e n d p oi nts. Meas ures c o n d ucte d f or e x pl orat or y  f urt her e n d p oi nts mi g ht be ne w

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 5 1 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
met h o d ol o gies t hat ha ve alrea d y bee n use d i n cli nical trials i n L N b ut n ot yet vali date d f or 
t his rare disease. T his i ncl u des meas ure me nts of patie nt re p orte d o utc o mes e. g. L u p us Pr o 
a n d Fa cit-F.

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 5 2 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
6. 
I N V E S TI G A TI O N A L P L A N
6. 1 
VI SI T S C H E D U L E
All patie nts are t o a d here t o t he visit sc he d ule as s pecifie d i n t he Fl o w C harts . If a n y visit 
nee ds t o be resc he d ule d o utsi de of t he pr ot oc ol all o we d wi n d o w, a p pr o val m ust be o btai ne d 
fr o m t he C T M/ C T L  a n d s u bse q ue nt visits s h o ul d f oll o w t he ori gi nal visit sc he d ule.
A d diti o nal u nsc he d ule d visits mi g ht be arra n ge d at t he discreti o n of t he i n vesti gat or (e. g, i n 
case of rela pses). F or u nsc he d ule d visit, it is s ufficie nt t o rec or d o nly t he cli nicall y rele va nt 
la b orat or y para meters a n d safety fi n di n gs i n t he patie nts’ me dical rec or ds a n d o n t he a d verse 
e ve nt e C R F. D uri n g or at t he e n d of eac h visit, site m ust re gister t he res pecti ve visit i n I R T 
f or eac h patie nt.
F or a detaile d o ver vie w of t he trial pr oce d ures a n d t he acce pta ble ti me wi n d o ws f or eac h 
visit, please refer t o t he Fl o w C harts .
I n e xce pti o nal cases, if sta n dar d visits at t he trial sites are i m p ossi ble beca use of C O VI D- 1 9 
relate d safety ris ks or l ocal restricti o ns , t he f oll o wi ng trial pr oce d ures ma y  be perf or me d 
re m otel y, e. g. via tele p h o ne a n d/ or i nter net base d mea ns of c o m m u nicati o n, as l ocall y 
all o we d:

C ollecti o n of i nf or mati o n of e xisti n g or ne w a d verse e ve nts

C o nfir mi n g c urre nt or ne w c o nc o mita nt me dicati o n or d ose c ha n ges

S L E- disease state

C o m plia nce c hec k, i ncl u di n g st u d y dr u g i njecti o ns a n d t he use of t he e diar y

O utc o me of h o me pre g na nc y  test, if a p plica ble
I n a d diti o n t he f oll o wi n g alter nati ves t o st u d y pr oce d ures ma y be use d

La b pr oce d ures: i n case critical st u d y  visits s uc h as wee k 1 2, 2 6, 4 2 a n d/ or 5 2 ca n n ot 
be d o ne at t he cli nical site, t he patie nt will be as ke d t o ha ve at least certai n 
para meters ( he mat ol o g y , c he mistr y, uri ne tests, C 3/ C 4 a n d A nti-ds D N A) teste d i n a 
l ocal la b if p ossi ble. T he res ults of t he la b tests m ust be tra nsferre d t o t he i n vesti gat or 
w h o e ns ures me dical re vie w a n d pr o per d oc u me ntati o n i n t he e C R F.

If a 2 4 hr uri ne sa m ple will be re q uire d per pr ot oc ol, t he res pecti ve c o ntai ners s h o ul d 
be s hi p pe d t o t he patie nt a n d U P/ U C- val ues meas ure d i n a l ocal la b.

If patie nts’ q uesti o n naires will be re q uire d per pr ot oc ol, t hese s h o ul d be se nt t o t he 
patie nt’s h o me a n d c o m plete d b y  t he patie nt. It is c o nsi dere d t o be a n a p pr o priate 
meas ure as all patie nts ha ve pre vi o usl y c o m plete d s uc h q uesti o n naires at t he site a n d 
are fa miliar wit h t heir use.

T he i n vesti gat or ma y  as k t he patie nt t o meas ure t he b o d y te m perat ure a n d wei g ht at 
h o me a n d ver ball y  re p ort t o t he i n vesti gat or.If t he patie nt is als o n ot all o we d t o pic k 
u p re -s u p ply of i n vesti gati o nal pr o d uct at t he site, a direct t o patie nt’s h o me s hi p me nt 
ma y  be arra n ge d by usi n g a BI -q ualifie d c o urier ser vice.

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 5 3 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
All of t he a b o ve me nti o ne d w or kar o u n ds s hall o nl y be perf or me d after pri or a p pr o val b y C T L 
or T M M a n d wit h t he c o nse nt b y  t he patie nt ( preferre d i n writin g, b ut ver bal c o nse nt 
p ossi ble) a n d if l ocal re g ulati o ns d o all o w s uc h e xce pti o nal meas ures.
All re m ote visits nee d t o be disc usse d wit h a n d a p pr o ve d b y t he s p o ns or`s trial tea m. L ocal 
re g ulat or y a n d le gal re q uire me nts of t he partici pati n g c o u ntr y still a p pl y.
I n case of strict m o ve me nt restricti o ns i n a certai n re gi o n a n d n o w or kar o u n ds are p ossi ble, 
t he f oll o wi n g a p plies

If a patie nt has t o i nterr u pt treat me nt wit h i n vesti gati o nal pr o d uct f or m ore t ha n 6
wee ks t he patie nt s hall be disc o nti n ue d fr o m t he trial.

If n o safet y la b ca n be ta ke n f or m ore t ha n 1 2 wee ks, t he patie nt s hall be disc o nti n ue d 
fr o m t he trial.
All C O VI D- 1 9 relate d de viati o ns fr o m t he ori gi nal sc he d ule of visits a n d pr oce d ures will be 
d oc u me nte d a n d t he i m plicati o ns c o nsi dere d f or t he a n al ys is of t he trial data.
6. 2   
D E T AI L S O F T RI A L P R O C E D U R E S A T S E L E C T E D VI SI T S
Re fer t o t he st u dy Fl o w C harts f or a detaile d descri pti o n of trial pr oce d ures d uri n g t he trial 
peri o d. O nl y a d diti o nal a n d critical i nf or mati o n are o utli ne d bel o w. 
6. 2. 1 
B aseli ne ( Gr o u p 1) 
Writte n i nf or me d c o nse nt m ust be o btai ne d pri or t o a n y st u d y relate d pr oce d ures or 
assess me nts are bei n g perf or me d.
F or r oll- over patie nts ( Gr o u p 1), t he preli mi nar y decisi o n o n re nal res p o nse f or partici pati o n 
i n t his trial will be base d o n la b orat or y res ults fr o m visit 1 5 of t he 1 2 9 3. 1 0 trial. 
I n case visit 1 5 of t he 1 2 9 3. 1 0 trial ca n n ot be use d t o c o me t o a clear r oll o ver decisi o n, V 1 6 
/ E O T-res ults ca n be use d. It is preferre d t o use t he res ults fr o m t he 2 4 hr uri ne c ollecti o n, 
h o we ver U P/ U C -res ults fr o m s p ot uri ne are als o acce pta ble.
T he baseli ne visit m ust ta ke place o n t he sa me da y or at a ma xi m u m wit hi n 3 da y s fr o m E O T 
visit of t he 1 2 9 3. 1 0 trial. All assess me nts perf or me d at t he 1 2 9 3. 1 0 E O T visit will be use d as 
baseli ne assess me nts f or t his trial a n d s h o ul d n ot be re peate d. 
I n case t he baseli ne visit c o ul d n ot be perf or me d o n t he sa me da y  or wit hi n 7 da ys fr o m t he
1 2 9 3. 1 0 E O T visit, a p pr o val m ust be o btai ne d fr o m t he C T M/ C T L pri or t o pr ocee di n g. 
I n case t he baseli ne visit will be later t ha n 7 da ys after E O T of 1 2 9 3. 1 0, selecte d la b val ues 
s hall be re peate d ( bi oc he mistr y, he mat ol o g y, A nti-ds D N A c o m ple me nt C 3/ C 4 a n d ser u m 
creati ni ne a n d U P/ U C).
I n case t he treat me nt i nterr u pti o n bet wee n t he trials is l o n ger t ha n t he a b o ve me nti o ne d 
ti mefa me, i n e xce pti o nal cases patie nts ca n r oll o ver f or et hical reas o ns. Please refer t o 
secti o n 4. 1. 4.

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 5 4 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
F o r a detaile d descri pti o n of t he trial pr oce d ures at t he baseli ne ( Gr o u p 1) visit, please refer 
t o Fl o w C harts .
Baseli ne C o n diti o ns a n d Me dical Hist or y
As a preca uti o n, ris k fact ors f or t hr o m b oe m b olic disease (i ncl u di n g me dical hist or y  of 
D V T/ T E) s h o ul d be s pecificall y  c hec ke d. If cli nicall y rele va nt, t he case s h o ul d be disc usse d 
wit h t he C T L  pri or t o e nr oll me nt.
Hist or y  of a nti p h os p h oli pi d s yn dr o me s h o ul d be rec or de d a n d patie nts s h o ul d be e xcl u de d 
fr o m t he st u d y.
6. 2. 2 
Tre at me nt peri o d
Patie nts fr o m Gr o u p 1 will n ot be ra n d o mise d as t he y  will c o nti n ue recei vi n g t he sa me 
treat me nt all ocati o n as pre vi o usl y assi g ne d i n 1 2 9 3. 1 0 . Patie nts will recei ve t he first d ose of 
st u d y me dicati o n at V isit 1, after all eli gi bilit y criteria ha ve bee n c o nfir me d, t o e ns ure n o 
i nterr u pti o n t o t heir c urre nt treat me nt. 
I n vesti gat ors will n ot be gi ve n access t o t he treat me nt i nf or mati o n of r oll o ver patie nts u ntil 
t he trial is c o m plete d .
T he 2 4 hr uri ne c ollecti o n s will be perf or me d f or e n d p oi nt assess me nts at t he visits i n dicate d 
i n t he Fl o w C harts. Patie nts will be gi ve n i nstr ucti o ns a n d materials t o all o w t he c ollecti o n of 
2 x 2 4 hr uri ne sa m ples d uri n g t he wee k bef ore t he sc h e d ule d visit. At all ot her visits, 
pr otei n uria will be assesse d b y  s p ot uri ne.
I n ge neral, if se veral pr oce d ures i ncl u di n g ve ne p u nct ure are sc he d ule d at t he sa me ti me p oi nt, 
ve ne p u nct ure s h o ul d be perf or me d last d ue t o its i nc o n ve nie nce a n d p ossi ble i nfl ue nce o n 
s u bject’s p hys i ol o gic para meters.
At a n y  visit, s h o ul d a decisi o n be ma de t o disc o nti n ue t he patie nt fr o m st u d y me dicati o n, 
please c o m plete E O T visit i nstea d.
F or a detaile d descri pti o n of trial pr oce d ures d uri n g t he treat me nt peri o d, refer t o Fl o w 
C harts .
A n y  treat me nt i nterr u pti o n of m ore t ha n 2 c o nsec uti ve misse d i njecti o ns s hall be 
c o m m u nicate d t o t he C T L.
6. 2. 3 
F oll o w u p p eri o d a n d tri al co m pleti o n
6. 2. 3. 1  
E n d of Treat me nt ( E O T) Visit
T he E O T visit will be perf or me d wit hi n 7 da y s after t he last a d mi nistrati o n of trial 
me dicati o n i n all patie nts w h o eit her c o m plete t he 5 2 -wee k treat me nt peri o d or pre mat urel y 
disc o nti n ue t he st u d y  me dicati o n f or a ny reas o n.
F or a detaile d descri pti o n of t he trial pr oce d ures at E O T, refer t o Fl o w C harts .

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 5 5 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
6. 2. 3. 2 
F oll o w -U p ( F U p) a n d E n d of St u d y  ( E O S) Visits
After t he E O T visit, patie nts w h o ha ve c o m plete d t he 5 2- wee k treat me nt peri o d will ret ur n 
f or a safety F U p visit 4 wee ks later, f oll o we d b y t he E O S visit 1 2 wee ks after E O T. 
I n case a patie nt has t o disc o nti n ue t he trial me dicati o n pri or t o ha vi n g c o m plete d t he 5 2-
wee k treat me nt peri o d , t he patie nt will be i n vite d t o atte n d a s u bset of visits as per secti o n 
6. 2. 3. 3 bel o w.
T he i n vesti gat or will c o nti n ue t o rec or d a n d f oll o w- u p o n all A Es u ntil t he resi d ual effect 
peri o d ( R E P). Refer t o secti o n 5.2. 5. 2 f or A E c ollecti o n pr oce d ures after t he R E P. At E O S 
visit, t he i n vesti gat or nee ds t o c o nfir m w het her t he A Es are s ufficie ntl y f oll o we d u p a n d 
pr o vi de d oc u me ntati o n i n t he patie nt’s me dical rec or ds a n d o n t he e C R F.
F or a detaile d descri pti o n of t he trial pr oce d ures at F U p a n d E O S visits, refer t o Fl o w C h arts.  
6. 2. 3. 3 
A d diti o nal f oll o w -u p f or pre mat urel y disc o nti n ue d patie nts
F or pre mat urel y disc o nti n ue d patie nts , it is i m p orta nt t hat t heir re nal f u ncti o n para meters a n d 
safety assess me nts are perf or me d a n d rec or de d u ntil t he e n d of t he 5 2- wee k peri o d .
T h eref ore, all earl y disc o nti n ue d patie nts will be i n vite d t o atte n d a s u bset of F U p visit s at t he 
f oll o wi n g ti me p oi nts: Wee k 1 2, Wee k 2 6, Wee k 4 2
a n d Wee k 5 2.
At t hese F U p visits, t he f oll o wi n g assess me nts will be perf or me d: p h y sical e xa mi nati o n, A E 
a n d C T c ollecti o n, ser u m creati ni ne a n d s p ot uri ne test t o assess re nal f u ncti o n. Ot her safet y 
la b orat or y tests, P K, A D A, s ol u ble pr otei n bi o mar kers, a nti- ds-D N A a n d c o m ple me nt le vels
will be c ollecte d at t hese visits . 
If t he ne xt F U p visit is pla n ne d m ore t ha n 1 2 wee ks after E O T, all o pti o nal tests s hall be 
perf or me d at least o nce i n t he F U p peri o d: i.e. if t he patie nt E O T is at wee k 2 6 a n d t he ne xt 
visit will be o nl y  at wee k 4 2: o pti o nal tests m ust be d o ne at wee k 4 2, e ve n if t he ti me 
bet wee n wee k 2 6 & 4 2 is > 1 2 wee ks.
D uri n g t he a d diti o nal f oll o w -u p peri o d, after t he patie nts ha ve disc o nti n ue d t he trial 
me dicati o n a n d ha ve bee n f oll o we d -u p f or 4 wee ks, t he patie nt s will be all o we d t o partici pate 
i n a n ot her i n vesti gati o nal st u d y w hilst c o nti n u e t o atte n d t hese a d diti o nal st u d y visits as 
descri be d a b o ve. 
I n case t he patie nt disc o nti n ue d m ore t ha n 1 2 wee ks bef ore wee k 5 2, n o a d diti o nal f oll o w u p 
visits w o ul d be re q ui re d after wee k 5 2 . I n case t he patie nt disc o nti n ue d less t ha n 1 2 wee ks 
bef ore wee k 5 2 , t he last f oll o w-u p visit will be 1 2 wee ks +/ - 5 d a y s after disc o nti n uati o n.
I n case t he patie nt was u na ble t o atte n d t hese a d diti o nal st u d y visits, vital stat us i nf or m ati o n 
will be c ollect e d at - Wee k 5 2 or 6 4 de pe n di n g o n disc o nti n uati o n date (see a b o ve) .

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 5 6 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
7. 
S T A TI S TI C A L M E T H O D S A N D D E T E R MI N A TI O N O F
S A M P L E SI Z E
7. 1  
S T A TI S TI C A L D E SI G N – M O D E L
T his e x pl orat or y P hase II mai nte na nce trial is desi g ne d t o st u d y t he l o n g ter m efficac y a n d 
safety of differe nt d oses of BI 6 5 5 0 6 4 vers us place b o as a d d- o n t hera p y  t o sta n dar d of care;
a n d t he effect of ster oi d ta peri n g a n d ster oi d wit h dra wal d uri n g t he 5 2 wee ks of mai nte na nce
treat me nt.
T he trial is a parallel- desi g n , d ose-ra n gi n g, place b o-c o ntr olle d, d o u ble-bli n d, m ulti -ce ntre
a n d m ulti -nati o nal. T he trial will i ncl u de patie nts w h o res p o n de d t o eit her BI 6 5 5 0 6 4 or 
place b o i n t he i n d ucti o n trial.  Patie nts will re mai n o n t he treat me nt t o w hic h t he y were 
ra n d o ml y assi gne d at t he start of t he i n d ucti o n trial .
Base d o n t hese desi g n c o nsi derati o ns, a nal ys es will be e x pl orat or y a n d descri pti ve. 
7. 2 
N U L L A N D A L T E R N A TI V E H Y P O T H E S E S
N o f or mal statistical h y p ot heses will be teste d . I nfere ntial tests will be perf or me d wit h 
n o mi nal p -val ues a n d c o nfi de nce i nter vals pr o vi de d t o descri be t he efficac y of BI 6 5 5 0 6 4 
vers us place b o as a d d -o n t hera p y  t o sta n dar d of care d uri n g a n d f oll o wi n g 5 2 wee ks of 
mai nte na nce treat me nt.
7. 3 
P L A N N E D A N A L Y S E S
As t he o bjecti ves of t he trial are t o st u d y l o n g ter m efficac y a n d safet y a n d all patie nts will 
ha ve ha d a d d -o n i n d ucti o n t hera p y  wit h eit her BI 6 5 5 0 6 4 or place b o, t he a nal yses will 
i nc or p orate data fr o m 1 2 9 3. 1 0.  T his will all o w c o m paris o n of treat me nt gr o u ps o ver t he t w o-
ye ar treat me nt peri o d.  U nless ot her wise n ote d, t he baseli ne fr o m 1 2 9 3. 1 0 will be use d as t he 
baseli ne f or all c ha n ge fr o m baseli ne assess me nts.
Baseli ne c haracteristics of patie nts w h o e nter t he 1 2 9 3- 0 0 1 3 trial will be c o m pare d t o t he 
baseli ne c haracteristics of patie nts w h o e ntere d trial 1 2 9 3. 1 0.  A n y  c ha n ges wit h res pect t o 
o verall baseli ne c haracteristics or t he distri b uti o n of rele va nt baseli ne c haracteristics acr oss 
treat me nt gr o u ps will be n ote d.
T he pri mar y  a nalys is will f oll o w t he i nte nti o n t o treat (I T T) pri nci ple t h us it is base d o n t he
treate d set, i.e., all patie nts treate d i n 1 2 9 3- 0 0 1 3 Safet y  a nalys is will be base d o n all treate d 
patie nts a n d t he safet y  pr ofile will be c o m pare d i n a descri pti ve ma n ner bet wee n t he 
e x peri me ntal ar ms a n d t he c o ntr ol ar m. 
All i n d i vi d ual data will be liste d. A d here nce t o t he pr ot oc ol (e. g. i ncl usi o n/e xcl usi o n criteria, 
ti mes of meas ure me nt, c o m plete ness a n d c o nsiste nc y of data etc.) will be c hec ke d usi n g t he 
data rec or de d. I mp orta nt pr ot oc ol vi olati o ns will be descri be d i n t he Tria l Statistical A nal ysis 
Pla n ( T S A P). Sta n dar d statistical para meters ( n u m ber of n o n- missi n g val ues, mea n, sta n dar d 

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 5 7 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
de viati o n, me dia n, q uartiles, mi ni m u m a n d ma xi m u m) or fre q ue nc y  ta bles will be calc ulate d 
w here a p pr o priate. I n ge neral, t hese para meters or fre q ue ncies will be calc ulate d se paratel y 
f or eac h treat me nt gr o u p.
7. 3. 1 
Pri m ar y e n d p oi nt a n al yses
T he pri mar y  e n d p oi nt is t he pr o p orti o n of patie nts wit h c o m plete re nal res p o nse after 5 2 
wee ks of treat me nt a n d wit h o ut a n y re nal flares. T he pri mar y  a nalys is wil l be perf or me d i n 
all treate d patie nts usi n g I T T . 
C o m paris o ns bet wee n treat me nt gr o u ps will be e x pl orat or y  i n nat ure a n d base d o n n u merical 
c o m paris o n of t he res pecti ve res p o nse rates. 
Statistical met h o ds use d i n 1 2 9 3. 1 0 f or pair wise c o m paris o ns will be use d.  I nfere ntial tests are 
i nte n de d f or i nf or mati o nal a n d descri pti ve p ur p oses.
F urt her details will be pr o vi de d i n t he T S A P.
7. 3. 2  
Sec o n d ar y e n d p oi nt a n al yses
Sec o n dar y e n d p oi nts (Secti o n 2. 1. 3 ) will be a nal yse d i n t he sa me wa y as t he pri mar y 
e n d p oi nt. F or t he e n d p oi nt of ti me t o first re nal flare, a Ka pla n Meier c ur ve will be prese nte d. 
F urt her details will be pr o vi de d i n t he T S A P.
7. 3. 4 
S afet y a n al yses
A d verse e ve nts will be c o de d usi n g t he Me dical Dicti o nar y  f or Dr u g Re g ulat or y  Acti vities
( Me d D R A). Sta n dar d BI s u m mar y ta bles a n d listi n gs will be pr o d uce d. All a d verse e ve nts 
wit h a n o nset bet wee n start of treat me nt a n d e n d of t he resi d ual effect peri o d ( R E P), a peri o d 
of 5 0 d a y s after t he last d ose of trial me dicati o n , will be assi g ne d t o t he o n-t reat me nt peri o d 
f or e val uati o n. A nal ys is will be perf or me d base d o n ra n d o mise d treat me nt.
All treate d patie nt s will be i ncl u de d i n t he safety a nal ysis. I n ge neral, safet y a nal ys es will be 
descri pti ve i n nat ure a n d base d o n BI sta n dar ds. N o h y p ot hesis testi n g is pla n ne d. Statistical 
a nal ys is a n d re p orti n g of a d verse e ve nts will c o nce ntrate o n treat me nt-e mer ge nt a d verse 
e ve nts, i.e. all a d verse e ve nts occ urri n g bet wee n start of treat me nt a n d e n d of t he R E P .
A d verse e ve nts t hat start bef ore first dr u g i nta ke a n d deteri orate u n der treat me nt will als o be 
c o nsi dere d as ‘treat me nt -e mer ge nt’.

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 5 8 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
Fre q ue nc y , se verity a n d ca usal relati o ns hi p of a d verse e ve nts will be ta b ulate d by s ys te m 
or ga n class a n d preferre d ter m after c o di n g acc or di n g t o t he c urre nt versi o n of t he Me d D R A
at t he data base l oc k.
A E SI s will be s u m marize d se parately usi n g a sta n dar d BI s u m mar y ta ble.  N ote t hat t here is 
o ne S A E defi niti o n s pecifie d i n Secti o n 5. 2. 5. 1 f or Ja pa n o nl y.
La b orat or y  data will be a nal yse d b ot h q ua ntitati vel y  as well as q ualitati vel y. T he latter will 
be d o ne via c o m paris o n of la b orat or y data t o t heir refere nce ra n ges. Val ues o utsi de t he 
refere nce ra n ge as well as val ues defi ne d as cli nicall y  rele va nt will be s u m marise d. Treat me nt 
gr o u ps will be c o m pare d descri pti vel y wit h re gar d t o distri b uti o n para meters as well as wit h 
re gar d t o fre q ue nc y a n d perce nta ge of patie nt s wit h a b n or mal val ues or cli nicall y rele va nt 
a b nor mal val ues.
Vital si g ns, p h ys ical e xa mi nati o ns, or ot her safety- rele va nt data o bser ve d at scree ni n g, 
baseli ne, d uri n g t he c o urse of t he trial a n d at t he e n d- of-trial e val uati o n will be assesse d wit h 
re gar d t o p ossi ble c ha n ges c o m pare d t o fi n di n gs bef ore start of treat me nt.
7. 4  
I N T E RI M A N A L Y S E S
N o i nteri m a nalys is is pla n ne d b ut D M C will be i n place wit h tas ks as descri be d in Secti o n 
8. 7 .
7. 5 
H A N D LI N G O F MI S SI N G D A T A
As a n i m p utati o n tec h ni q ue t o deal wit h missi n g data i n t his st u d y , f or t he a nal ysis of pri mar y 
a n d C R R -relate d sec o n dar y e n d p oi nts, n o n-c o m pleters c o nsi dere d fail ure will be use d. 
F urt her details o n t he i m p utati o n a p pr oac hes will be s pecifie d i n t he T S A P.
7. 6 
R A N D O MI S A TI O N
Patie nts e nteri n g t he trial fr o m 1 2 9 3. 1 0 ( Gr o u p 1) will re mai n o n t heir assi g ne d treat me nt. 

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 5 9 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
B I will arra n ge f or t he pac ka gi n g a n d t he la belli n g of trial me dicati o n. 
7. 7 
D E T E R MI N A TI O N O F S A M P L E SI Z E
It is esti mate d t hat 6 0 res p o n ders fr o m 1 2 9 3. 1 0 will be pre pare d t o r oll -o ver i nt o 1 2 9 3- 0 0 1 3.
T here is n o p o wer calc ulati o n f or t his .

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 6 0 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
8. 
I N F O R M E D C O N S E N T, T RI A L R E C O R D S , D A T A 
P R O T E C TI O N, P U B LI C A TI O N P O LI C Y , A N D 
A D MI NI S T R A TI V E S T R U C T U R E
T he trial will be carrie d o ut i n c o m plia nce wit h t he pr ot oc ol, t he et hical pri nci ples lai d d o w n 
i n t he Declarati o n of Helsi n ki, i n acc or da nce wit h t he IC H Har m o nize d Tri partite G ui deli ne 
f or G o o d Cli nical Practice ( G C P), rele va nt BI Sta n dar d O perati n g Pr oce d ures ( S O Ps), t he E U 
re g ulati o n 5 3 6/ 2 0 1 4, t he Ja pa nese G C P re g ulati o ns ( Mi nistr y of Healt h a n d Welfare 
Or di na nce N o. 2 8, Marc h 2 7, 1 9 9 7) a n d ot her rele va nt re g ulatio ns.
Sta n dar d me dical care ( pr o p h y lactic, dia g n ostic a n d t hera pe utic pr oce d ures) re mai ns t he 
res p o nsi bilit y of t he treati n g p h ysicia n of t he patie nt .
T he i n vesti gat or will i nf or m t he s p o ns or i m me diatel y of a n y ur ge nt safety meas ures ta ke n t o 
pr otect t he trial patie nts a gai nst a n y i m me diate hazar d, as well as of a n y s eri o us breac hes of 
t he pr ot oc ol or of I C H G C P.
T he B oe hri n ger I ngel hei m tra ns pare nc y  a n d p u blicati o n p olic y ca n be f o u n d o n t he f oll o wi n g 
we b pa ge : trials. b oe hri n ger-i n gel hei m.c o m. T he ri g hts of t he i n vesti gat or a n d of t he s p o ns or
wit h re gar d t o p u blicati o n of t he res ults of t his trial are descri be d i n t he i n vesti gat or c o ntract. 
As a r ule , n o trial res ults s h o ul d be p u blis he d pri or t o fi nalisati o n of t he Cli nical Trial Re p ort.
T he certificate of i ns ura nce c o ver is ma de a vaila ble t o t he i n vesti gat or a n d t he patie nt s a n d is
st ore d i n t he IS F.
8. 1 
T RI A L A P P R O V A L, P A TI E N T I N F O R M A TI O N, I N F O R M ED C O N S E N T
T his trial will be i nitiate d o nl y  after all re q uire d le gal d oc u me ntati o n has bee n re vie we d a n d 
a p pr ove d b y t he res pecti ve I nstit uti o nal Re vie w B oar d (I R B) / I n de pe n de nt Et hics C o m mittee 
(I E C) a n d c o m pete nt a ut h orit y ( C A) acc or di n g t o nati o nal a n d i nter nati o nal re g ulati o ns. T he 
sa me a p plies f or t he i m ple me ntati o n of c ha n ges i ntr o d uce d b y a me n d me nts.
Pri o r t o patie nt partici pati o n i n t he trial, writte n i nf or me d c o nse nt m ust be o btai ne d fr o m eac h 
patie nt ( or t he patie nt ’s le gall y acce pte d re prese ntati ve) acc or di n g t o I C H / G C P a n d t o t he 
re g ulat or y a n d le gal re q uire me nts of t he partici pati n g c o u ntr y. Eac h si g nat ure m ust be 
pers o nall y date d b y eac h si g nat or y a n d t he i nf or me d c o nse nt a n d a n y a d diti o nal patie nt -
i nf or mati o n f or m retai ne d b y t he i n vesti gat or as part of t he trial rec or ds. A si g ne d c o p y of t he 
i nf or me d c o nse nt a n d a n y a d diti o nal patie nt i nf or mati o n m ust be gi ve n t o eac h patie nt or t he 
patie nt ’s le gally ac ce pte d re prese ntati ve.
F or J a p a n o nly: T he i n vesti gat or m ust gi ve a f ull e x pla nati o n t o trial patie nt s base d o n t he
patie nt i nf or mati o n f or m. A la n g ua ge u n dersta n da ble t o t he patie nt s h o ul d be c h ose n, 
tec h nical ter ms a n d e x pressi o ns a v oi de d, if p ossi ble. T he patie nt m ust be gi ve n s ufficie nt 
ti me t o c o nsi der partici pati o n i n t he trial. T he i n vesti gat or o btai ns writte n c o nse nt of t he 
patie nt ’s o w n free will wit h t he i nf or me d c o nse nt f or m after c o nfir mi n g t hat t he patie nt

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 6 1 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
u n dersta n ds t he c o nte nts. T he i n vesti gat or m ust si g n ( or place a seal o n) a n d date t he 
i nf or me d c o nse nt f or m. If a trial c olla b orat or has gi ve n a s u p ple me ntar y e x pla nati o n, t he trial
c olla b orat or als o si g ns ( or places a seal o n) a n d dates t he i nf or me d c o nse nt.
Re -c o nse nti n g ma y bec o me necessar y  w he n ne w rele va nt i nf or mati o n bec o mes a vaila ble a n d 
s h o ul d be c o n d ucte d acc or di n g t o t he s p o nsor’s i nstr ucti o ns. T he c o nse nt a n d re -c o nse nti n g 
pr ocess s h o ul d be pr o perl y  d oc u me nte d i n t he s o urce d oc u me ntati o n.
8. 2   
D A T A Q U A LI T Y A S S U R A N C E
A q ualit y  ass ura nce a u dit/i ns pecti o n of t his trial ma y be c o n d ucte d b y t he s p o ns or, s p o ns or’s 
desi g nees , or b y I RB / I EC or b y  re g ulat or y a ut h orities. T he q ualit y ass ura nce a u dit or will 
ha ve access t o all me dical rec or ds, t he i n vesti gat or’s trial-relate d files a n d c orres p o n de nce, 
a n d t he i nf or me d c o nse nt d oc u me ntati o n of t his cli nical trial.
8. 3 
R E C O R D S
Electr o nic case re p ort f or ms (e C R F s) f or i n di vi d ual patie nt s will be pr o vi de d b y t he s p o ns or.
See Secti o n 4. 1. 5. 2 f or r ules a b o ut e mer ge nc y c o de brea ks. F or dr u g acc o u nta bilit y, refer t o 
Secti o n 4. 1. 8 .
8. 3. 1 
S o urce d oc u me nts
I n acc or da nce wit h re g ulat or y re q uire me nts t he i n vesti gat or s h o ul d pre pare a n d mai ntai n 
a de q uate a n d acc urate s o urce d oc u me nts a n d trial rec or ds t hat i ncl u de all o bser vati o ns a n d 
ot her data perti ne nt t o t he i n vesti gati o n o n eac h trial patie nt . S o urce data as well as re p orte d 
data s h o ul d f oll o w g o o d d oc u me ntati o n practices a n d be attri b uta ble, le gi ble,
c o nte m p ora ne o us, ori gi nal a n d acc urate. C ha n ges t o t he data s h o ul d be tracea ble (a u dit trail).
Data re p orte d o n t he eC R F m ust be c o nsiste nt wit h t he s o urce d ata or t he discre pa ncies m ust 
be e x plai ne d.
T he c urre nt me dical hist or y of t he patie nt m a y  n ot be s ufficie nt t o c o nfir m eli gi bilit y f or t he 
trial a n d t he i n vesti gat or ma y  nee d t o re q uest pre vi o us me dical hist ories a n d e vi de nce of a n y 
dia g n ostic tests. I n t his case t he i n vesti gat or m ust ma ke t hree d oc u me nte d atte m pts t o retrie ve 
pre vi o us me dical rec or ds. If t his fails a ver bal hist or y  fr o m t he patie nt , d oc u me nte d i n t heir 
me dical rec or ds, w o ul d be acce pta ble.
If t he patie nt is n ot c o m plia nt wit h t he pr ot oc ol, a n y c orrecti ve acti o n e. g. re-trai ni n g m ust be 
d oc u me nte d i n t he patie nt file.
F or t he eC R F, data m ust be deri ve d fr o m s o urce d oc u me nts, f or e xa m ple:

Patie nt i de ntificati o n: ge n der, year of birt h (i n acc or da nce wit h l ocal la ws a n d 
re g ulati o ns)

Patie nt partici pati o n i n t he trial (s u bsta nce, trial n u m ber, patie nt n u m ber, date patie nt was 
i nf or me d)

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 6 2 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6

Dates of patie nt ’s visits, i ncl u di n g dis pe nsi n g of trial me dicati o n

Me dical hist or y  (i ncl u di n g trial i n dicati o n a n d c o nc o mita nt diseases, if a p plica ble)

M e dicati o n hist or y

A d verse e ve nts a n d o utc o me e ve nts ( o nset date ( ma n dat or y ), a n d e n d date (if a vaila ble))

S eri o us a d verse e ve nts ( o nset date ( ma n dat or y ), a n d e n d date (if a vaila ble))

C o nc o mita nt t hera p y (start date, c ha n ges)

Ori gi nals or c o pies of la b orat or y  res ults a n d ot her i ma gi n g or testi n g res ults, wit h pr o per 
d oc u me nte d me dical e val uati o n (i n vali date d electr o nic f or mat, if a vaila ble)

C o m pleti o n of p atie nt’s p artici pati o n i n t he trial” (e n d date; i n case of pre mat ure 
disc o nti n uati o n d oc u me nt t he reas o n f or it)

Pri or t o all ocati o n of a patie nt t o a treat me nt i nt o a cli nical trial, t here m ust be 
d oc u me nte d e vi de nce i n t he s o urce data (e. g. me dical rec or ds) t hat t he trial partici pa nt 
meets all i ncl usi o n criteria a n d d oes n ot meet a n y  e xcl usi o n criteria. T he a bse nce of 
rec or ds (eit her me dical rec or ds, ver bal d oc u me nte d fee d bac k of t he patie nt or testi n g 
c o n d ucte d s pecific f or a pr ot oc ol) t o s u p p ort i ncl usi o n/e xcl usi o n criteria d oes n ot ma ke 
t he patie nt eli gi ble f or t he cli nical trial
8. 3. 2   
Direct access t o s o urce d at a a n d d oc u me nts
T he s p o ns or will m o nit or t he c o n d uct of t he trial b y re g ular o n -site m o nit ori n g visits a n d i n-
h o use data q ualit y re vie w. T he fre q ue nc y of site m o nit ori n g will be deter mi ne d b y  assessi n g 
all c haracteristics of t he trial, i ncl u di n g its nat ure, o bjecti ve, met h o d ol o g y a n d t he de gree of 
a n y de viati o ns of t he i nter ve nti o n fr o m n or mal cli nical practice.
T he i n vesti gat or /i nstit uti o n will all o w site trial-relate d m o nit ori n g, a u dits, I R B / I E C re vie w 
a n d re g ulat or y i ns pecti o ns. Direct access m ust be pr o vi de d t o t he eC R F a n d all s o urce 
d oc u me nts/ data, i ncl u di n g pr o gress n otes, c o pies of la b orat or y  a n d me dical test res ults, w hic h 
m ust be a vaila ble at all ti mes f or re vie w b y t he C R A , a u dit or a n d re g ulat or y i ns pect or 
(e. g. F D A). T h e y  m a y  re vie w all eC R Fs a n d i nf or me d c o nse nts. T he acc urac y  of t he data will 
be verifie d b y  direct c o m paris o n wit h t he s o urce d oc u me nts descri be d i n secti o n 8. 3. 1. T he 
s p o ns or will als o m o nit or c o m plia nce wit h t he pr ot oc ol a n d I C H-G C P.
D ue t o C o vi d -1 9 pa n de mic restricti o ns), site access ma y  be restricte d t h us li miti n g t he a bilit y 
t o perf or m sta n dar d site m o nit ori n g acti vities o n site s uc h as o n-site s o urce data re vie w a n d 
s o urce data verificati o n. T heref ore, s o me of t hese acti vities ma y be perf or me d re m otely or 
re place d by ce ntralize d m o nit ori n g t o t he e xte nt p ossi b le, base d o n a d oc u me nte d ris k 
assess me nt a n d i n ali g n me nt wit h l ocal re g ulati o ns.
8. 3. 3  
St or a ge peri o d of rec or ds
Trial sites:
T he trial sites m ust retai n t he s o urce a n d esse ntial d oc u me nts (i ncl u di n g I SF) acc or di n g t o 
c o ntract or t he l ocal re q uire me nts vali d at t he ti me of t he e n d of t he trial ( w hic he ver is 
l o n ger).
S p o ns or :
T he s p o ns or m ust retai n t he esse ntial d oc u me nts acc or di n g t o t he s p o ns or’s S O Ps.

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 6 3 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
8. 4  
E X P E DI T E D R E P O R TI N G O F  A D V E R S E E V E N T S
BI is res p o nsi ble t o f ulfil t heir le gal a n d re g ulat or y re p orti n g o bli gati o n i n acc or da nce wit h 
re g ulat or y re q uire me nts. 
8. 5 
S T A T E M E N T O F C O N FI D E N TI A LI T Y A N D P A TI E N T P RI V A C Y
I n di vi d ual patie nt data o btai ne d as a res ult of t his trial is c o nsi dere d c o nfi de ntial a n d 
discl os ure t o t hir d parties is pr o hi bite d wit h t he e xce pti o ns n ote d bel o w. Patie nt pri vac y will 
be e ns ure d b y usi n g patie nt i de ntificati o n c o de n u m bers.
Data pr otecti o n a n d data sec urit y meas ures are i m ple me nte d f or t he c ollecti o n, st ora ge a n d 
pr ocess i n g of patie nt data i n acc or da nce wit h t he pri nci ples 6 a n d 1 2 of t he W orl d H ealt h 
O r ga nisati o n G C P ha n d b o o k.
Treat me nt data ma y  be gi ve n t o t he patie nt ’s pers o nal p h ysicia n or t o ot her a p pr o priate 
me dical pers o n nel res p o nsi ble f or t he patie nt ’s welfare. Data ge nerate d as a res ult of t he trial
nee d t o be a vaila ble f or i ns pecti o n o n re q uest b y t he partici pati n g p h ys icia ns, t he s p o ns or’s 
re prese ntati ves, by t he I R B / I E C a n d t he re g ulat or y a ut h orities .
8. 5. 1 
C ollecti o n, st or a ge a n d f ut ure use of bi ol o g ic al s a m ples a n d c orres p o n di n g 
d at a 
Meas ures are i n place t o c o m pl y wit h t he a p plica ble r ules f or t he c ollecti o n, st ora ge a n d 
f ut ure use of bi ol o gical sa m ples fr o m cli nical trial partici pa nts a n d t he c orres p o n di n g data, i n 
partic ular

A Q ualit y  Ma na ge me nt S y ste m has bee n i m ple me nte d t o e ns ure t he a d here nce wit h 
t he Pri nci ples of G o o d Cli nical Practice as o utli ne d i n ' N ote F or G ui da nce O n G o o d 
Cli nical Practice' ( C P M P/I C H/ 1 3 5/ 9 5) .

T he BI -i nter nal facilities st ori n g a n d a nalys i n g bi ol o gical sa m ples a n d data fr o m 
cli nical trial partici pa nts as well as t he la b orat ories' acti vities f or cli nical trials 
s p o ns ore d by B oe hri n ger I n gel hei m are re g ularl y a u dite d. T he a nal ytical gr o u ps a n d 
t he ba n ki n g facility are t heref ore assesse d t o be q ualifie d f or t he st ora ge a n d use of 
bi ol o gical sa m ples a n d data c ollecte d i n cli nical trials.

Sa m ples a n d data are use d o nl y  if a n a p pr o priate i nf or me d c o nse nt is a vaila ble.
8. 6 
T RI A L M I L E S T O N E S
T he st art of t he tri al is defi ne d as t he date w he n t he first patie nt i n t he w h ole trial si g ns 
i nf or me d c onse nt .
T he e n d of t he tri al is defi ne d as t he date of t he last visit of t he last patie nt i n t he w h ole trial
(“ Last Patie nt O ut” ).

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 6 4 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
T he “ L ast P atie nt Dr u g Disc o nti n u ati o n ” ( L P D D) date is defi ne d as t he date o n w hic h t he 
last patie nt at a n i n di vi d ual trial site e n ds trial me dicati o n (as sc he d ule d per pr ot oc ol or 
pre mat urel y). I n di vi d ual i n vesti gat ors will be n otifie d of S U S A Rs occ urri n g wit h t he trial
me dicati o n u ntil 3 0 da y s after L P D D at t heir site.
E arl y ter mi n ati o n of t he tri al is defi ne d as t he pre mat ure ter mi nati o n of t he trial d ue t o a n y 
reas o n bef ore t he e n d of t he trial as s pecifie d i n t his pr ot oc ol.
Te m p or ar y h alt of t he tri al is defi ne d as a ny u n pla n ne d i nterr u pti o n of t he trial b y  t he 
s p o ns or wit h t he i nte nti o n t o res u me it.
S us pe nsi o n of t he tri al is defi ne d as a n i nterr u pti o n of t he trial base d o n a Healt h A ut h orit y  
re q uest.
T he IE C / c o m pete nt a ut h orit y i n eac h partici pati n g E U me m ber state will be n otifie d a b o ut 
t he trial milest o nes acc or di n g t o t he res pecti ve la ws.
A fi nal re p ort of t he cli nical trial data will be writte n o nl y  after all patie nt s ha ve c o m plete d 
t he trial i n all c o u ntries ( E U or n o n- E U) t o i nc or p orate a n d c o nsi der all data i n t he re p ort.
T he s p o ns or wi ll s u b mit t o t he E U data base a s u m mar y of t he fi nal trial res ults wit hi n o ne 
ye ar fr o m t he e n d of a cli nical trial as a w h ole, re gar dless of t he c o u ntr y  of the last patie nt
( E U or n o n-E U).
8. 7   
A D MI NI S T R A TI V E S T R U C T U R E O F T H E T RI A L
T he trial is s p o ns ore d by B oe hri n ger I n gel hei m ( BI).
A C o or di nati n g I n vesti gat or is res p o nsi ble t o c o or di nate in vesti gat ors at t he differe nt sites 
partici pati n g i n t his trial. Tas ks a n d res p o nsi bilities are defi ne d i n a c o ntract. 
A Data M o nit ori n g C o m mittee ( D M C), i n de pe n de nt of t he S p o ns or, will be esta bl is he d. T he y  
are p h ys icia ns e x perie nce d i n t he treat me nt of t he disease u n der i n vesti gati o n a n d a 
statisticia n. Re g ular D M C meeti n gs will be hel d at s pecifie d i nter vals t o e val uate safet y data
a n d t he y will als o recei ve ur ge nt si g nifica nt safet y c o ncer ns i ncl u di n g DI LI f or i m me diate 
e val uati o n . T he D M C will rec o m me n d c o nti n uati o n, m o dificati o n or ter mi n ati o n of t he trial 
as detaile d i n t he D M C c harter. D M C rec o m me n dati o ns as well as t he fi nal BI decisi o n will 
be re p orte d t o t he a p pr o priate R As/ H As, I R Bs/ E C s, a n d t o i n vesti gat ors as re q ueste d by l ocal 
la w. W hile D M C me m bers ma y  be u n bli n de d, meas ures are i n place t o e ns ure t he bli n di n g 
f or e ver yo ne else i n v ol ve d i n t he trial. T he tas ks a n d res p o nsi bilities of t he D M C are 
s pecifie d i n a c harter.
Rele va nt d oc u me ntati o n o n t he partici pati n g ( Pri nci pal) I n vesti gat ors (e. g. t heir c urric ula 
vitae ) will be file d i n t he I n vesti gat or Site File (I SF ). T he i n vesti gat ors will ha ve access t o t he 
BI cli nical trial p ortal ( Cli ner gize) t o facilitate d oc u me nt e xc ha n ge a n d mai ntai n electr o nic 
I SF. 

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 6 5 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
BI has a p p oi nte d a Cli nical Trial Lea der , res p o nsi ble f or c o or di nati n g all re q uire d acti vities, 
i n or der t o:
-
ma na ge t he trial i n acc or da nce wit h a p plica ble re g ulati o ns a n d i nter nal S O Ps,
-
direct t he cli nical trial tea m i n t he pre parati o n, c o n d uct, a n d re p orti n g of t he trial,
-
e ns ure a p pr o priate trai ni n g a n d i nf or mati o n of L ocal C li nical Trial Ma na gers (C T M s), 
Cli nica l Researc h Ass ociates ( C R As), a n d i n vesti gat ors of partici pati n g c o u ntries.
T he or ga nisati o n of t he trial i n t he partici pati n g c o u ntries will be perf or me d b y t he res pecti ve 
l ocal or re gi o nal BI -or ga nisati o n ( O perati n g U nit, O P U) i n acc or da nce wit h a p plica ble 
re g ulati o ns a n d BI S O Ps , or b y  a C o ntract Researc h Or ga nisati o n ( C R O) wit h w hic h t he 
res p o nsi bilities a n d tas ks will ha ve bee n a gree d a n d a writte n c o ntract file d bef ore i nitiati o n 
of t he cli nical trial. Data Ma na ge me nt a n d Statistical E val uati o n will be d o ne b y  BI acc or di n g 
t o BI S O Ps. Tas ks a n d f u ncti o ns assi g ne d i n or der t o or ga nise, ma na ge, a n d e val uate t he trial
are defi ne d acc or di n g t o BI S O Ps. A list of res p o nsi ble pers o ns a n d rele va nt l ocal 
i nf or mati o n ca n be f o u n d i n t he IS F.
A ce ntral la b orat or y ser vice a n d a n I RT ve n d or will be use d i n t his trial. Details will be 
pr o vi de d i n t he Ce ntral La b orat or y  a n d I R T m a n uals a vaila ble i n t he I SF.

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 6 6 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
9. 
R E F E R E N C E S
9. 1 
P U B LI S H E D R E F E R E N C E S
P 1 2 - 1 1 0 0 5 
A p pel G B, C o ntreras G, D o ole y  M A, Gi nzler E M, Ise n ber g D, Jay ne D, Li  
L S, M ys ler E, Sa nc hez-G uerrer o J, S ol o m o ns N, W ofs y  D, As pre va L u p us.
Ma na ge me nt St u d y  Gr o u p M y c o p he n olate m ofetil vers us c ycl o p h os p ha mi de 
f or i n d ucti o n treat me nt of l u p us ne p hritis. J A m S oc Ne p hr ol 2 0, 1 1 0 3 - 1 1 1 2 
( 2 0 0 9)
P 1 5 - 0 1 9 1 6 
R uiz -Arr uza I , U garte A, Ca bezas-R o dri g uez I , Me di na J A, M ora n M A, R uiz-
Irast orza G Gl uc oc ortic oi ds a n d irre versi ble da ma ge i n patie nts wit h s yste mic 
l u p us er yt he mat os us. R he u mat ol o g y ( O xf or d) 5 3 ( 8), 1 4 7 0 - 1 4 7 6 ( 2 0 1 4)
R 1 0 - 1 4 2 4 
Pi n heir o J, B or n ka m p B, Bretz F; Desi g n a n d a nal ysis of d ose-fi n di n g st u dies 
c o m bi ni n g m ulti ple c o m paris o ns a n d m o delli n g pr oce d ures. J Bi o p har m Stat 
1 6 ( 5), 6 3 9 - 6 5 6 ( 2 0 0 6)
R 1 1 - 4 8 9 0 
Sa m ps o n H A, et al. Sec o n d s y m p osi u m o n t he defi niti o n a n d ma na ge me nt of 
a na p h yl a xis: s u m mar y re p ort - sec o n d Nati o nal I nstit ute of Aller g y a n d 
I nfecti o us Disease/ F o o d Aller g y a n d A na p h yla xis Net w or k sy m p osi u m. 2 n d 
S y m p of t he Nati o nal I nstit ute of Aller g y  a n d I nfecti o us Disease 
( NI AI D)/ F o o d Aller g y a n d A na p h yla xis ( F A A) Net w or k o n t he Defi niti o n a n d 
Ma na ge me nt of A n a p h yl a xis, J ul 2 0 0 5.J Aller g y Cli n Im m u n ol 1 1 7 ( 2), 3 9 1 -
3 9 7 ( 2 0 0 6)
R 1 2 - 3 0 9 0   
Del mas Y, Viallar d J F, S ola nilla A, Ville ne u ve J, Pas q uet J M, Bell oc F, 
D u b us I , Dec ha net-Mer ville J, Mer ville P, Bla nc o P, Pelle gri n J L,  N ur de n A T, 
C o m be C, Ri p oc he J Acti vati o n of mesa n gial cells b y  platelets i n sys te mic 
l u p us er yt he mat os us via a C D 1 5 4- de pe n de nt i n d ucti o n of C D 4 0. Ki d ne y  I nt 
6 8, 2 0 6 8 - 2 0 7 8 ( 2 0 0 5)
R 1 2 - 4 2 7 3 
Ha h n B H, et al; A merica n C olle ge of R he u mat ol o g y  g ui deli nes f or scree ni n g, 
treat me nt, a n d ma na ge me nt of L N; Art hritis Care Res ( H o b o ke n) 6 4 ( 6), 7 9 7 -
8 0 8 ( 2 0 1 2)
R 1 3 - 3 5 1 5   
W o o d w ort h T, F urst D E, Alte n R, Bi n g ha m C, Y oc u m D, Sl oa n V, Ts uji W, 
Ste ve ns R, Fries J, Witter J, J o h ns o n K, L assere M, Br o o ks P. Sta n dar dizi n g 
assess me nt a n d re p orti n g of a d verse effects i n r he u mat ol o g y cli nical trials II: 
t he R he u mat ol o g y C o m m o n T o xicit y Criteria v. 2. 0. J R he u mat ol 2 0 0 7. 
3 4( 6): 1 4 0 1 -1 4 1 4.
R 1 2 - 4 2 8 4 
M o ore R A, Derr y  S S y ste matic re vie w a n d meta-a nal ys is of ra n d o mise d trials 
a n d c o h ort st u dies of m yc o p he n olate m ofetil i n l u p us ne p hritis. Art hritis Res 
T her 8 ( 6), R 1 8 2 ( 2 0 0 6)

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 6 7 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
R 1 2 - 4 2 8 5 
Las kari K, Ma vra ga ni C P, Tzi o ufas A G, M o uts o p o ul os H M M y c o p he n olate 
m ofetil as mai nte na nce t hera p y f or pr oliferati ve l u p us ne p hr itis: a l o n g-ter m 
o bser vati o nal pr os pecti ve st u d y . Art hritis Res T h er 1 2 ( 6), R 2 0 8 ( 2 0 1 0)
R 1 2 - 4 3 2 2 
D o ole y  M A, Ja yne D, Gi nzler E M, I se n ber g D, Olse n NJ, W ofs y D, Eit ner F, 
A p pel G B, C o ntreras G, Lis k L, S ol o m o ns N, A L M S Gr o u p M y c o p he n olate 
vers us azat hi o pri ne as mai nte na nce t hera p y f or l u p us ne p hritis. N E n gl J Me d 
3 6 5 ( 2 0), 1 8 8 6 - 1 8 9 5 ( 2 0 1 1)
R 1 2 - 4 3 2 6 
Gi nzler E M, D o ole y  M A, Ara n o w C, Ki m M Y, B u yo n J, Merrill J T, Petri M, 
Gil kes o n G S, Wallace DJ, Weis ma n M H, A p pel G B M y c o phe n olate m ofetil 
or i ntra ve n o us c ycl o p h os p ha mi de f or l u p us ne p hritis. N E n gl J Me d 3 5 3 ( 2 1), 
2 2 1 9 - 2 2 2 8 ( 2 0 0 5)
R 1 2 - 4 8 6 6   
Gra m mer A C, Sl ota R, Fisc her R, G ur H, Girsc hic k H, Yar b or o C, Illei G G, 
Li ps k y P E A b n or mal ger mi nal ce nter reacti o ns i n s y ste mic l u p us 
er yt he mat os us de m o nstrate d b y  bl oc ka de of C D 1 5 4-C D 4 0 i nteracti o ns. J Cli n 
I n vest 1 1 2 ( 1 0), 1 5 0 6 - 1 5 2 0 ( 2 0 0 3)
R 1 2 - 4 9 2 1 
Bertsias G K, et al. J oi nt E ur o pea n Lea g ue A gai nst R he u matis m a n d E ur o pea n 
Re nal Ass ociati o n -E ur o pea n Dial ys is a n d Tra ns pla nt Ass ociati o n 
( E U L A R/ E R A-E D T A) rec o m me n dati o ns f or t he ma na ge me nt of a d ult a n d 
pae diatric L N. A n n R he u m Dis 2 0 1 2; 7 1 : 1 7 7 1- 1 7 8 2
R 1 2 - 5 0 4 0 
Wee ni n g JJ, et al, T he classificati o n of gl o mer ul o ne p hritis i n s y ste mic l u p us 
er yt he mat os us re visite d. Ki d ne y  Int 6 5, 5 2 1 - 5 3 0 ( 2 0 0 4)
R 1 2 - 5 5 3 0 
B o u m pas D T, F urie R, Ma nzi S, I llei G G, Wallace DJ, Bal o w J E, Vais h na w 
A, B G 9 5 8 8 L u p us Ne p hr itis Trial Gr o u p A s h ort c o urse of B G 9 5 8 8 (a nti-
C D 4 0 li ga n d a nti b o d y) i m pr o ves ser ol o gic acti vit y a n d decreases he mat uria i n 
patie nts wit h pr oliferati ve l u p us gl o mer ul o ne p hritis. Art hritis R he u m 4 8 ( 3), 
7 1 9 - 7 2 7 ( 2 0 0 3)
R 1 5 - 0 4 0 7 
Kli n ge n ber g B . Pr o of of c o nce pt a n d d ose esti mati o n wit h bi nar y  res p o nses 
u n der m o del u ncertai nt y.  Stat Me d 2 8 ( 2), 2 7 4 - 2 9 2 ( 2 0 0 9)
R 1 5 - 1 9 6 1 
E ur o pea n Me dici nes A ge nc y ; Q ualificati o n O pi ni o n of M C P-M o d as a n 
efficie nt statistical met h o d ol o g y  f or m o del-base d desi g n a n d a nal ys is of P hase 
II d ose fi n di n g st u dies u n der m o del u ncertai nty;  2 3 Ja n uar y 2 0 1 4
R 1 5 - 3 1 5 6 
P orter A, C o n d o n M B, D o y le A F, Griffit h M, C o o k T, Cai ms T, Li ghtst o ne L
Pr os pecti ve l o n g ter m f oll o w u p of t he Rit u xil u p ster oi d s pari n g re gi me n i n 
l u p us ne p hritis. E R A -E D T A 2 0 1 5, 5 2 n d C o n g of t he E ur o pea n Re nal 
Ass ociati o n ( E R A) a n d t he E ur o pea n Dial ys is a n d Tra ns pla nt Ass ociati o n 
( E D T A), L o n d o n, 2 8 - 3 1 Ma y  2 0 1 5 Ne p hr ol Dial Tra ns pla nt 3 0 ( S u p pl 3), 
III 4 1, A bstr Sa O 0 4 1 ( 2 0 1 5)
R 1 5 -3 1 5 7 
Ta mir o u F, D' Cr uz D, Sa n gle S , Re my P, Vasc o ncel os C, Fie h n C, A y ala 
G uttierez M M, Gil b oe I M, Te kt o ni d o u M, Bl oc k ma ns D, Ra veli n gie n I, G uer n 

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 6 8 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
V le, De presse u x G, G uille vi n L , Cer vera R, H o ussia u F A, M AI N T AI N 
Ne p hritis Trial Gr o u p; L o n g- ter m f oll o w-u p of t he M AI N T AI N Ne p hritis 
Trial, c o m pari n g azat hi o pri ne a n d m yc o p he n olate m ofetil as mai nte na nce 
t hera py of L N; A n n R he u m Dis, ( 2 0 1 5)
R 1 5 - 3 7 1 6 
E ur o pea n Me dici nes A ge nc y  ( E M A) C o m mittee f or Me dici nal Pr o d ucts f or 
H u ma n Use ( C H M P): g ui deli ne o n cli nical i n vesti gati o n of me dici nal pr o d ucts 
f or t he treat me nt of sys te mic l u p us er yt he mat os us a n d l u p us ne p hritis ( 2 6 
Fe br uar y  2 0 1 5, E M A/ C H M P/ 5 1 2 3 0/ 2 0 1 3).
htt p:// w w w.e ma.e ur o pa.e u/ d ocs/e n _ G B/ d oc u me nt _li brar y / Scie ntific _ g ui deli ne
/ 2 0 1 5/ 0 3/ W C 5 0 0 1 8 4 8 8 9. p df (access date: 1 0 J ul y 2 0 1 5) ; Lo n d o n: E ur o pea n 
M e dici nes A ge nc y ( E M A) ( 2 0 1 5)
R 1 5 - 3 7 1 7  
F urie R, Nic h olls K, C he n g T T, H o ussia u F, B ur g os-Var gas R, C he n S L , 
Hills o n J L,  Mea d o ws-S hr o ps hire S, Ki naszcz u k M, Merrill J T; Efficac y  a n d 
safety of a batace pt i n L N: a t wel ve -m o nt h, ra n d o mize d, d o u ble -bli n d st u d y; 
Art hritis R he u mat ol 6 6 ( 2), 3 7 9 - 3 8 9 ( 2 0 1 4)
R 1 5 - 3 7 1 8 
W ofs y  D, Hills o n J L, Dia m o n d B; C o m paris o n of alter nati ve pri mar y o utc o me 
meas ures f or use i n L N cli nical trials; Art hritis R he u m 6 5 ( 6), 1 5 8 6 - 1 5 9 1 
( 2 0 1 3)
R 1 5 - 3 7 2 3 
Ka ma na m o ol N, Mc E v o y M, Attia J, I n gs at hit A, N ga mja n ya p or n P, 
T ha k ki nstia n A. Efficac y a n d a d verse e ve nts of m yc o p he n olate m ofetil vers us 
c ycl o p h os p ha mi de f or i n d ucti o n t hera p y of l u p us ne p hritis: s ystematic re vie w 
a n d meta-a nal ys is. Me dici ne ( Balti m ore) 8 9 ( 4), 2 2 7 -
2 3 5 ( 2 0 1 0)
R 1 5 - 3 7 2 4 
Wil hel m us S, Baje ma I M, Bertsias G K, B o u m pas D T, G or d o n C, L i ghtst o ne 
L, Tesar V, Ja y ne D R L u p us ne p hritis ma na ge me nt g ui deli nes c o m pare d.
Ne p hr ol Dial Tra ns pla nt, ( 2 0 1 5)
R 1 5 - 3 7 2 5 
Zic kert A et al. R ole of earl y re peate d re nal bi o psies i n l u p us ne p hritis; L u p u s 
2 0 1 4
R 1 5 - 4 2 0 6 
H ua n g W, Si n ha J, Ne w ma n J, Re d d y  B, B u d hai L, F urie R, Vais h na w A, 
Da vi ds o n A T he effect of a nti- C D 4 0 li ga n d a nti b o d y  o n B cells i n h u ma n 
s yste mic l u p us er yt he mat os us. Art hritis R he u m 4 6 ( 6), 1 5 5 4 - 1 5 6 2 ( 2 0 0 2)
R 1 5 - 4 2 9 3 
Pi n heir o J., B or n ka m p, B., Gli m m, E. a n d Bretz, F. ( 2 0 1 4) M o del-base d d ose 
fi n di n g u n der m o del u ncertai nt y usi n g ge neral para metric m o dels. Statistics i n 
Me dici ne, 3 3( 1 0): 1 6 4 6 – 1 6 6 1
R 1 5 - 4 2 9 4 
T o u ma Z, Ur o witz M. B., I ba nez D., Gla d ma n D. D; Ti me t o rec o ver y  fr o m 
pr ot ei n uria i n patie nts wit h l u p us ne p hritis recei vi n g sta n dar d treat me nt. J 
R he u mat ol 4 1, 6 8 8 -6 9 7, ( 2 0 1 4)
R 1 5 - 4 9 2 0 
Dall' Era M, Cister nas M G, S mile k D E, Stra u b L , H o ussia u F A, Cer vera R, 
R o vi n B H, Mac ka y  M Pre dict ors of l o n g -ter m re nal o utc o me i n l u p us ne p hritis 

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 6 9 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
trials: less o ns lear ne d fr o m t he E ur o-L u p us Ne p hritis c o h ort. Art hritis 
R he u mat ol 6 7 ( 5), 1 3 0 5 - 1 3 1 3 ( 2 0 1 5)
R 1 5 - 5 3 3 0 
R he u mat ol. 2 0 1 4 Oct; 4 1( 1 0): 1 9 9 8 -2 0 0 7. d oi: 1 0. 3 8 9 9/j r he u m. 1 4 0 0 5 0. E p u b 
2 0 1 4 Se p 1 5. I mm u n os u p pressi ve t hera pies f or t he i n d ucti o n treat me nt of 
pr oliferati ve l u p us ne p hritis: a s y ste matic re vie w a n d net w or k metaa nal ys is. 
Tia n S Y 1, Fel d ma n B M 1, Be y e ne J 1, Br o w n P E 1, Uler yk E M 1, Sil ver ma n 
E D 1
9. 2 
U N P U B LI S H E D R E F E R E N C E S
U 1 1 - 1 9 2 5
 In vesti gat or’s Br oc h ure, BI 6 5 5 0 6 4

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 7 0 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
1 0. 
A P P E N DI C E S
N ot a p plica ble.

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 7 1 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
1 1. 
D E S C RI P TI O N O F G L O B A L A M E N D M E N T( S)
1 1. 1   
G L O B A L A M E N D M E N T 1
D ate of 
a me n d me nt
0 4 Ma y
2 0 1 8
E u dr a C T 
n u m ber
E U n u m ber
2 0 1 7- 0 0 3 1 0 1 - 1 7
BI Tri al
n u m ber
1 2 9 3- 0 0 1 3
BI 
I n vesti g ati o n al 
Pr o d uct(s)
BI 6 5 5 0 6 4
Title of 
pr ot oc ol
A n e x pl orat or y mai nte na nce trial e val uati n g t he effect of BI 6 5 5 0 6 4 
i n Lu p us Ne p hritis patie nts w h o ha ve ac hie ve d a mea ni n gf ul res p o nse 
eit her at t he e n d of 1 2 9 3. 1 0 or after a n i n d ucti o n treat me nt o utsi de of 
1 2 9 3. 1 0 .
T o be 
i m ple me nte d 
o nl y after 
a p pr o v al of 
t he I R B / I E C 
/ C o m pete nt 
A ut h orities

T o be 
i m ple me nte d 
i m me di atel y 
i n or der t o 
eli mi n ate 
h az ar d –
I R B / I E C / 
C o m pete nt 
A ut h orit y t o 
be n otifie d of 
c h a n ge wit h 
re q uest f or 
a p pr o v al
C a n be 
i m ple me nte d 
wit h o ut I R B / 
I E C / 
C o m pete nt 
A ut h orit y 
a p pr o v al as 
c h a n ges 
i n v ol ve 

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 7 2 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
l o gistic al or 
a d mi nistr ati ve 
as pects o nl y
Secti o n t o be 
c h a n ge d
Fl o wc h art 1 a n d 2
Descri pti o n of 
c h a n ge
1. A d di n g “e n d of treat me nt” 
2. A d di n g t hat a li ne f or dis pe nsi n g/re vie wi n g t he e diar y
3. Fl o wc hart 1 O N L Y: a da pti n g t he w or di n g f or i nfecti o us scree ni n g 
i n r oll-o ver patie nts
4. C ha n ge w or di n g t o c o m plete c o m plia nce rec or ds f or L N -
c o nc o mita nt me dicati o n
5. A d di n g a se nte nce c o ncer ni n g vital si g ns c ollecti o n after t he f oll o w 
u p peri o d 
R ati o n ale f or 
c h a n ge
1. T o clarif y t he a b bre viati o n f or E O T
2. T o e ns ure t hat sites re vie w t he patie nt’s c o m plia nce w he n usi n g t he 
e diar y a n d c o nsi der re-trai ni n g.
3. T o clarif y  t hat i nfecti o us scree ni n g i n r oll o ver patie nts is n ot 
ma n dat or y  as t he y ha ve bee n teste d i n t he pre vi o us trial.
4. T o clarif y  t hat o nly t he c o m plia nce t o L N -me dicati o n is t o be 
rec or de d i n t he e diar y ( n ot d osi n g etc)
5. T o e ns ure patie nts n ot ret ur ni n g f or f oll o w u p visit s hall n ot be l ost 
a n d a vital stat us s hall be c ollecte d as a mi ni m u m
Secti o n t o be 
c h a n ge d
Descri pti o n of 
c h a n ge
R ati o n ale f or 
c h a n ge
Secti o n t o be 
c h a n ge d
3. 2. DI S C U S SI O N O F T RI A L D E SI G N, I N C L U DI N G T H E 
C H OI C E O F C O N T R O L G R O U P
Descri pti o n of 
c h a n ge
A d di n g t he criteria f or selecti n g a d ose f or treat me nt of gr o u p 2 
patie nts
R ati o n ale f or 
c h a n ge
Pre -defi ne criteria f or selecti n g a d ose f or gr o u p 2 patie nts f oll ow i n g 
t he i nteri m a nalys is of t he pre vi o us trial 1 2 9 3. 1 0
Secti o n t o be 
c h a n ge d
3. 3. 2. I ncl usi o n criteri a
Descri pti o n of 
c h a n ge
- Re m o vi n g i nc o nsiste ncies
-A d di n g c o ntrace pti o n i nstr ucti o ns f or patie nts o n Azat hi o pri ne
R ati o n ale f or 
c h a n ge
-t o clarif y t hat t w o met h o ds of c o ntrace pti o n are n ot p ossi ble
-a dj ust t he c o ntrace pti o n re q uire me nts f or Azat hi o pri ne f or fe male 
a n d male patie nts f oll o wi n g t he S P C of Azat hi o pri ne

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 7 3 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
Secti o n t o be 
c h a n ge d
3. 3. 3. E xcl usi o n criteri a
Descri pti o n of 
c h a n ge
A d di n g t hat t he i n vesti gat or w o ul d j u d ge w het her t he dia betes 
mellit us of t he patie nt is well c o ntr olle d
R ati o n ale f or 
c h a n ge
T o clarif y  t hat t here is n o trial pr oce d ure or la b para meter t o 
deter mi ne w het her t he dia betes c o n diti o n is u n der c o ntr ol. T his w o ul d 
be left t o t he i n vesti gat or’s me dical j u d ge me nt
Secti o n t o be 
c h a n ge d
3. 3. 4 Wit h dr a w al of p atie nts fr o m t her a p y or assess me nts
Descri pti o n of 
c h a n ge
A da pti n g t he w or di n g f or safety f oll o w u p of earl y wit h dra w n 
patie nts
R ati o n ale f or 
c h a n ge
T o clarif y  t hat if p ossi ble a n y eff ort s h o ul d be ma de t o f oll o w u p 
patie nts w h o wit h dre w earl y  fr o m t he trial (eit her b y f oll o w u p visit 
or p h o ne call). It s h o ul d be e x plaine d t o t he patie nt u pfr o nt d uri n g 
i nf or me d c o nse nt pr ocess.
Secti o n t o be 
c h a n ge d
4. 1. 5. 1. Bli n di n g
Descri pti o n of 
c h a n ge
A d di n g a se nte nce re gar di n g t he p ote ntial u n bli n di n g of trial tea m 
me m bers or site staff re gar di n g gr o u p 1 patie nts
R ati o n ale f or 
c h a n ge
T o c o nfir m t hat meas ures will be ta ke n t hat tea m me m bers a n d site 
staff of 1 2 9 3-0 0 1 3 will n ot be u n bli n de d f or gr o u p 1 -patie nts w he n 
t he 1 2 9 3. 1 0 trial will be a nalys e d a n d u n bli n de d 
Secti o n t o be 
c h a n ge d
4. 2. 1 Ot her tre at me nts a n d e mer ge nc y pr oce d ures
Descri pti o n of 
c h a n ge
1. defi ne t hat M M F a n d A Z A will be c o nsi dere d t o be A M P
2. a d di n g a se nte nce a b o ut r o u n di n g of A Z A -d oses
3. a d d w or di n g o n baseli ne d oses f or gl uc oc ortic oi ds f or gr o u p 1 a n d 2 
patie nts
4. a d di n g w or di n gs t hat t he ta peri n g sc he me ca n be de viate d fr o m
R ati o n ale f or 
c h a n ge
1. f or mal defi niti o n of S O C me dicati o n
2. t o e ns ure t hat t he d osi n g of t he patie nt s hall be d o ne per me dical 
j u d ge me nt of t he i n vesti gat or a n d w hat is l ocall y feasi ble per size of 
si n gle d ose a vaila ble
3.t o s u p p ort t he ta peri n g sc he d ule as me nti o ne d i n fi g ures 3. 1. 1 a n d 
3. 1. 2
4. t o clarif y t hat f or patie nt’s safety t he ta peri n g sc he me ca n be 
de viate d fr o m if nee de d f or t he me dical c o n diti o n of t he patie nt. I n 
s uc h case t he patie nt w o ul d n ot be e xcl u de d fr o m t he trial
Secti o n t o be 
c h a n ge d
4. 2. 3. 1 Restricti o ns re g ar di n g c o nc o mit a nt tre at me nt
Descri pti o n of 
Deleti n g a se nte nce referri n g t o A Z A o nl y bei n g use d i n case M M F is 

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 7 4 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
c h a n ge
n ot t olerate d.
R ati o n ale f or 
c h a n ge
T o clarif y  A Z A is all o we d as bac k gr o u n d me dicati o n i n a n y case
Secti o n t o be 
c h a n ge d
5. 1. 3.
Assess me nt of S L E D AI
Descri pti o n of 
c h a n ge
C orrect t he versi o n of S L E D AI- 2 K assess me nt t o S E LE N A -S L E D AI
R ati o n ale f or 
c h a n ge
T o c orrect a n err or. T he S L E D AI assess me nt use d i n t he pre decess or 
trial was S E LE N A -S L E D AI w hic h is c o nti n ue d i n t his trial as well.
Secti o n t o be 
c h a n ge d
5. 2. 3 S afet y a n d i m m u n ol o g y l a b or at or y p ar a meters
Descri pti o n of 
c h a n ge
A d di n g w or di n gs f or gr o u p 1 a n d gr o u p 2
R ati o n ale f or 
c h a n ge
T o matc h t he fl o wc harts wit h ta ble 5. 2. 3. 1. a n d t o clarif y w hic h 
para meters are ta ke n f or gr o u p 1 patie nts a n d w hic h f or gr o u p 2 
patie nts. Als o defi ni n g t he visit na mi n g f or baseli ne. Baseli ne i n 
gr o u p 1 is V 1. Baseli ne f or gr o u p 2 is V 2.
Secti o n t o be 
c h a n ge d
5. 2. 5. 1 Defi niti o n of A Es
Descri pti o n of 
c h a n ge
E xc ha n gi n g t he refere nce t o a versi o n of t he  
-
Ter mi n ol o g y  Criteria 
R ati o n ale f or 
c h a n ge
T o a da pt t he refere nce t o a ne wer versi o n of t he R C T C A E Criteria f or 
rati n g of A E i nte nsities.
Secti o n t o be 
c h a n ge d
5. 2. 5. 2. A d verse e ve nt c ollecti o n a n d re p orti n g
Descri pti o n of 
c h a n ge
E xc ha n ge “trial” b y “st u d y”
R ati o n ale f or 
c h a n ge
T o clarif y  E O T sta n ds f or “e n d of treat me nt” a n d E O S sta n ds f or 
“e n d of st u d y”
Secti o n t o be 
c h a n ge d
5. 3. 3. M M F pl as m a c o nce ntr ati o ns
Descri pti o n of 
c h a n ge
A d di n g a se nte nce t hat t he M M F -sa m ple is ta ke n as liste d i n t he 
fl o wc harts 1 a n d 2
R ati o n ale f or 
c h a n ge
T o be c o nsiste nt wit h all ot her la b para meters w hic h are me nti o ne d i n 
t he fl o wc harts as well as secti o n 5.

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 7 5 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
Secti o n t o be 
c h a n ge d
6. 2. 1 B aseli ne ( Gr o u p 1) / Scree ni n g ( Gr o u p 2) peri o d
Descri pti o n of 
c h a n ge
C ha n ge t he ti me wi n d o w bet wee n E O T of 1 2 9 3. 1 0 a n d V 1 of 1 2 9 3-
0 0 1 3 fr o m 7 t o 3 da y s
R ati o n ale f or 
c h a n ge
T he re d ucti o n of t he ti me wi n d o w was c h ose n, beca use t he pre vi o us 
wi n d o w of 7 da y s w o ul d alrea dy be c o nsi dere d a treat me nt 
i nterr u pti o n of t he wee kl y i njecti o ns. Treat me nt i nterr u pti o n i n a r oll 
o ver trial s hall be a v oi de d f or me dical reas o ns (treat me nt c o nti n uit y ) 
Secti o n t o be 
c h a n ge d
6. 2. 2. Tre at me nt per oi d
Descri pti o n of 
c h a n ge
A d di n g a se nte nce t hat i n vesti gat ors will re mai n bli n de d f or gr o u p 1
R ati o n ale f or 
c h a n ge
T o be c o nsiste nt t hr o u g h o ut t he pr ot oc ol t hat gr o u p 1 patie nts will 
re mai n bli n de d e ve n after fi nal a nal ys is a n d u n bli n di n g of t he 
pre decess or trial 1 2 9 3. 1 0.
Secti o n t o be 
c h a n ge d
6. 2. 3. 3 A d diti o n al f oll o w -u p f or pre m at urel y disc o nti n ue d 
p atie nts
Descri pti o n of 
c h a n ge
C ha n gi n g t he ti me wi n d o w f or f oll o w u p visits f or earl y disc o nti n ue d 
patie nts fr o m 8 t o 1 2 wee ks bef ore wee k 5 2
R ati o n ale f or 
c h a n ge
T o be c o nsiste nt wit h t he f oll o w u p peri o d of 1 2 wee ks f or 
c o m pleti n g patie nts. 
Secti o n t o be 
c h a n ge d
7. 3. 1. Pri m ar y e n d p oi nt a n al ysis
Descri pti o n of 
c h a n ge
A d di n g f urt her details o n stratificati o n fact ors a n d ot her statistical 
para meters
R ati o n ale f or 
c h a n ge
T o be m ore precise o n statistical a nal ys is
Secti o n t o be 
c h a n ge d
9. Refere nces
Descri pti o n of 
c h a n ge
A d d a ne wer refere nce t o assess me nt of a d vers e ve nts
R ati o n ale f or 
T o be c o nsiste nt wit h secti o n 5. 2. 5. 1

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 7 6 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
c h a n ge
1 1. 2    
G L O B A L A M E N D M E N T 2
D ate of a m e n d me nt
2 1 Dec 2 0 2 0
E u dr a C T n u m ber
E U n u m ber
2 0 1 7- 0 0 3 1 0 1- 1 7
BI Tri al n u m ber
1 2 9 3- 0 0 1 3
BI I n vesti g ati o n al Pr o d uct(s)
BI 6 5 5 0 6 4
Title of pr ot oc ol
A n e x pl orat or y  mai nte na nce trial e val uati n g t he 
effect of BI 6 5 5 0 6 4 i n L u p us Ne p hritis patie nts 
w h o ha ve ac hie ve d a mea ni n gf ul res p o nse eit her at 
t he e n d of 1 2 9 3. 1 0 or after a n i n d ucti o n treat me nt 
o utsi de of 1 2 9 3. 1 0.
Gl o b al A m e n d me nt d ue t o ur ge nt s afet y re as o ns
Gl o b al A me n d me nt
X
Secti o n t o be c h a n ge d
Cli nical Trial Pr ot oc ol S y n o psis
Descri pti o n of c h a n ge
A d di n g sec o n dar y  e n d p oi nts
R ati o n ale f or c h a n ge
T o be c o nsiste nt wit h secti o n 2. 1. 3, f or rati o nale 
f or c ha n ge see bel o w
Secti o n t o be c h a n ge d
Cli nic al Tri al Pr ot oc ol S y n o psis
Descri pti o n of c h a n ge
Re m o vi n g refere nce t o gr o u p 2 i n secti o ns 
“ n u m ber of patie nts e ntere d/ per treat me nt ar m”, 
Mai n i n - a n d e xcl usi o n criteria” a n d “ d ose”
R ati o n ale f or c h a n ge
T he start of gr o u p 2 was ca ncelle d d ue t o t he 
o utc o me of cli nical trial 1 2 9 3. 1 0
Secti o n t o be c h a n ge d
Fl o w C h art 1
Descri pti o n of c h a n ge
1. A d di n g i m m u n ol o g y tests ( C 3/ C 4 c o m ple me nt, 
A nti- ds D N A) t o visit wee k 4 2
2. Re -p hrasi n g t he descri pti o n of data tra nscri pti o n 
f or r oll o ver patie nts fr o m t he pre vi o us trial t o 
1 2 9 3- 0 0 1 3
3. C ha n gi n g r ole na mes of Cli nical Trial L ea der 
( pre vi o usly calle d Trial Cli nical M o nit or) a n d 
Cli nical Trial Ma na ger ( pre vi o usl y calle d 
Cli nical M o nit or L ocal)
R ati o n ale f or c h a n ge
1. T o be c o nsiste nt wit h t he S L E D AI -q uesti o n naire 
w hic h is ta ke n at Wee k 4 2 w hic h as ks f or C 3/ C 4 
a n d A nti -ds D N A -le vels
2. F or better clarit y
3. T o c o m pl y  wit h BI’s ne w r ole titles
Secti o n t o be c h a n ge d
Fl o w C h art 2

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 7 7 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
Descri pti o n of c h a n ge
Delete d
R ati o n ale f or c h a n ge
Gr o u p 2 was ca ncelle d
Secti o n t o be c h a n ge d
A b bre viati o ns, als o t hr o u g h o ut t he e ntire C T P
Descri pti o n of c h a n ge
Ne w A b bre viati o ns a d de d
R ati o n ale f or c h a n ge
T o c o m pl y  wit h BI’s ne w r ole titles
Secti o n t o be c h a n ge d
1. 2 Dr u g Pr ofile
Descri pti o n of c h a n ge
1. A d di n g u n bli n de d safet y data f oll o wi n g t he fi nal 
a nal ys is of 1 2 9 3. 1 0
2. A d di n g u n bli n de d efficac y  data f oll o wi n g t he 
fi nal a nalys is of 1 2 9 3. 1 0
R ati o n ale f or c h a n ge
T o ma ke m ore c urre nt data a vaila ble
Secti o n t o be c h a n ge d
2. 1 M ai n O bjecti ves, pri m ar y a n d sec o n d ar y 
e n d p oi nts
Descri pti o n of c h a n ge
1. Mai n O bjecti ves: Baseli ne val ues are re -defi ne d
2. Sec o n dar y e n d p oi nts: a d de d pri mar y  e n d p oi nt 
fr o m 1 2 9 3. 1 0 a n d c o nfir me d C R R e n d p oi nt fr o m 
1 2 9 3. 1 0  
R ati o n ale f or c h a n ge
1. t o be a ble t o a nal yz e t he f ull t w o treat me nt 
ye ars fr o m 1 2 9 3. 1 0 a n d 1 2 9 3 - 0 0 1 3
2. t o ali g n wit h e n d p oi nts fr o m 1 2 9 3. 1 0
Secti o n t o be c h a n ge d
Descri pti o n of c h a n ge

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 7 8 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
R ati o n ale f or c h a n ge
Secti o n t o be c h a n ge d
3. 1 O ver all tri al desi g n a n d Pl a n
Descri pti o n of c h a n ge
1. Deleti n g t he w or d “ra n d o mise d”
2. Deleti n g refere nces a n d descri pti o ns relate d t o 
gr o u p 2
R ati o n ale f or c h a n ge
1. Gr o u p 1 patie nts were ra n d o mize d t o t heir 
treat me nt ar m i n t he fr o nt r u n ni n g trial 1 2 9 3. 1 0
2. Gr o u p 2 was ca ncelle d
Secti o n t o be c h a n ge d
3. 3. 2 I ncl usi o n criteri a
Descri pti o n of c h a n ge
1. S pecificati o n of hi g hl y effecti ve c o ntrace pti ves
2. Re m o val of i ncl usi o n criteria f or gr o u p 2
R ati o n ale f or c h a n ge
1. T o c o m pl y  wit h t he c urre nt BI sta n dar ds
2. Gr o u p 2 was ca ncelle d
Secti o n t o be c h a n ge d
3. 3. 3 E xcl usi o n criteri a
Descri pti o n of c h a n ge
Re m o val of e xcl usi o n criteria f or gr o u p 2
R ati o n ale f or c h a n ge
Gr o u p 2 was ca ncelle d
Secti o n t o be c h a n ge d
3. 3. 4. 1 Wit h dr a w al fr o m tri al tre at me nt
Descri pti o n of c h a n ge
A d diti o n of a Sars C o V 2 -i nfecti o n
R ati o n ale f or c h a n ge
T o clarif y  t hat a n i nfecti o n mi g ht n ot necessaril y 
res ult i n a per ma ne nt disc o nti n uati o n, b ut re -start 
of trial me dicati o n is p ossi ble.

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 7 9 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
Secti o n t o be c h a n ge d
4. 1. 1 I de ntit y of i n vesti g ati o n al me dici n al 
pr o d ucts
Descri pti o n of c h a n ge
Re m o val of a n y refere nce t o gr o u p 2
R ati o n ale f or c h a n ge
Gr o u p 2 was ca ncelle d
Secti o n t o be c h a n ge d
4. 1. 3 Met h o d of assi g ni n g p atie nts t o tre at me nt 
gr o u ps
Descri pti o n of c h a n ge
Re m o val of treat me nt assi g n me nts f or gr o u p 2
R ati o n ale f or c h a n ge
Gr o u p 2 was ca ncelle d
Secti o n t o be c h a n ge d
4. 1. 4. Dr u g assi g n me nt a n d a d mi nistr ati o n of 
d oses f or e ac h p atie nt
Descri pti o n of c h a n ge
1. Delete d o bser vati o n peri o d f or gr o u p 2 patie nts
2. A d de d per missi o n f or gr o u p 1 t o self- i nject t he 
first trial i njecti o n at h o me
3. Delete d l oa di n g d ose f or gr o u p 2 patie nts
4. Delete d d ose a n d treat me nt sc he d ule f or gr o u p 
2
5. A d de d t hat a de viati o n fr o m r oll o ver ti me 
wi n d o w mi g ht be all o we d 
6. A d di n g I P s u p pl y meas ures d uri n g t he C o vi d -1 9 
pa n de mic restricti o ns
R ati o n ale f or c h a n ge
1., 3., 4. Gr o u p 2 was ca ncelle d
2. T o all o w m ore fle xi bilit y at r oll o ver.
5. D ue t o et hical i m plicati o ns, as descri be d i n t his 
secti o n
6. W or kar o u n d t o e ns ure c o nti n ue o us I P s u p pl y 
d uri n g C o vi d -1 9 relate d m o ve me nt restricti o ns.
Secti o n t o be c h a n ge d
4. 1. 5. 1. Bli n di n g
Descri pti o n of c h a n ge
1. Re m o vi n g secti o n o n i nteri m a nal ys is
2. A d di n g t he rati o nale f or u n bli n di n g s o me gr o u p 
1 patie nts
R ati o n ale f or c h a n ge
1. D ue t o ca ncellati o n of gr o u p 2, o nl y a fi nal 
a nal ys is will ta ke place.
2. T o descri be t he c o urse of acti o ns after t he fi nal 
a nal ys is of 1 2 9 3. 1 0
Secti o n t o be c h a n ge d
4. 2. 1. ot her tre at me nts a n d e mer ge nc y 
pr oce d ures
Descri pti o n of c h a n ge
1. A d di n g M yc o p he n olate s o di u m t o t he list of 
S O Cs
2. A d di n g t hat de viati o ns fr o m S O C -d osa ges are 
p ossi ble

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 8 0 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
3. Re m o vi n g refere nce t o gr o u p 2
R ati o n ale f or c h a n ge
1. T o clarif y  t hat t here is n o me dical differe nce i n 
t hese c o m p o u n ds
2. T o clarif y  t hat o nly u n der certai n circ u msta nces 
a de viati o n is p ossi ble a n d t o as k f or prea p pr o val
3. Gr o u p 2 was ca ncelle d
Secti o n t o be c h a n ge d
4. 2. 2. M a n a ge me nt of A d verse E ve nts
Descri pti o n of c h a n ge
1. S pecif y i n g i nfecti o ns, Mali g na ncies, 
ne utr o pe nia, s ur geries, i njecti o n reacti o ns, 
l ym p h o pr oliferati ve diseases
2. A d di n g Azat hi o pri ne as S O C 
R ati o n ale f or c h a n ge
1. T o pr o vi de g ui da nce t o i n vesti gat ors h o w t o 
ha n dle I P i nta ke a n d S O C d osi n g i n case t hese 
e ve nts occ ur. T o ali g n wit h i nstr ucti o ns pr o vi de d 
i n 1 2 9 3. 1 0.
2. F or c o nsiste nc y  wit hi n t he d oc u me nt. 
Azat hi o pri ne ha d bee n all o we d S O C bef ore
Secti o n t o be c h a n ge d
4. 2. 3. 1 Restricti o n re g ar di n g c o nc o mit a nt 
tre at me nt
Descri pti o n of c h a n ge
1. Re m o vi n g pri or t o st u d y  a n d scree ni n g peri o d
2. C orrecti o ns of per mitte d S O C d oses 
R ati o n ale f or c h a n ge
T hese p hases are n ot a p plica ble t o gr o u p 1 patie nts 
as t he y r oll o ver fr o m 1 2 9 3. 1 0
T o be c o nsiste nt wit h secti o n 4. 2. 1
Secti o n t o be c h a n ge d
4. 3 Tre at me nt c o m pli a nce
Descri pti o n of c h a n ge
1. A d d t he ti me p oi nt of d oc u me ntati o n of M M F 
i nta ke bef ore M M F d osi n g la b sa m ple is ta ke n
2. Descri pti o n of e diar y  use
R ati o n ale f or c h a n ge
1. T o a d d clarit y t o t he pr ocess
2. T o a d d clarit y t o t he i m p orta nce of c o m plia nce 
c hec ks
Secti o n t o be c h a n ge d
5. 1. 1. Assess me nt of re n al res p o nse
Descri pti o n of c h a n ge
A d di n g met h o ds of h o w t o defi ne C R R or P R R
R ati o n ale f or c h a n ge
T o a d d m ore clarit y  h o w t o deter mi ne t he C R R 
a n d P R R fr o m la b val ues
Secti o n t o be c h a n ge d
5. 2. 2. Vit al si g ns
Descri pti o n of c h a n ge
A d di n g t hat a b n or mal fi n di n gs mi g ht q ualif y  as 
A E
R ati o n ale f or c h a n ge
T o clarif y  t he i m p orta nce of vital si g n e val uati o n 
b y  t he i n vesti gat or.

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 8 1 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
Secti o n t o be c h a n ge d
T a ble 5. 2. 3. 1 S afet y a n d i m m u n ol o g y 
l a b or at or y tests
Descri pti o n of c h a n ge
1. Re m o vi n g sa m ple ti me p oi nts f or gr o u p 2 
2. A d di n g sa m ple ti me p oi nt C 3/ C 4 a n d A nti -
ds D N A at wee k 4 2 f or gr o u p 1
3. A d di n g ar ule h o w t o ha n dle a m bi gi o us He p B 
a n d C test res ults
R ati o n ale f or c h a n ge
1. Gr o u p 2 was ca ncelle d
2. T o be c o nsiste nt wit h t he Fl o wc hart a n d f or t he 
i n vesti gat or t o be a ble t o c o m plete t he S L E D AI 
q uesti o n naire at wee k 4 2
3. T o be c o nsiste nt wit h i nstr ucti o ns pr o vi de d i n 
1 2 9 2. 1 0
Secti o n t o be c h a n ge d
5. 2. 5. 1 Defi niti o ns of A Es 
Descri pti o n of c h a n ge
1. A d di n g i n vasi ve her pes si m ple x
2. A d di n g a w or di n g f or t he i n vesti gat ors t o 
re q uest i nf or mati o n o n A Es relate d t o i nfecti o ns
3. A d di n g ne utr o pe nia a n d i nstr ucti o ns
4. Clarif y i n g t he se verity gra di n g of A Es
5. A da pti n g t he S A E re p orti n g pr ocess descri pti o n
6. A d di n g a refere nce t o t he i nf or me d c o nse nt 
f or m f or pre g na nt part ners
R ati o n ale f or c h a n ge
1. T o a d d clarit y f or i n vesti gat ors
2., 3. T o pr o vi de i nstr ucti o ns t o i n vesti gat ors, a n d 
t o be c o nsiste nt wit h 1 2 9 3. 1 0
4. T o be c o nsiste nt wit h t he alrea d y use d R C T C 
5. T o a d d a m ore fle xi ble w or di n g a n d acc o u nti n g 
f or t he differe nt re p orti n g pr ocesses i n t he re gi o ns
6. T o be c o nsiste nt wit h t he pr ocess t o c ollect 
i nf or mati o n als o fr o m pre g na nt part ners of male 
st u d y patie nts.

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 8 2 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
starts
Secti o n t o be c h a n ge d
6. 1. Visit sc he d ule
Descri pti o n of c h a n ge
C o vi d -1 9 pa n de mic w or k ar o u n ds were a d de d
R ati o n ale f or c h a n ge
T o all o w patie nts t o re mai n o n t he trial d uri n g 
m o ve me nt restricti o ns d ue t o t he C o vi d - 1 9 
pa n de mic. Als o t o e ns ure me dical o versi g ht b y 
i n vesti gat ors a n d e ns ure critical safet y a n d la b 
data ca n still be o btai ne d.
Secti o n t o be c h a n ge d
6. 2. 1 B aseli ne ( gr o u p 1)
Descri pti o n of c h a n ge
1. A d di n g a descri pti o n of t he ti me p oi nt w he n t he 
r oll o ver decisi o n ca n be ma de
2. A d di n g a w or di n g f or cases w he n t he 
i nterr u pti o n bet wee n t he trial is l o n ger t ha n 7 
da y s.
3. re place ra n d o mizati o n b y  e nr oll me nt
R ati o n ale f or c h a n ge
1. T o clarif y  t hat t he latest ti me p oi nt f or r oll o ver 
decisi o n ca n als o be E O T of 1 2 9 3. 1 0
2. T o clarif y t hat i n case of l o n ger i nterr u pti o n 
certai n la b para meters s hall be ta ke n as baseli ne 
f or 1 2 9 3- 0 0 1 3
3. T o a da pt t o gr o u p 1 ( wit h n o ra n d o mizati o n)
Secti o n t o be c h a n ge d
6. 2. 2. Tre at me nt peri o d
Descri pti o n of c h a n ge
1. Re m o vi n g refere nce t o gr o u p 2
2. A d di n g a w or di n g o n treat me nt i nterr u pti o ns
R ati o n ale f or c h a n ge
1. Gr o u p 2 was ca ncelle d
2. T o clarf y  t hat t he C T L s hall be i nf or me d a b o ut 
l o n ger treat me nt i nterr u pti o ns.
Secti o n t o be c h a n ge d
6. 2. 3. 3. A d diti o n al f oll o w -u p f or pre m at urel y 
disc o nti n ue d p atie nts
Descri pti o n of c h a n ge
A d di n g a w or di n g re gar di n g f oll o w u p visit 
i nter vals
R ati o n ale f or c h a n ge
T o clarif y  w he n early disc o nti n ue d patie nts s hall 
c o me f or f oll o w u p visits
Secti o n t o be c h a n ge d
7. 1 St atic al desi g n - m o del

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 8 3 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
Descri pti o n of c h a n ge
M o difie d desi g n descri pti o n t o hi g hli g ht i m p orta nt 
feat ures of t he Gr o u p 1-o nl y  trial
R ati o n ale f or c h a n ge
Gr o u p 2 was ca ncelle d
Secti o n t o be c h a n ge d
7. 2 N ull a n d Alter n ati ve H y p ot heses
Descri pti o n of c h a n ge
F urt her descri pti o n/j ustificati o n of statistical 
a p pr oac h a d de d. 
R ati o n ale f or c h a n ge
T o m ore clearl y descri be h o w t he statistical testi n g 
a d dresses t he trial o bjecti ves.
Secti o n t o be c h a n ge d
7. 3. Pl a n ne d a n al ysis
Descri pti o n of c h a n ge
1. A nal y ses will i nc or p orate data fr o m 1 2 9 3. 1 0.
2. Baseli ne f or 1 2 9 3 - 0 0 1 3 is defi ne d as t he 
baseli ne fr o m 1 2 9 3. 1 0 u nless ot her wise i n dicate d. 
3. Baseli ne c haracteristics f or patei nts w h o e nter 
1 2 9 3- 0 0 1 3 ( Gr o u p 1) will be c o m pare d t o baseli ne 
c haracteristics f or t he treate d p o p ulati o n of 
1 2 9 3. 1 0.
4. P o p ulati o n data set defi ne d as I T T.
R ati o n ale f or c h a n ge
1 & 2. Wit h ca ncellati o n of Gr o u p 2, t he a nal ys is 
f oc us ca n be t he l o n g ter m (t w o-ye ar) efficac y a n d 
safety assess me nt f or t he Gr o u p 1 patei nts.
3. A n y  releva nt s hifts i n baseli ne c haracteristics 
c o ul d affect i nter pretati o n of res ults & s h o ul d be 
n ote d.
4. A p pr oac h will be t o c o nsi der disc o nti n ue d 
patie nts as fail ures & i ncl u de i n a nal ys is of t he 
pri mar y  e n d p oi nt.
Secti o n t o be c h a n ge d
7. 3. 1 Pri m ar y e n d p oi nt a n al ysis
Descri pti o n of c h a n ge
1. P o p ulati o n data set defi ne d as I T T.
2. Descri pti o ns of Gr o u p 2 a nal ys es re m o ve d.
3. Statistical met h o ds i n 1 2 9 3. 1 0 will be use d i n 
1 2 9 3 - 0 0 1 3.
4. Re m o ve d a nal ys es b y et h nicit y a n d race.
R ati o n ale f or c h a n ge
1. A p pr oac h will be t o c o nsi der disc o nti n ue d 
patie nts as fail ures & i ncl u de i n a nal ys is of t he 
pri mar y  e n d p oi nt.
2. Gr o u p 2 ca ncelle d.
3. F or c o nsiste nc y /c o m paris o n wit h 1 2 9 3. 1 0 
res ults
4. S mall n u m bers of patie nts per treat me nt gr o u p.
Secti o n t o be c h a n ge d
7. 3. 2 Sec o n d ar y e n d p oi nt a n al ysis
Descri pti o n of c h a n ge
Si m plifie d a nal y sis pla n f or ti me t o first re nal flare 
b y  re m o vi n g hazar d rati o & 9 5 % c o nfi de nce 
i nter val.

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 8 4 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
R ati o n ale f or c h a n ge
N u m bers of re nal flares t o date are s mall. Pla n t o 
prese nt Ka pla n Meier c ur ve s h o ul d be a de q uate.
Secti o n t o be c h a n ge d
Descri pti o n of c h a n ge
R ati o n ale f or c h a n g e
Secti o n t o be c h a n ge d
7. 3. 4 S afet y a n al yses
Descri pti o n of c h a n ge
1. A d de d t hat a nal ys is of A Es will be base d o n 
ra n d o mise d treat me nt.
2. A nal y sis of A E SIs a n d a d diti o nal S A E r ule f or 
Ja pa n me nti o ne d.
R ati o n ale f or c h a n ge
M ore c o m plete s pecificati o n of a nal ys is a n d f or 
c o nsiste nc y wit h Secti o n 5. 2.
Secti o n t o be c h a n ge d
7. 4 I nteri m A n al yses
Descri pti o n of c h a n ge
Delete d refere nce t o a n i nteri m a nal ys is
R ati o n ale f or c h a n ge
D ue t o ca ncellati o n of gr o u p 2, t he pre vi o usl y  
s pecifie d i nteri m a nal ysis after c o m pleti o n of 
Gr o u p 1 is n o w t he fi nal a nal ys is of t he trial.
Secti o n t o be c h a n ge d
7. 5 H a n dli n g of missi n g d at a
Descri pti o n of c h a n ge
1. A d de d te xt t o i n dicate t hat t he ‘ n o n- c o m pleters 
c o nsi dere d fail ure’ a p pr oac h is o nl y  f or C R R-
relate d e n d p oi nts
2. Re m o ve d state me nt t hat n o i m p utati o n will be 
perf or me d f or all ot her e n d p oi nts.
R ati o n ale f or c h a n ge
1. C orrecti o n t o pre vi o us s pecificati o n
2. Nee d f or i m p utati o n of ot her e n d p oi nts will be 
assesse d d uri n g data re vie w.  If t here are 
si g nifica nt n u m bers of patei nts wit h missi n g data, 
i m p utati o n tec h ni q ues ma y be c o nsi dere d & 
s pecifie d i n t he T S A P.
Secti o n t o be c h a n ge d
7. 6 R a n d o mis ati o n
Descri pti o n of c h a n ge
Re m o ve d descri pti o n of t he ra n d o misati o n of 
Gr o u p 2 patie nts.
R ati o n ale f or c h a n ge
Gr o u p 2 is ca ncelle d.
Secti o n t o be c h a n ge d
7. 7 Deter mi n ati o n of s a m ples size

B oe hri n ger I n gel hei m
2 1 Dec 2 0 2 0
BI Tri al N o.: 1 2 9 3- 0 0 1 3
c 1 3 7 9 5 0 1 3- 0 4
Cli nic al Tri al Pr ot oc ol
P a ge 8 5 of 8 5
Pr o prietar y c o nfi de ntial i nf or mati o n © 2 0 2 0 B oe hri n ger I n gel hei m I nter nati o nal G m b H or o ne or m ore of its affiliate d c o m pa nies
0 0 1- M C S -4 0 - 1 0 6-R D - 0 3 ( 1 4. 0) / Sa ve d o n: 1 7 Oct 2 0 1 6
Descri pti o n of c h a n ge
Re m o ve d refere nces t o Gr o u p 2 i ncl u di n g 
refere nces t o sa m ple size calc ulati o ns, 
ass u m pti o ns a n d e x pecte d p o wer f or Gr o u p 2. 
Als o re m o ve d disc ussi o n of n u m ber(s) of d oses t o 
be st u die d i n Gr o u p 2.
R ati o n ale f or c h a n ge
Gr o u p 2 was ca ncelle d
Secti o n t o be c h a n ge d
8. 3. 2. Direct access t o s o urce d at a a n d 
d oc u me nts
Descri pti o n of c h a n ge
A d di n g a w or di n g t o all o w f or re m ote s o urce data 
verificati o n
R ati o n ale f or c h a n ge
D ue t o m o ve me nt restricti o n d uri n g t he C o vi d 1 9 
pa n de mic, re m ote S D V mi g ht be p ossi ble i n 
re gi o ns w here per mitte d per l ocal re g ulati o ns.

 
 
 
 
A P P  R  O  V  A  L /  SI  G  N  A  T  U  R  E  P  A  G  E 
 
D o c u  m e nt   N u  m b e r: 
     
T e c h ni c al   V e rsi o n   N u  m b e r:
 
D o c u  m e nt   N a  m e: 
 
 
 
                                                                                                                 
 
Titl e: 
 
 
 
 
                                                                                                                   
 
Si g n at u r es ( o bt ai n e d  el e ct r o ni c all y) 
 
M e a ni n g  of  Si g n at u r e    
Si g n e d  b y 
D at e  Si g n e d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c 1 3 7 9 5 0 1 3
4. 0
cli ni c al-tri al- pr ot o c ol- v ersi o n- 0 3
A n  e x pl or at or y   m ai nt e n a n c e tri al  e v al u ati n g t h e  eff e ct  of   BI  6 5 5 0 6 4 i n  L u p us
N e p hritis  p ati e nts   w h o  h a v e  a c hi e v e d  a   m e a ni n gf ul r es p o ns e  eit h er  at t h e  e n d  of
1 2 9 3. 1 0  or  aft er  a n i n d u cti o n tr e at  m e nt  o utsi d e  of  1 2 9 3. 1 0
A p pr o v al- T h er a p e uti c   Ar e a 
2 1   D e c  2 0 2 0  1 8: 3 8   C E T
A p pr o v al- T e a  m   M e  m b er   M e di ci n e
2 1   D e c  2 0 2 0  1 8: 4 7   C E T
A p pr o v al-  Cli ni c al  Tri al  L e a d er
2 1   D e c  2 0 2 0  1 9: 5 1   C E T
A p pr o v al- T e a  m   M e  m b er   Dr u g
S af et y
2 2   D e c  2 0 2 0  1 2: 2 6   C E T
A ut h or- Tri al  St atisti ci a n
2 2   D e c  2 0 2 0  1 4: 5 5   C E T
A p pr o v al-  Cli ni c al  Tri al  L e a d er
2 3   D e c  2 0 2 0  1 2: 0 8   C E T
Si n c e t h e r e- or g a ni z ati o n, s o m e j o b titl e s h a v e c h a n g e d, b ut I t hi n k w e 
ar e n ot a d a pti n g a n yt hi n g h er e b e c a u s e t hi s i s C T P v 3 fr o m 2 0 2 0. A m 
I ri g ht ?
Si n c e t h e r e- or g a ni z ati o n, s o m e j o b titl e s h a v e c h a n g e d, b ut I t hi n k w e 
ar e n ot a d a pti n g a n yt hi n g h er e b e c a u s e t hi s i s C T P v 3 fr o m 2 0 2 0. A m 
I ri g ht ?
Si n c e t h e r e- or g a ni z ati o n, s o m e j o b titl e s h a v e c h a n g e d, b ut I t hi n k w e 
ar e n ot a d a pti n g a n yt hi n g h er e b e c a u s e t hi s i s C T P v 3 fr o m 2 0 2 0. A m 
I ri g ht ?
Since the re-organization, some job titles have changed, but I think we 
are not adapting anything here because this is CTP v3 from 2020. Am 
I right?

B o e h ri n g e r I n g el h ei m 
P a g e   2  of  2
D o c u m e nt  N u m b e r: 
  T e c h ni c al  V e rsi o n  N u m b e r :
 
 
 
( C o nti n u e d)  Si g n at u r es ( o bt ai n e d  el e ct r o ni c all y) 
 
M e a ni n g  of  Si g n at u r e   
Si g n e d  b y 
D at e  Si g n e d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c 1 3 7 9 5 0 1 3
4. 0