Clinical trial NCT03385564
Conditions: Lupus Nephritis
Sponsor: Boehringer Ingelheim
Start date: 2018-01-09; Completion date: 2021-07-27
Enrollment: 69 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main objectives of this trial are to evaluate the long term efficacy and safety of different doses of BI 655064 versus placebo as add-on therapy to Standard of Care (SOC) during maintenance therapy for lupus nephritis.

Detailed description:
Initially planned participating countries:

Argentina, Australia, Canada, Colombia, Czech Republic, France, Germany, Greece, Hong Kong, Italy, Japan, Republic of Korea, Malaysia, Mexico, Philippines, Poland, Portugal, Serbia, Spain, Taiwan, Thailand, United Kingdom, United States

Arms: arm 1: 120 milligrams (mg) BI 655064 were administered as solution for subcutaneous injection in a prefilled syringe once every 2 weeks plus the administration of matching placebo as subcutaneous injection in a prefilled syringe once every 2 weeks (in the alternative weeks without BI 655064 administration) over a treatment period of 52 weeks, followed by a 12-week follow-up period. The patients received 1 injection per week. arm 2: Matching placebo were administered as solution for subcutaneous injection in a prefilled syringe once every week over a treatment period of 52 weeks, followed by a 12-week follow-up period. The patients received 1 injection per week. arm 3: 180 milligrams (mg) BI 655064 were administered as solution for subcutaneous injection in a prefilled syringe once every 2 weeks plus the administration of matching placebo as subcutaneous injection in a prefilled syringe once every 2 weeks (in the alternative weeks without BI 655064 administration) over a treatment period of 52 weeks, followed by a 12-week follow-up period. The patients received 1 injection per week. arm 4: 120 milligrams (mg) BI 655064 were administered as solution for subcutaneous injection in a prefilled syringe once every week (240 mg every 2 weeks) over a treatment period of 52 weeks, followed by a 12-week follow-up period. The patients received 1 injection per week.
Interventions: intervention 1: BI 655064 intervention 2: Placebo
Intervention descriptions: intervention 1: subcutaneous injection intervention 2: subcutaneous injection

Protocol documents:
Prot_002.pdf: 
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
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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

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c21284764-02
BI Trial No.:
1293-0013
Title:
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
Including Protocol Amendment 2
1293-0013-revised-protocol-03 [c13795013-04]
Investigational
Product(s):
BI 655064
Responsible trial 
statistician(s):
Phone: 
Fax: 
Date of statistical 
analysis plan:
17 JUN 2021 REVISED
Version:
2
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS ......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ...............................................................................5
3.
INTRODUCTION..................................................................................................8
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY.......................9
5.
ENDPOINT ..........................................................................................................10
5.1
PRIMARY ENDPOINT......................................................................................10
5.2
SECONDARY ENDPOINTS..............................................................................11
5.2.1
Key secondary endpoint ......................................................................................11
5.2.2
Secondary endpoints............................................................................................11
6.
GENERAL ANALYSIS DEFINITIONS...........................................................16
6.1
TREATMENTS....................................................................................................16
6.2
IMPORTANT PROTOCOL DEVIATIONS ....................................................16
6.3
SUBJECT SETS ANALYSED............................................................................19
6.5
POOLING OF CENTRES ..................................................................................20
6.6
HANDLING OF MISSING DATA AND OUTLIERS.....................................20
6.6.1
Primary, secondary and further endpoints .......................................................20
6.6.2
Other endpoints and safety endpoints ...............................................................22
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ....................22
7.
PLANNED ANALYSIS.......................................................................................24
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS..........24
7.2
CONCOMITANT DISEASES AND MEDICATION ......................................24
7.3
TREATMENT COMPLIANCE.........................................................................25
7.4
PRIMARY ENDPOINT......................................................................................25
7.4.1
Primary analysis of the primary endpoint.........................................................25
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the primary 
endpoint ................................................................................................................26
7.5
SECONDARY ENDPOINTS..............................................................................26
7.5.1
Key secondary endpoint ......................................................................................26
7.5.1.1
Primary analysis of the key secondary endpoint....................................................26
7.5.1.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the key 
secondary endpoint ...............................................................................................26
7.5.2
(Other) Secondary endpoints..............................................................................26
7.7
EXTENT OF EXPOSURE..................................................................................29
7.8
SAFETY ANALYSIS...........................................................................................29
7.8.1
Adverse events......................................................................................................29
7.8.2
Laboratory data ...................................................................................................30
7.8.3
Vital signs..............................................................................................................31
7.8.4
ECG.......................................................................................................................31


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7.8.5
Others....................................................................................................................31
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION..............32
9.
REFERENCES.....................................................................................................33
11.
HISTORY TABLE...............................................................................................35


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LIST OF TABLES
Table 6.2: 1
Handling of iPDs..............................................................................................17
Table 6.3: 1
Subject sets analysed........................................................................................20
Table 11: 1
History table .....................................................................................................35


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ACEi
Angiotensin-converting enzyme inhibitor
AE
Adverse event
AESI
Adverse events of special interest
ARB
Angiotensin receptor blocker
Anti-dsDNA
Anti-double stranded DexoxyriboNucleic Acid
AUC
Area under the curve
BI
Boehringer Ingelheim
C3
Complement Component C3
C4
Complement Component C4
CD
Cluster of Differenciation
CMH
Cochran-Mantel-Haenszel
CRR
Complete Renal Response
CTC
Common Terminology Criteria
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DMC
Data Monitoring Committee
ECG
Electrocardiogram
eCRF
electronic Case Report Form
eGFR
estimated Glomerular Filtration Rate
EMA
European Medicines Agency
EOS
End of study
EoT
End of text
EOT
End of trial
FACIT-F
Functional Assessment Chronic Illness Therapy-Fatigue
FU
Follow Up
GFR
Glomerular Filtration Rate
h
hour
HRQoL
Health Related Quality of Life
IA
Interim analysis


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Term
Definition / description
ICH
International Conference on Harmonisation
iPD
important Protocol Deviation
IRT
Interactive Response Technology
ITT
Intent To Treat
IV
Intravenous
KOL
Key Opinion Leader
LLN
Lower limit of normal
LLOQ
Lower limit of quantification
LN
Lupus Nephritis
MedDRA
Medical Dictionary for Regulatory Activities
min
minute
MQRM
Medical Quality Review Meeting
MRR
Major Renal Response
ms
millisecond
PCSA
Possible clinically significant abnormality
PPS
Per protocol set
PR
Time interval of ECG
PRR
Partial Renal Response
PT
Preferred term
RCTC
Rheumatology Common Toxicity Criteria
REP
Residual effect period
RPM
Report Planning Meeting
QRS
Time interval of ECG
QT
Time interval of ECG
SAS
Statistical Analysis System (SAS® System, 
, 
SD
Standard deviation
SELENA
Safety of Estrogens in Lupus National Assessment
SF-36
36-Item Short-Form Health Survey
SLE
Systemic Lupus Erythematosus


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Term
Definition / description
SLEDAI
SLE Disease Activity Index
SOC
System organ class
TOC
Table of contents
TSAP
Trial statistical analysis plan
UP
Urine protein
UC
Urine creatinine
WBC
White blood cell
WHO-DD
World Health Organization-Drug dictionary


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3.
INTRODUCTION
The purpose of this document is to provide a more technical and detailed elaboration of the 
principal features of the analysis than was described in the protocol, and to include detailed 
procedures for executing the statistical analysis of the primary and secondary endpoints and 
other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as 
written in CTP Section 7 “Statistical Methods and Determination of Sample Size”.  
Therefore, TSAP readers may consult the CTP for more background information on the 
study, e.g., on study objectives, study design and population, treatments, definition of 
measurements and variables, planning of sample size, randomization.
SAS® Version 9.4 (or later version) will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
With Amendment #2 to the CTP (21-Dec-2020), Group 2 was cancelled. Group 2 was to be 
a cohort of patients who achieved a meaningful response to induction treatment outside of 
1293.10.  With all patients in 1293.13 now coming from trial 1293.10 (Group 1), the sole 
focus in 1293.13 can be long-term (now 2-year) assessment of their induction and continued 
maintenance therapy in 1293.13. Efficacy and safety tables and figures will include data 
from 1293.10 for assessment of BI655064 doses versus placebo over this 2-year treatment 
period.
Amendment #2 describes the unblinding of treatment codes for 29 patients (20 on treatment 
and 9 in follow-up) in the trial on 20-Oct-2020. At that time, the investigator was asked to 
discuss with the patient their treatment options and continued participation in 1293.13. It is 
not expected that this partial unblinding introduced meaningful reporting bias.  The primary 
endpoint and most of the secondary endpoints are derived from laboratory measurements.
With respect to the SLEDAI, most domains are lab-based and other domains are examination 
findings.  No analyses to address potential bias are planned.
The CTP list of secondary and further endpoints was reviewed (prior to release of treatment 
codes) resulting in some additions and a few deletions essentially driven by learnings from 
the 1293.10 trial. Section 5.2 lists the secondary endpoints noting the addition of one
endpoint (proportion of patients with partial renal response (PRR) without renal flare) 
inadvertently left off the CTP list of secondary endpoints (but specified in another section) 
and one deletion with explanation for the deletion (proportion of patients with CRR at Week 
52). 
Important Protocol Deviations (iPDs) were updated during trial conduct to reflect learnings 
and input from Key Opinion Leaders (KOLs).  The Per protocol set (PPS) was dropped with 
the second CTP amendment.
Sensitivity, subgroup and exploratory analyses added to the TSAP for the primary endpoint 
are listed in Sections 7.4.2. Sensitivity, subgroup and exploratory analyses were also added 
to the TSAP for an important secondary endpoint; these are listed in Sections 7.5.2.
The biomarker analysis will be outlined outside of this TSAP.


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5.
ENDPOINT
5.1
PRIMARY ENDPOINT
The primary endpoint is the proportion of patients with complete renal response (CRR) and 
without any renal flares at week 52.  CRR is defined as:
UP<0.5 g/d at week 52
and either
eGFR within normal range at week 52
or
decrease in eGFR<20% from baseline at week 52 if eGFR is below normal range (i.e., below 
Lower Limit of Normal, where LLN =90 ml/min)
For the assessment of proteinuria, 24h urine collection was performed at baseline (which is 
Week 52 in trial 1293.10) and Week 52 in trial 1293.13.  Collection was performed in 
duplicate (2 times 24h collection). The value of proteinuria is the average of the two values.
Blinded review of the volumes of the 24h collections and durations of collection in trial 
1293.10 raised concern that some collections may have been incomplete.  The rules
implemented in 1293.10 that the 24h samples should be ≥500mL/day and at least 19.5 hours 
(approximately 80% of 24 hours) to be evaluable were applied in 1293.13 also.  With respect 
to UP, any collections <500mL/day or < 19.5 hours were not evaluated.
Rules for deriving UP from 24h urine collections to determine CRR
Protein excretion rates were transferred to BI in units of mg/dL.  The following steps were 
performed to convert to g/day for deriving CRR.
Protein excretion rate (mg/dL) x 1/100 = Protein excretion rate (mg/ml)
Protein excretion rate (mg/ml) x 24-hour total volume (ml) = UP (mg)
UP (mg) * 1/1000= UP (g/day)
An alternative way to derive CRR is based on the ratio of urine protein/urine creatinine 
(UP/UC) determined from the 24h collections.  As the total amount of creatinine excreted 
daily in the urine is quite stable, UC can be used to stabilize the estimate of proteinuria and is 
generally accepted as a correction for incomplete collections. When this derivation was 
applied, collections <500mL/day or < 19.5 hours were evaluated.
Both derivations of CRR are included in the CTP section on assessments of renal response. 
The CTP specifies that the decision which derivation to select as primary endpoint will be 
based on review of blinded data.  However, it was decided to use UP from the 24h collection 
as the primary derivation for CRR to be consistent with 1293.10.  The alternate derivation 
will be analysed and presented using the same methods/format used for CRR derived from 
UP.


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Rules for imputing missing data or data that was not evaluable are provided in Section 6.6.1.  
Also specified in Section 6.6.1 are rules for defining CRR for patients who discontinued 
study medication and/or participation in the trial.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint
This section is not applicable as there is no key secondary endpoint.
5.2.2
Secondary endpoints
The secondary endpoints were re-ordered in order of perceived importance as follows:

Proportion of patients with confirmed CRR (defined as CRR at both week 42 and 
week 52 using UP/UC from spot urine) without renal flare
The endpoint, confirmed CRR, was introduced as a post hoc endpoint for 1293.10 
where it proved to be a more sensitive endpoint as it was able to detect treatment 
effect in the presence of an unexpected large placebo response.  With the requirement 
to demonstrate CRR at both time points, the placebo effect at Week 52 was reduced 
resulting in meaningful response rates for 180 mg and 240 mg BI655064.

Proportion of patients with proteinuria <0.8g/d and without any renal flares at week 
52.

Proportion of patients with CRR at week 52 and sustained steroid reduction to ≤5 
mg/d from week 26 to week 52.

Proportion of patients experiencing at least one renal flare during 52 weeks

Time to first renal flare over the course of 52 weeks.

Proportion of patients with PRR without renal flare derived from UP 24h collection at 
Week 52.
Although not included in the list of endpoints in the CTP, PRR is defined in the CTR 
along with CRR as an assessment of renal response.
It is defined as at least 50% reduction of proteinuria from baseline and either eGFR 
within normal range at time of assessment or decrease of eGFR < 20% from baseline 
if eGFR below normal range at time of assessment.

Change from baseline in SLEDAI at weeks 12, 26, 42 and 52.

Proportion of patients with CRR at Week 52.
It was decided that CRR alone without consideration of whether a patient experienced 
a renal flare was not appropriate as the occurrence of a flare indicates the patient was
not a responder.  This endpoint will not be analysed.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For reporting purposes, all patients will be classified into one of the following treatment 
groups as determined by random treatment assignment at the start of 1293.10:
Sort order
Treatment
Long label
Short label
01
B
BI 655064 120mg
BI 120mg
02
C
BI 655064 180mg
BI 180mg
03
D
BI 655064 240mg
BI 240mg
04
A
Placebo
Placebo
These will be the default labels and sort order for reporting the treatment groups.
The following study periods based on actual start and stop dates of study treatment 
administration are defined:
Treatment: start date of randomised to double-blind medication in 1293.10 to date of last 
dose in 1293.13
Follow-up: day after the last dose of randomised double-blind medication in 1293.13 through 
trial completion and after trial completion
Rules for assigning AEs/laboratory data to the study periods are as follows.
AEs/laboratory data will be assigned to the treatment period if they occur/samples were taken
after the first injection of study medication to the date of last administration of study 
medication plus 50 days.
Adverse events with onset on or after the 51st day after the last administration of trial 
medication will be considered ‘Follow-up’ events.
Laboratory data on or after the 51st day after the last administration of trial medication will be 
considered ‘Follow-up’ data.
6.2
IMPORTANT PROTOCOL DEVIATIONS
The following table defines the different categories of important protocol deviations (iPDs). 
The final column indicates which iPDs will be used to exclude patients from the different 
patient analysis sets.
Patients with iPDs will be documented. The following list of iPDs will be used; note that this 
is a working list and may not be finalised until the final Report Planning Meeting (RPM) 
prior to database lock.


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Excluded from ‘None’ denotes a safety iPD.
Table 6.2: 1
Handling of iPDs
Category/
Code
Description
Example/Comment
Excluded 
from
A
Entrance criteria not met -
automatic PVs
A1.1
Patient must have a CRR or a PRR 
or proteinuria ≤ 1g/d (or UP/UC ≤ 
1)
Note: This can be at Week 46 or Week 52 of 
1293.10.
PPS
A1.2
Women of childbearing potential 
must be ready and able to use two 
reliable methods of birth control 
simultaneously; one must be highly 
effective.  
Sexually active men must be ready 
to use condoms during & following 
treatment with MMF
None
A2.1
Clinically important acute or 
chronic infections including but not 
limited to HIV, hepatitis B or C.
PPS
A2.2
Estimated glomerular filtration rate 
(eGFR) < 30 ml/min/1.73m2 at 
screening (using CKD-EPI 
formula).
A2.3
The use of any restricted 
medications (see CTP) or any drug 
considered likely to interfere with 
the safe conduct of the trial.
B
Informed consent
B1
Informed consent not available/not 
done
Informed consent date missing (automatic 
PV)
All
B2
Informed consent too late
Informed consent date <actual consent date> 
was after Visit 1date <Visit 1 date> 
(automatic PV)
None
C
Trial medication and 
randomization
C1
Randomization not followed
Patient was not assigned to the treatment 
group specified in BI’s randomization 
schedule. (to be checked at time of DBL).
None 
(TBD at 
MQRM/
BRPM)


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Table 6.2: 1 (continued)
Handling of iPDs
C2
Wrong dosage schedule
(1)Medication number dispensed was not the 
medication number assigned OR 
(2)syringes used in the wrong order
PPS/ 
(TBD at 
MQRM/
BRPM)
C3
Non-compliance with study 
medication
Any evidence of gross non-compliance. 
(Patient meets the non-compliance criteria in
Section 5.4)
(manual or automatic PV)
PPS/ 
(TBD at 
MQRM/
BRPM)
C4
Medication code broken 
inappropriately
Medication code broken inappropriately -
reason for medication code break <reason>
(manual PV)
PPS
D
Concomitant medication
D1
Prohibited medication use (as 
described in CTP, section 4).
•
Abatacept or Cyclophosphamide
during treatment period 
•
Cyclosporine / Tacrolimus / 
Mizoribine during treatment period
(permitted during follow up per 
investigator’s decision)
•
Belimumab or other “anti- BLyS” 
or another investigational drug
during treatment period 
•
Biologic B-cell depleting therapy 
(e.g. anti-CD20) during treatment 
period
•
IV glucocorticoids during treatment 
period 
(Automatic & Manual iPVs)
PPS/ 
(TBD at 
MQRM/
BRPM)
D2
Non-permitted oral steroid use (as 
described in CTP, section 4.2.1)

Patients with a CRR or proteinuria 
of <0.8g/d at the end of 1293.10 
should start steroid tapering 
immediately at Visit 1. If necessary, 
patients may remain on a certain 
level of steroids due to other 
symptoms of SLE based on 
investigator’s judgement. Although 
the tapering schedule will allow 
some flexibility, however steroids 
should be stopped at 3 months 
(Week 12) after randomisation. If 
this this not possible due to the 
patient’s medical condition, the 
patient can stay on the lowest 
possible dose with the best benefit.

Patients with proteinuria of ≥0.8g/d 
at the end of 1293.10 should taper 
steroids down to ≤7.5mg/d at week 
26 and then to ≤5mg/d at week 52.
PPS/ 
(TBD at 
MQRM/
BRPM)


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Table 6.2: 1 (continued)
Handling of iPDs
D4 
Non-permitted AZA dose
AZA is allowed at a stable dose of 
2mg/kg/day. (In case of intolerance or the 
body weight <50kg, dose may be reduced to 
1mg/kg/day or the dosage should be rounded 
to the nearest 50mg. In regions where only a 
fixed single dosage is available on the 
market, the rounding should be done 
according to the investigators judgment, not 
exceeding 2mg/kg/day.)
PPS/ 
(TBD at 
MQRM/
BRPM)
D5
Non-stable dose of ACE inhibitors 
or ARBs
ACE inhibitors or ARBs allowed at stable 
dose.
PPS/ 
(TBD at 
MQRM/
BRPM)
G
Trial specific
G1
Failure to remove patient from 
therapy (=study medication)
As described in CTP section 3.3.4.1
PPS/ 
(TBD at 
MQRM/
BRPM
Z
Other
Z1
Other iPVs affecting efficacy and 
possibly safety
PPS/ 
(TBD at 
MQRM/
BRPM
Z2
Other iPVs affecting safety only
None
6.3
SUBJECT SETS ANALYSED

Randomised set:
This patient set includes all randomised patients, whether treated or not.

Treated set:
This patient set includes all patients who were dispensed study medication and were 
documented to have taken at least one dose of investigational treatment.

Intent to treat (ITT) set:
This patient set includes all patients from the treated set who have a baseline (or 
screening) proteinuria (spot urine can be a used if patient does not have 24-hour 
collections) and baseline or screening eGFR
The Per protocol set (PPS) was dropped with the second CTP amendment.


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Table 6.3: 1
Subject sets analysed
Patient set
Class of endpoint
Treated set
ITT
Primary endpoint:
  CRR at week 52
X
Secondary endpoints
X
Safety endpoints 
X
Demographic/baseline 
endpoints
X
Note that the number of patients with available data may differ across endpoints. For details, 
see Section 6.6 “Handling of missing data”.
6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
6.6.1
Primary, secondary 
 endpoints
As CRR is defined based on UP (and UP/UC) from the two 24h urine collections and eGFR 
calculated from serum creatinine, rules for derivation of CRR when one or both of the urine
samples and/or the serum sample is missing are specified below.
If one 24h urine collection is missing at any time point, then calculations should be based on 
the available 24h collection at that time point. If one 24h urine collection at any time point is 
suspected to be incomplete (<500mL/day or time of collection is <19.5 hours) or otherwise 
not evaluable, then calculations should be based on the unaffected collection at that time 
point.
Note that the restrictions on volume and duration of collection do not apply to the UP/UC 
derivation as the adjustment using UC is thought to compensate for incomplete collections.
The following rule was applied to the baseline of 1293.10.  If both 24h urine collections at 
baseline are missing, suspected to be incomplete or not evaluable, then UP/UC from the spot 
urine at baseline should be used to impute baseline UP (or UP/UC) from a 24h collection.


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Handling missing data for patients who do not prematurely stop trial medication
If a patient does not have 24h urine collections at week 52, then UP from a 24h collection
will be imputed as follows:

For the week 52 UP, use the mean of UP/UC from the spot urines at weeks 42 and 52 
UP/UC from two weeks are used to get a more stable estimate of UP as it is generally 
accepted that estimates from the spot urines are not as reliable as estimates from the 24h 
collections.
For the derivation of CRR using UP/UC from the 24h collection, averages of the two weeks 
as described above will also be used to impute missing UP/UC from the 24h collection.
For the derivation of CRR using UP/UC from the spot urine, the imputation would be as 
follows:  If UP/UC from the spot urine is missing at week 26, then use week 18.  If UP/UC 
from the spot is missing at 52; use 42.
If no serum creatinine value (to determine eGFR) was available at baseline in 1293.10, then it 
was imputed using the value at the screening visit. If no serum creatinine value is available at 
week 26 or week 52 in 1293.13, then it will be imputed using the value at week 18 or week 
42, respectively.
For secondary and further endpoints based on proteinuria and eGFR, the same imputation 
rules will be applied to derive response at weeks 26 and 52.
Definition/derivation of CRR for patients who prematurely stop trial medication (not 
applicable to unblinded Placebo patients who obtained BI approval to stop injections)
The CTP specified that as an imputation technique to deal with missing data, for the analysis 
of primary and CRR-related secondary endpoints, non-completers considered failure will be 
used.  To determine if this was a reasonable approach, the trial team reviewed the patients 
who discontinued early, including review of reasons for early treatment discontinuation, AEs, 
concomitant meds, renal labs.  The following handling rules better fit the circumstances 
around treatment discontinuation & were adopted.

(1) If the details around the early discontinuation of trial medication indicated that 
the patient discontinued due to worsening renal function, had a renal flare or needed 
rescue medication, then CRR & PRR will be defined as ‘Non-responder’.

(2) If there was no discernable worsening of renal function & the patient had a 
reasonable treatment duration, renal tests at the time of treatment discontinuation 
will be used to derive CRR & PRR.

(3) If neither of the above applies and if at the time of discontinuation, the patient 
could have been considered a responder, then the patient was considered censored or 
non-evaluable.   If the patient discontinued before Week 26, then both Week 26 & 
Week 52 are non-evaluable.  If the patient discontinued after Week 26, then CRR & 
PRR were derived for Week 26 & Week 52 is non-evaluable.


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For patients who took study drug for < 42 weeks, continued to participate in the trial and have 
urine collections and serum creatinine determinations, their data will be displayed in a 
separate listing.
6.6.2
Other endpoints and safety endpoints
With respect to the SLEDAI, no missing item(s) will be imputed.  If one item comprising the 
sub-score is missing, the sub-score will be set to missing.  Other sub-scores will be derived 
and analysed.  If one item is missing, the total score will be set to missing.
Missing or incomplete AE dates are imputed according to BI standards (see “Handling of 
missing and incomplete AE dates”). (1)
All other endpoints will be analysed without imputing for any missing data. 
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Since patients are randomized at the start of 1293.10 and on the same treatment in 1293.13, 
the baseline of trial 1293.10 will be used as baseline for all assessments of change from 
baseline if not specified otherwise.  The baseline is defined as the latest time point on or 
before the date of the first randomised treatment administration (the date of the first dose is 
acceptable because the first dose of medication is to be taken in clinic on the day of 
randomisation AFTER all baseline assessments have been made) in 1293.10. If there is no 
measurement for a particular variable on or before the date of first randomised treatment 
administration, then no baseline will be derived for that variable.
Visit 1 of trial 1293.1 3 was to be performed on the same day as the 1293.10 end of treatment 
(EOT) visit. All assessments performed at the 1293.10 EOT visit were used as baseline for 
this 1293.13 and were not repeated.
The following visit labels will be used in 1293.13 tables & graphics.  As specified in the 
CTP, EOT refers to the End of Treatment visit.  EOS is the End of Study visit.  FU is Follow 
Up.
For discontinued patients who do not continue participation in the trial:
EOT = ‘EOT’
For completed patients:
Week 52=’Week 52/ EOT’
Follow-up visit at Week 56=’FU’
End of study visit at Week 64=’EOS’
Patient who discontinued treatment before week 40 & continued in trial:


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EOT=’EOT’
Visit 4=’Visit 4/FU’
Visit 6=’Visit 6/FU’
Visit 8=’Visit 8/FU’
EOS=’EOS/FU’
Patient who discontinued treatment after week 40 & continued in trial:
EOT=’EOT’
Visit 8=’Visit 8/FU’
Visit EOS=’EOS/FU’
This is the ‘week 52’ visit
Visit EOS=’EOS + 12w/FU’
This is the ‘week 52’ plus 12 weeks visit
Visit labels containing ‘Visit’ or ‘FU’ occurred after the EOT visit; patient was not on drug 
for these visits.


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7.
PLANNED ANALYSIS
For End-Of-Text (EoT) tables, the set of summary statistics is: N / Mean / SD / Min / Median 
/ Max. 
For tables that are provided for endpoints with some extreme data, median, quartiles and 
percentiles should be preferred to mean, standard deviation, minimum and maximum.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group (unless otherwise specified, all patients in the respective patient 
set whether they have non-missing values or not). Percentages will be rounded to one decimal 
place. The category missing will be displayed only if there are missing values.
All calculated statistics will be presented to one more decimal place than the original 
measurement accuracy of the variable being summarised.
All p-values will be displayed to four decimal places (or “<0.0001” if appropriate).
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report. The display will include 
the following variables: gender, ethnicity, race, age, time since diagnosis (months) at the time 
of entry to 1293.10, height, weight, smoking status, alcohol status, LN class, FACIT-F total 
score, anti-double stranded DexoxyriboNucleic Acid (anti-dsDNA), Complement Component 
C3 (C3) and Complement Component C4 (C4) counts at baseline, eGFR at baseline, UP/UC 
from the spot urine at baseline, UP from the 24h collection at baseline and UP/UC from the 
24h collection at baseline, modified activity and chronicity index scores.  Baseline is the 
baseline of 1293.10.
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases and medications will be summarized.  Frequency counts are planned.
Concomitant diseases will be coded using the current version of MedDRA coding system.
Medications will be coded using the WHO Drug dictionary (WHO-DD). The coding version 
number will be displayed as a footnote in the respective output.
In addition to the standard display showing all concomitant medications, a separate display 
will be provided to characterize usage of ACEi (Angiotensin-converting enzyme inhibitors) 
and ARBs (Angiotensin receptor blockers) by treatment group as these therapies may impact 
renal response.  A separate display will be provided to characterize usage of antimalarial 
therapies by treatment group as usage of antimalarial therapies may impact occurrence of 
renal flares.
For individual patients who experience renal flares, their usage of antimalarial therapies may 
be explored.


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For the non-standard displays, it is of interest to capture the number of patients who use these 
meds at:

Baseline

On-treatment
Including any changes such as: therapies newly started, dose increases, therapies 
stopped and dose decreases

At week 52 (when patient is evaluated for the primary endpoint)
Concomitant diagnoses and medications will be listed by patient. Subjects without any 
concomitant diagnosis or therapy should be marked with a “No” in the respective column.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report.
7.4
PRIMARY ENDPOINT
7.4.1
Primary analysis of the primary endpoint
Primary analyses of the primary endpoint will be performed using the ITT patient set.
Proportion of patients with CRR at Week 52 without renal flare (derived using UP and 
derived using UP/UC from the 24h urine collections) will be analysed using a logistic 
regression model.  Factors in the model will include treatment and the covariates: race 
(Asian/non-Asian) and proteinuria at screening <3g/day or ≥3g/day (respectively 
Uprot/Ucreat<3 or Uprot/Ucreat≥3) in 1293.10.
Pairwise comparisons of the modelled proportion of patients at each dose level who are CRRs 
without renal flare will be compared to placebo.  In keeping with the exploratory nature of 
the trial, p-values will be interpreted in a nominal fashion (no adjustment for multiplicity will 
be performed).
Pairwise comparisons of the observed proportion of patients at each dose level who are CRRs 
without renal flare will be compared to placebo.  Confidence intervals will be calculated 
using the Newcombe method.  P-values from Barnard tests of association will be displayed.
Pairwise comparisons of stratified observed proportions of patients at each dose level who 
are CRRs without renal flare will be compared to placebo.  Confidence intervals will be 
calculated using the Cochran-Mantel-Haenszel (CMH) method.  A single p-value from a 
CMH test of general association will be displayed.
For 1293.10 it was decided that for the pairwise comparisons, an alpha level of < 0.20 (two-
sided) would be the cut-off for declaring statistical significance.  This will be adopted for 
1293.13.  However, it is important when interpreting the p-values (and numerical 
comparisons) to keep the trial design with its inherent biases in mind.  This is an extension 
trial with the requirement to entry that patients responded to treatment in 1293.10 and have 


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the desire to continue participation in a clinical trial.  Treatment assignments were not 
randomized and numbers of patients per treatment group are not balanced.
The partial unblinding of treatment codes for the risk-benefit discussions between 
investigators and patients is not expected to have a meaningful impact on this primary 
endpoint derived from laboratory measurements.
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the primary 
endpoint
Sensitivity analyses:
Pairwise comparisons of the observed proportions of patients at each dose level to placebo 
who are CRRs without renal flare will be stratified by race (Asian vs. non-Asian) as a 
sensitivity analysis.  Confidence intervals will be calculated using the Newcombe method.  P-
values from Barnard tests of association will be displayed.  This same analysis will be 
performed for observed placebo-adjusted proportions of patients at each dose stratified by 
proteinuria at screening in 1293.10 (UP/UC < 3 vs. UP/UC ≥3) as per the lab results.  These 
analyses will be performed for CRR derived using UP determined from the 24h collections, 
UP/UC determined from the 24h collections and confirmed CRR.
Exploratory analyses:
The observed proportion of patients who are CRRs without renal flare in the 180 mg and 240 
mg dose groups combined will be compared to placebo, displaying the same confidence 
intervals and p-values as noted above.  This is an exploratory analysis, based on unexpected 
findings/imbalances observed in the 120 mg group at the time of the interim analysis of
1293.10.  Analyses will be performed for CRR derived using UP determined from the 24h 
collections and confirmed CRR.  These analyses were added via this version of the TSAP.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.
7.5.1.1
Primary analysis of the key secondary endpoint
7.5.1.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the key secondary 
endpoint
7.5.2
(Other) Secondary endpoints
Analysis of all secondary endpoints will be performed using the ITT population.


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For the secondary endpoints listed below, the pairwise comparison of observed proportion of 
patients at each dose level will be compared to placebo using the same methods outlined for 
the primary endpoint.

Proportion of patients with confirmed CRR without renal flare

Proportion of patients with proteinuria <0.8g/d and without any renal flares

Proportion of patients with CRR and sustained steroid reduction to ≤5 mg/d without 
renal flare

Proportion of patients experiencing at least one renal flare

Proportion of patients with partial renal response (PRR) without renal flare
At the time this TSAP was prepared, 8 renal flares were known to have occurred. The 
secondary endpoint, time to renal flare, will be displayed using a Kaplan Meier curve across 
all treatment groups to explore the timing of renal flares with color-coding, symbols or an 
embedded table to indicate the treatment group in which they occurred.
For the secondary endpoint, change from baseline in the SLEDAI, descriptive statistics will 
be provided.
Due to the perceived importance of the secondary endpoint, confirmed CRR, the logistic 
analyses described for the primary analysis will be performed and the sensitivity analyses by 
race and by proteinuria at screening in 1293.10 will be performed.
The analysis of proportion of patients with CRR having sustained steroid reduction <= 5 mg 
from week 26 will be repeated for confirmed CRR.  The proportion of patients with 
confirmed CRR or confirmed PRR will be analysed.  The analysis of proportion of patients 
with CRR who were steroid free from week 26 will be repeated for confirmed CRR. The 
exploratory analysis combining 180mg and 240mg BI 655064 versus placebo will repeated 
for confirmed CRR.
At the time this TSAP was prepared, the expectation is that confirmed CRR will be more 
sensitive than the primary endpoint for detecting treatment effects within subgroups.  For this 
reason, the secondary endpoint, confirmed CRR, will be used for exploring treatment effects 
within subgroups.
Time since diagnosis (of LN) was identified in trial 1293.10 as prognostic of obtaining CRR.  
A subgroup analysis of confirmed CRR will be performed based on the ITT, defined by time 
since diagnosis at the time of entry to 1293.10.  One group will include those patients with 
time of diagnosis from 0- < 6 months.  The second group will include patients with time of 
diagnosis >=6 months.
A subgroup analysis of confirmed CRR at week 52 will be performed based on the ITT data 
set, defined by proteinuria at baseline.  An important CTP inclusion criterion in 1293.10 was 
active renal disease evidenced by proteinuria ≥ 1.0 g/day [(UP/UC) ≥ 1] at screening.  
However, by baseline, there were patients for whom UP and/or UP/UC determined from 24h 


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urine collections were < 1.0 g/day.  Subgroups will be created based on the UP from the 24h 
collections at baseline.  One group will include patients with UP < 1.0 g/day.  The second 
group will include all other patients.
Subgroup analyses of confirmed CRR at week 52 will be performed based on the ITT data set 
stratified using biopsy-derived disease activity index and chronicity index scores. The scoring 
was performed by a renal pathologist who evaluated biopsy slides submitted by the sites.  
Subgroup analyses will be performed based on the activity score and on the chronicity score.  
The median score will be used as the cut-point to split the patients into one group with scores 
less than the median versus the group with scores greater than or equal to the median.
Graphical displays will be used to explore relationships between biomarkers and clinical 
endpoints.  The biomarkers were determined from samples obtained at Week 26 of 1293.10.  
Five biomarkers were selected for this exploratory analysis based on meaningful post-
treatment decreases from baseline distinguishing these biomarkers from other biomarkers 
observed.  Individual patient change from baseline for the biomarker, change from baseline in 
SLEDAI score and confirmed CRR status will be displayed.  The biomarkers from 1293.10 
will be displayed with SLEDAI scores and confirmed CRR status.  In each figure, the clinical 
endpoints will be from the same time points with separate figures for 1293.10 - Weeks 26, 
1293.10 – Week 52 and 1293.13- Week 52.


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7.7
EXTENT OF EXPOSURE
Duration of time on treatment starting with the first injection in 1293.10 to the last injection 
in 1293.13 will be derived for each patient & summarized by treatment group.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set and performed in accordance with BI 
standards. Tabulations of frequencies/proportions will be used for the evaluation of 
categorical (qualitative) data, and tabulations of descriptive statistics will be used to analyse 
continuous (quantitative) data. 
The format of the listings and tables will follow the BI guideline ‘Reporting of clinical trials 
and project summaries’ (3).
The individual values of all subjects will be listed, sorted by treatment, subject number and 
visit. The listings will be contained in Appendix 16.2.
7.8.1
Adverse events
AEs will be analysed using BI standards, as described in the guideline, ‘Handling and 
summarization of adverse event data for clinical trial reports and integrated summaries’ (4).
Unless otherwise specified, the analyses of adverse events will be descriptive in nature. All 
analyses of AEs will be based on the number of patients with AEs and NOT on the number of 
AEs.
The analysis of AEs will be based on the concept of treatment emergent AEs. This means that 
all AEs occurring between first drug intake and end of the residual effect period (REP) will 
be assigned to the randomised treatment. The residual effect period is defined as 50 days. All 
AEs occurring before first drug intake will be assigned to ‘Screening’ and all AEs occurring 
after last drug intake + 50 days will be assigned to ‘Follow-up’ (and presented in listings 
only). For details on the treatment definition, see Section 6.1
According to ICH E3 (5), in addition to Deaths and Serious Adverse Events, ‘other 
significant’ AEs need to be listed in the clinical trial report. These will be any non-serious 
adverse event that led to an action taken with study drug (e.g. discontinuation or dose reduced 
or interrupted).


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An overall summary of adverse events will be presented. The frequency of patients with 
adverse events will be summarised by treatment, primary system organ class and preferred 
term. Separate tables will be provided for patients with adverse events leading to treatment 
discontinuation, other significant adverse events according to ICH E3 (5), related adverse 
events and serious adverse events. AEs will also be summarised by maximum RCTC grade.
Adverse events of special interest (AESI) will be presented in tables and listings for the 
following:
-
Injection site reactions and hypersensitivity, including anaphylaxis reaction
-
Malignancies, lymphoproliferative disorders
-
Severe infections and opportunistic infections
-
Thromboembolism (Thrombosis and adjunct immunosuppression)
-
Cytokine release syndrome
-
Drug induced liver injury (DILI) (if applicable)
The system organ classes will be sorted by frequency, PTs will be sorted by frequency 
(within SOC).
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (6).
The residual effect period of 50 days will be applied to the laboratory data.  Laboratory data 
will be assigned to the treatment period if samples were taken after the first injection of study 
medication to the date of last administration of study medication plus 50 days.  Laboratory 
data from samples taken on or after the 51st day after the last administration of trial 
medication will be considered ‘Follow-up’ data.
Tables and figures in Section 15 of the CTR will include laboratory data from the treatment 
period; data from the follow-up period will not be included.  Listings of laboratory data will 
display on-treatment and follow-up data, with follow-up data flagged to identify they are 
from samples taken during the follow-up period.
Possibly clinically significant abnormalities (PCSA) were identified using BI standard rules 
plus RCTC.
Figures displaying mean and median WBC and neutrophils over time will be provided.
Descriptive statistics for anti-dsDNA, C3 and C4 counts over time will be displayed for all 
patients in the treated set.  For anti-dsDNA, descriptive statistics for patients who are positive 
at baseline [i.e., >ULN (=75 IU/mL)] will tabulated and displayed in a figure.  For C3 and 
C4, patients who are below lower limit of normal (LLN) at baseline will tabulated and 
displayed in figures.  LLN for C3 is 0.9 g/L.  LLN for C4 is 0.1 g/L.
Descriptive statistics over time for erythrosedimentation rate will be provided.


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IgG & IgM values will be listed by treatment, patient and visit. Values outside the normal 
range will be flagged.  Possibly clinically significant abnormalities will be flagged.
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.
7.8.4
ECG
No analysis of ECG data is planned.  Mean heart rate, PR interval, QRS duration and QT 
interval will be listed by treatment group by patient.
7.8.5
Others
Not applicable.


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8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION
Once the last patient has completed their End-of-Treatment (EOT) visit and all corresponding 
data has been entered and cleaned to the level documented in the “Data Delivery Request” 
(DDR) form, the data will be declared ready to be unblinded via the “Data Ready to be 
Unblinded and/or Final Trial Closure Notification” (RUN) form. Then the treatment 
information will be released for analysis.
The data collection for the off-treatment residual effect period until the End-of-Study (EoS)/ 
Follow-Up visit will continue into the unblinded trial database. Once trial data collection has 
been completed and all data has been entered and cleaned as documented on the RUN form, a 
final data lock will be performed.


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9.
REFERENCES
1
BI-KMED-BDS-HTG-0035: “Handling of missing and incomplete AE dates”, 
current version; KMED platform.
3
BI-KMED-BDS-HTG-0045: “Reporting of clinical trials and project summaries”, 
current version, KMED platform.
4
BI-KMED-BDS-HTG-0041: “Handling and summarization of adverse event data 
for clinical trial reports and integrated summaries”, current version; KMED 
platform.
5
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical Study 
Reports, current version, EMA webpage.
6
BI-KMED-BDS-HTG-0042: “Display and Analysis of Laboratory Data”, current 
version, KMED platform.


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11.
HISTORY TABLE
This is a revised TSAP including the following modifications to the final TSAP
Table 11: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections changed
Brief description of 
change
1
14-DEC-17
None
This is the final TSAP
2
17-JUN-21
All
This is a revised TSAP 
updated to reflect issues 
identified during data 
review, learnings from 
project team & KOLs and 
specifications to execute the 
statistical analysis.  Updates 
based on CTP Amendment 
#2 are also included.