Clinical trial NCT03669861
Conditions: IgG4-related Disease
Sponsor: Massachusetts General Hospital
Start date: 2018-11-13; Completion date: 2020-11-10
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 2, single center, proof of concept clinical trial in subjects with active IgG4-Related Disease (IgG4-RD). Approximately 10 subjects with active IgG4-RD will be enrolled into this study. Subjects will receive weekly subcutaneous doses of abatacept (125mg) for 24 doses (24 weeks).

Detailed description:
After obtaining informed consent, all screening procedures and tests establishing eligibility will be performed on the initial screening visit. Subjects determined to be eligible at screening will receive an initial subcutaneous dose of abatacept (125mg), which will be continued weekly for a total of up to 24 doses (24 weeks). Steroid therapy must be tapered off and discontinued over a 4 week period (taper must be completed no later than week 4). Should patients be deemed to have worsening disease or failing therapy at 4 weeks then a trial of steroids can be considered.

Subjects will return on weeks 1, 2, 4, 8, 12, 16, 20, and 24 while on treatment for their injections, and for the scheduled safety and disease response assessments. Subjects will be allowed to self-administer their injections at home. The full treatment period is 24 doses given weekly for 24 weeks. Subjects who are not able to be tapered off corticosteroids or who require reinstitution of corticosteroid therapy at any time during the study will be counted as treatment failures, but may continue on study. Should the IgG4-RD responder index fail to improve by 8 weeks or should there be development of new organ failure at 4 weeks, patient's will be deemed treatment failure and can begin corticosteroid or alternative immunosuppressive therapy at the Investigator's discretion. Those who require rituximab or who require addition of other oral immunosuppressives will be counted as treatment failures and will terminate the study.

All subjects completing the treatment period will have follow up visits off protocolized treatment at 28 and 36 weeks. All adverse events (including serious adverse events (AEs) and deaths) and use of concomitant medication information will be collected throughout the study from screening through study termination. Subjects developing treatment-emergent adverse events or clinically significant safety lab abnormalities will be followed until resolution or until stabilization of the adverse events/abnormalities.

Arms: arm 1: To assess the effect of weekly subcutaneous (SC) administration of abatacept on complete remission of IgG4-RD
Interventions: intervention 1: Abatacept
Intervention descriptions: intervention 1: Subjects will receive weekly subcutaneous doses of abatacept (125mg) for 24 doses (24 weeks)

Protocol documents:
Prot_000.pdf: 
Brist ol  M yers  S q uib b  
Pr ot oc ol  S yno psis:  A batace pt in  I g G 4 -R D  
Clinica l  St ud y  S yno psis 
C O N FI D E N TI A L  
Pa ge 1  of 6 6  
V 3. 1: O ct 2 8, 2 0 1 8  
 
 
1  
TI T L E  P A G E  
C LI NI C A L  S T U D Y  P R O T O C O L  
A pros pe cti ve, o pe n -l a bel,  si ngle ce nte r a bat ace pt i n  I g G 4-R el ate d Dis e as e 1 0 -patie nt pro of - 
of- c o nce pt  s t u dy  
 
 
B M S Pr ot oc ol   N o.: 
I M 1 0 1- 7 4 4 
Trial  Re gistrat io n  N u mber/ E U D R A C T   N o.:  
N C T 0 3 6 6 9 8 6 1 
Test  Pr o d uct: 
A batace pt  
I ndicatio n: 
I g G 4-Relate d  Disease  
S p o ns or: 
Massac husetts  Ge neral   H os pital 
De velo p me nt  P hase:  
P hase  2 
Principa l  I nvestiga t or : 
J o hn  H.  St o ne, M D,  M P H  
J H St o ne @ mgh. har var d.e d u 
 
Date of  t he  Pr ot oc ol: 
O ct o ber 2 8, 2 0 1 8 
 
Versio n  of  t he Pr ot oc ol: 
 3. 1


Brist ol  M yers  S q uib b  
Pr ot oc ol  S yno psis:  A batace pt in  I g G 4 -R D  
Clinica l  St ud y  S yno psis 
C O N FI D E N TI A L  
Pa ge 2  of 6 6  
V 3. 1: O ct 2 8, 2 0 1 8  
 
 
 
P R O T O C O L  S Y N O P SI S  
 
Prot oc ol  Title:  
A pr os pective,  o pe n -la bel,  single  ce nter  a batace pt  in  I g G 4-Relate d  Disease 
1 0 -patie nt  pr o of-of-c o nce pt  st ud y 
Prot oc ol  S hort 
 
A batace pt  in  I g G 4 -Relate d  Dise ase:  A 1 0 -patie nt  pr o of-of-c o nce pt  st ud y 
St u dy  N u m be r:  
B M S Pr ot oc ol  N o.: I M 1 0 1 -7 4 4  
I nvesti g ati o nal 
 
A batace pt  
D e vel o p me nt 
 
P hase 2  
I n dic ati o n 
I g G 4-Relate d  Disease  (I g G 4 -R D)  
S po ns or:  
Massac husetts  Ge neral  H os pital  
Co or di n ati n g 
I nvesti g at or: 
Dr. J o hn  H. St o ne, Har var d,  Massac husetts  Ge neral  H os pital  
St u dy  Ce nte r(s):  
Single  C e nter:  Massac husetts  Ge neral  H os pital  
St u dy  O bje cti ve s :  
Pri mary  O bje cti ve  
•  
T o  assess t he effect  of wee kly  s ubc uta ne o us ( S C) a d minis tra t io n  of a batace pt  
o n c o mplete  re missio n  of I g G 4-R D  
Se c o n dary  O bje cti ve s 
•  
T o  assess  t he  effect  of  a batace pt  o n  disease  res p o nse  at 4, 1 2 a nd  2 4 wee ks 
a nd c o mplete  re missio n  at 3 6  wee ks  
•  
T o  assess t he effect  of a batace pt o n ti me t o disease  re missio n (I g G 4-R D  RI  = 
0),  re missio n  rates,  nu mber  of disease  flares  per s ubject  o ver  ti me 
•  
T o  assess t he effect  of a batace pt  o n p hysicia n  glo bal assess me nt ( P G A), 
S y mpt o m Se verit y  I nde x,  a nd c u mulati ve  c ortic oster oid   d oses 
•  
T o  assess  t he  effect  of  a batace pt  o n  ser u m  i m m u no glo b uli n  le vels,  I g G 4 
s ubclass  c o nce ntratio ns,  I g E  le vels,  e osino p hils,  a nd ser u m  C 3 a nd C 4 le vels 
at 4, 1 2, 2 4 a nd 3 6 wee ks 
E x pl orat ory  O bje cti ves  
T o assess t he effect  of a batace pt  o n C D 4 + T cells  a nd B cell  s ubsets, 
s pecificall y: 
- C D 4 + c yt ot o xic  T ly mp hoc yte s 
- C D 8 + c yt ot o xic  T ly mp hoc yte s 
- C D 4 + T  follic ula r  helper  cells 
- C D 4 + perip heral  helper  T  cells 
- Plas ma blast s  
- Activate d  B  cells 
 


Brist ol  M yers  S q uib b  
Pr ot oc ol  S yno psis:  A batace pt in  I g G 4 -R D  
Clinica l  St ud y  S yno psis 
C O N FI D E N TI A L  
Pa ge 3  of 6 6  
V 3. 1: O ct 2 8, 2 0 1 8  
 
 
St u dy  D e s i g n:  
T his  is  a P hase   2, single ce nter,   pr o of  of c o nce pt clinica l trial in s ubjects wit h  
active I g G 4-R D.  A p pr o xi matel y  1 0  s ubjects  wit h  active  I g G 4 -R D  will 
be 
e nr olle d  int o  t his  st ud y.  S ubjects  will  receive  wee kly  s ubc uta ne o us  d oses  of 
a batace pt  ( 1 2 5 mg)  for 2 4 d oses.  S ubjects  w ho  are o n pre d nis o ne  at baseline  will 
be gin  a n  investi ga t or -dire cte d  c ortic oster oid  ta per  designe d  t o  disc o nti n ue 
pre d nis o ne  not  later  t ha n  8 wee ks after  t he  baseline  visit.    
I nvesti g ati o nal 
M e dici nal 
Pro d uct(s);  I M P, 
D os e  a n d  R o ute  
of 
 
D ose a nd r o ute  of a d ministrati o n:  a batace pt  ( 1 2 5 mg)  will  be give n  b y S C 
injectio n  e ver y  7 da ys for  up t o 2 4 d oses ( 2 4 wee ks). 
 
R efe re n ce 
 
N o ne  
N u m be r  of 
S u bje cts   Pl a n ne d:  
A p pr o xi mate l y  1 0 s ubjects  wit h  active  I g G 4 -R D  
Dia gnos is  a nd  Main 
Criteria  for 
I nclus io n: 
Male  a nd fe male  s ubjects  a ge 1 8 or older  w ho fulfill  t he A C R/ E U L A R  2 0 1 8 
C lassifica t io n  C riteria  for  I g G 4 -R D  wit h  a mini m u m  I g G 4 -R D  Res p o nder  I nde x 
sc ore of 2 
St u dy  D urati o n:  
After  scree ning  a nd e nr oll me nt,  eligible  s ubjects  will  receive  a n initial 
s ubc uta ne o us  d ose of a batace pt ( 1 2 5 mg)  follo we d  b y wee kly  s ubc uta ne o us  d oses 
of a batace pt  ( 1 2 5 mg)  for  a t otal  of up t o 2 4 d oses  ( 2 4 wee ks). If  s ubjects  are o n 
pre d nis o ne  at baseline,  t he y  will be gin  a n  investi ga t or -directe d  c ortic oster oid 
ta per designe d  t o disc o nti n ue  pre d nis o ne  not  later  t ha n  8 wee ks after  t he  baseline 
visit.  S ubjects  will  be follo we d  o n st ud y  for  1 2 wee ks follo wi n g  t he  last  d ose for 
a t otal  st ud y  perio d  of up t o 3 6 wee ks.  
I ncl usi o n  Crite ri a: S ubjects  w ho  meet  t he follo wi n g  criteria  will  be c o nsidere d  eligible  t o participate 
in  t he  clinica l  st ud y  if  t he y: 
1.  Are male  or fe male  1 8 years  of a ge or older  
2.  Meet t he A C R/ E U L A R  2 0 1 8 C lassifica t io n  C riteria  for  I g G 4 -R D (see 
a p pe ndix  G) 
3.  Ha ve  active  disease  base d o n a n I g G 4 -R D  RI ≥2 at scree ning  wit h  disease 
ma nife sta tio n  in  at least  o ne  or ga n  s yste m  e xcludi n g  ly mp h  no des  at 
scree ning  
4.  Ma y or ma y  not  ha ve  receive d  prior  I g G 4 -R D  t hera p y  
5.  M ust  be willi n g  t o ta per off  a ny  s yste mic  c ortic oster o id  t hera p y  wit hi n 8 
wee ks of first  d ose of  trial  dr ug.  
6.  M ust  be a ble  a nd willi n g  t o disc o ntin ue  a ny  i m mu nos up pr essi ve  a ge nt  at 
scree ning  (e. g.  met hotre xate,  myc o p he nolate  mofetil,  6-merca pt o p uri ne, 
tacr oli m us,  c yclo p hos p ha mid e  or azat hio pri ne). 
7.  N o hist or y of se vere  aller gic  reactio ns  t o mo noclo nal  a ntib o dies.    
8.  Are a ble  a nd willi n g  t o c o mplete  t he  e ntire  st ud y  per t he  st ud y  sc he d ule.  
9.  Are  willi n g  t o  fore go  ot her  for ms  of  e xperi me nta l  treat me nt  d uring  t he 
st ud y.  
1 0.  ca n pr o vide  writte n  infor me d  c o nse nt.  
 


Brist ol  M yers  S q uib b  
Pr ot oc ol  S yno psis:  A batace pt in  I g G 4 -R D  
Clinica l  St ud y  S yno psis 
C O N FI D E N TI A L  
Pa ge 4  of 6 6  
V 3. 1: O ct 2 8, 2 0 1 8  
 
 
 
E xcl usi o n  Crite ri a:  
S ubjects  w ho  meet  o ne or more  of  t he follo wi n g  criteria  will  not be c o nsidere d 
eligib le  t o participate  in  t he  clinica l  st ud y: 
 
1.  Hist or y  or e vide nce  of  a clinicall y  unsta ble/ u nc o ntr olle d  dis or der, 
c o nditio n  or  disease  (includ i n g  b ut  not  li mit e d  t o car dio p ul mo nar y, 
o nc olo gic,  re nal,  he patic,  meta b olic,  he mat olo gic  or ps yc hiatric)  ot her 
t ha n  I g G 4-R D  t hat,  in  t he  o pinio n  of t he  I nvestigat or,  w o uld  p ose a ris k 
t o patie nt  safet y  or interfere  wit h  t he  st ud y  e valuatio n,  pr oce d ures  or 
c o mpletio n.  
2.  Mali gna nc y  wit hi n  5 years  (e xce pt  s uccessfull y  treate d in  sit u  cer vical 
ca ncer,  resecte d s q ua mo us  cell  or basal  cell  carcino ma  of  t he s kin,  or 
pr ostate  ca ncer wit h  no rec urre nce  ≥3 years  follo wi n g  pr ostatect o my).  
3.  Liver  disease:  Ac ute  or c hr o nic  no n -I g G 4-related  liver  disease  dee me d 
s uffic ie nt l y  se vere  t o i mpair  t heir  a bilit y  t o  participate  in  t he  trial. 
4.  U nc o ntr olle d  disease:  e vide nce  of a not her  unc o ntr olle d  c o nditio n, 
includ i n g  dr ug  a nd  alc o hol  a b use,  w hic h  c o uld  interfere  wit h 
participatio n  in  t he  trial  acc or d ing  t o t he  pr ot oc ol. 
5.  Prese nce  of rec urre nt  or c hr o nic  infectio ns,  define d  as ≥3 infectio ns 
re q uiri n g  a nti micr o b ia ls  o ver  t he  past  6 mo nt hs  prior  t o  scree ning. 
6.  Active  infectio n  re q uirin g  hos pitalizatio n  or treat me nt  wit h  pare nteral 
a nti micr o bials  wit hin  t he  3 0 da ys prior  t o ra nd o mizat io n.  
7.  Prior  use  of  rit uxi ma b  ( or  ot her  B  cell  de pletin g  a ge nts)  wit hi n  6 mo nt hs 
of e nr oll me nt  unless  B cells  ha ve  bee n de mo nstrate d  t o ha ve 
re p o p ulate d. 
8.  Use  of  a ny  investi ga tio na l  a ge nt  wit hi n  5 half -li ve s  of  t he  a ge nt  ( or  6 
mo nt hs  if  t he  half -li fe  is  unk no w n)  prior  t o e nr oll me nt. 
9.  W hite  blo o d  cell  c o unt  < 2. 5 x 1 0 3/ µ L. 
1 0.  A bs olute  ne utr o p hil  c o unt  ( A N C) < 1. 0 x 1 0 3/ µ L. 
1 1.  I g G 4-relate d  re nal  disease  wit h  ser u m  creatini ne  > 2. 0 mg/ d L.  
1 2.  He mo glo bi n  < 1 0 g/ d L. 
1 3.  Platelet  c o unt  < 7 5 x 1 0 9/ L. 
1 4.  K no w n  p ositive  res ult  fo r  HI V  I or II a ntib o d y,  he patitis  B s urface 
a ntige n,  he patitis  B c ore a ntib o d y  or he patitis  C a ntib o d y.  
1 5.  Has receive d  live  vaccines  wit hi n  4 wee ks’ o k e nr oll me nt.  
1 6.  I na bilit y  t o  c o m munica te  relia bl y  wit h  t he  invest i gat or. 
1 7.  Patie nt  is  pre gna nt  or breast  fee din g  or pla nni n g  t o  bec o me  pre gna nt 
w hile  e nr olle d  in  t he  st ud y,  up  t o E O S visit.  
1 8.  P ositive  pre gna nc y  test  at  scree ning  or  d uring  t he  st ud y.  
1 9.  S ubjects  of  c hild beari n g  p ote ntial  w ho d o not  a gree t o use me dicall y 
acce pta ble  met ho ds  of c o ntrace ptio n.  
2 0.  K no w n  or s us p ecte d  se nsiti vit y  t o ma m malia n  cell-derive d  pr o d ucts  or 
a ny  c o mp o ne nts  of  t he  st ud y  dr ug.  
2 1.  Hist or y  of alc o hol  a nd/ or  s ubsta nce  a b use wit hi n  1 2 mo nt hs  prior  t o 
scree ning. 
2 2.  U na ble  or un willi n g  t o parta ke in  follo w -up  assess me nts  or re q uire d 
pr ot oc ol  pr oce d ures . 
 


Brist ol  M yers  S q uib b  
Pr ot oc ol  S yno psis:  A batace pt in  I g G 4 -R D  
Clinica l  St ud y  S yno psis 
C O N FI D E N TI A L  
Pa ge 5  of 6 6  
V 3. 1: O ct 2 8, 2 0 1 8  
 
 
 
St u dy  Proce d ure s :  
After  o btainin g  infor me d  c o nse nt,  all  scree ning  pr oce d ures  a nd  tests 
esta blis hi n g  eligib il it y  will  be perfor me d  o n  t he  init ia l  scree nin g  visit. 
S ubjects  deter mine d  t o be eligible  at scree nin g  will  receive  a n initial 
s ubc uta ne o us  d ose of a batace pt ( 1 2 5 mg),  w hic h  will  be c o ntinue d  wee kly 
for  a t otal  of  up t o 2 4 d oses ( 2 4 wee ks). Ster oid  t hera p y  must  be ta pere d 
off  a nd disc o ntin ue d  o ver 8 -wee k perio d  (ta per must  be c o mplete d  no 
later  t ha n  wee k 8 ). S ho uld  patie nts  be dee me d  t o ha ve w orse nin g  disease 
or faili n g  t hera p y  at 4 wee ks t he n  a trial  of ster oids  ca n be c o nsidere d.  
 
S ubjects  will  ret ur n  o n wee ks 1, 2, 4, 8, 1 2, 1 6, 2 0, a nd  2 4 w hile  o n 
treat me nt  for  t heir  injectio ns,  a nd for t he  sc he d ule d  safet y  a nd disease 
res p o nse  assess me nts.  S ubjects  will  be allo we d  t o  self-a d mi nister  t heir 
injectio ns  at ho me.  The  full  treat me nt  perio d  is  2 4 d oses give n  wee kly  for 
2 4 wee ks. S ubjects  w ho  are not  a ble t o be ta pere d off  c ortic oster oids  or 
w ho  re q uire  reinstit utio n  of  c ortic oster oid  t hera p y  at a ny  ti me  d uring  t he 
st ud y  will  be c o unte d  as  treat me nt  failures  b ut  ma y  c o ntinue  st ud y. 
S ho uld  t he  I g G 4 -R D  res p o nder  inde x  fail  t o i mpr o ve  b y 8 wee ks or w ho 
de velo p  ne w or ga n  I N V O L V E M E N T  b y wee k 4 will  be dee me d  a 
treat me nt  fail ure,  patie nt’s  will  be dee me d treat me nt  failure  a nd ca n 
be gin  c ortic oster oid  or alter nati ve  i m m u nos up pr essi ve  t hera p y  at t he 
I nvesti gat or’s  discretio n.  Those  w ho  re q uire  rit uxi ma b  or w ho re q uire 
a d ditio n  of  ot her  oral  i m mu nos up pressi ve  will  be c o unte d  as treat me nt 
failures  a nd  will  ter minate  t he  st ud y. 
 
All  s ubjects  c o mpleti n g  t he  treat me nt  perio d  will  ha ve  follo w  up  visits 
off  pr ot oc olize d  treat me nt  at 2 8 a nd 3 6 wee ks. All  A E(s)  (includi n g 
serio us  A Es  a nd deat hs)  a nd use  of c o nc o mita nt  me dicatio n  infor mati o n 
will  be c ollecte d  t hr o ugho ut  t he  st ud y  fr o m  scree nin g  t hr o ugh  st ud y 
ter minati o n.  S ubjects  de velo pin g  treat me nt-e mer ge nt  A Es  or clinica l l y 
significa nt  safet y  la b  a b nor malit ies  will  be  follo we d  until  res olutio n  or 
until  sta bilizati o n  of t he A Es/a b nor malities.  
Crite ri a  f or 
E v al uati o n: 
Dis e as e Acti vit y:  
T he  follo wi n g  disease  activit y  para meters  will  be rec or de d at sc he d ule d 
inter va ls  t hr o ugho ut  t he  st ud y: 
•  
I g G 4-R D  RI  sc ore 
•  
P hysicia n  Glo bal  Assess me nt  of  Disease  Activit y  ( Vis ual  Activit y  Sc ore)  
•  
S y mpt o m  Se verit y  I nde x 
•  
Gluc oc ortic oid  To xic it y I nde x 


Brist ol  M yers  S q uib b  
Pr ot oc ol  S yno psis:  A batace pt in  I g G 4 -R D  
Clinica l  St ud y  S yno psis 
C O N FI D E N TI A L  
Pa ge 6  of 6 6  
V 3. 1: O ct 2 8, 2 0 1 8  
 
 
 
 
S afe t y:  
T he f ollo win g  s afet y para meters will  be re c or de d at re g ular inter vals  d urin g  t he st u d y:  
•  
A d vers e  e ve nts  
•  
P h ysic al  e xa minatio ns  
•  
Vita l  sig ns (s u pine blo o d  press ure  [ B P], he art  rate [ H R], oral b o d y  te m perat ure, 
res pirat or y rate [ R R]) 
•  
Clini c al  la b orat or y  testin g  (clinic al  c he mistr y,  he mat olo g y,  s er u m 
i m m u n o glo b uli ns,  s er u m I g G4  s u bclass es, c o m ple me nts,  a n d urina lysis)  
•  
C o nc o mita nt  me dic atio ns  
 
Se r ol o gic I n dic at o rs of R es p o ns e:  
•  
I m m u n o glo b uli n le ve ls 
•  
I g G4 s u bclass es 
•  
I g E 
•  
E osin o p hil  le ve ls 
•  
C 3 a n d  C 4 le ve ls 
 
C o rre l ati v e  St u dies:  
A d ditio nal  me c ha nistic  st u dies  will  be  c o n d ucte d  t hr o u g h  t he  M G H  NI H -f u n de d 
A ut oi m m u nit y  Ce nter of E xc elle nc e f or I g G4 -R D,  w hic h has esta blis he d  tra nslatio na l 
c olla b oratio ns  bet w e e n t he  M G H  Clinic  a n d  t he  Ra g o n  I nstit ute  of  H ar var d,  M G H, 
a n d MI T (t he la b orat or y  of Dr. S hiv  Pillai).  
Briefly,  perip heral  blo o d  m o n o n ucle ar  c ells  ( P B M Cs) a n d plas ma will  be is olate d  a n d 
fr oze n fr o m e a c h s u bje ct at w e e ks  0,  1,  4,  1 2  a n d 2 4  c orres p o n din g wit h  c linic a l blo o d  
dra ws.  P B M Cs a n d  plas ma  w ill  be  st ore d  in  liq uid  nitr o ge n  f or  pres er vatio n.  T he 
f ollo win g  e x peri me nts  will  be  c arrie d  o ut  in  batc hes  of  1 0  patie nt  ti me  p oints  per 
e x peri me nt: 
1.  Flo w  c yt o metric q ua ntific atio n  of plas ma blasts,  a ctivate d B c ells,  ter minall y 
differe ntiate d  C D 4 + c yt ot o xic T c ells ( C D 4 + C T Ls), ter minally  differe ntiate d 
C D 8 + c yt ot o xic T c ells ( C D 8 + C T Ls), a ctivate d f ollic ular  helper T ( T F H) c ells 
a n d perip heral  helper T ( T P H) c ells. Ter minal  differe ntiatio n  will  be define d 
b y  t he  loss  of  C D 2 8  s urfa c e e x pressio n a n d ga in  of  C D5 7  s urfa c e e x pressio n 
wit hin  t he res pe ctive effe ct or ( C D 4 5 R A- C C R 7-) T c ell p o p ulatio n.  T hes e  c ell 
p o p ulatio ns  will  be  ass ess e d at  w e e ks  0,  1,  4,  1 2  a n d  2 4  t o  deter mine  t he 
tre at me nt effe ct o n t he a bs olute  n u m bers a n d pr o p ortio ns  of t hes e c ell t y pes. 
2.  Q ua nti fie d  c ell  p o p ulatio ns  will  be a nalyze d  f or c orrelatio n  wit h  o ne a n ot her, 
dis e as e a ctivit y,  plas ma I g G4 le vels a n d clinic al  res p o nsive ness t o  a bata c e pt.  
3.  Fr o m  5 of  t he e nr olle d s u bje cts wit h  k n o w n  e x pa nsio ns  of  t he res pe ctive c ell 
t y pe a n d  clinic al  res p o nsive ness  t o  a bata c e pt,  ter minally  differe ntiate d 
C D 4 + C T Ls,  ter minally  differe ntiate d C D 8 + C T Ls a n d a ctivate d B c ells will  be 
s orte d b y  F A C S at w e e ks 0,  1 2 a n d 2 4.  R N A will  be  is ola te d t o u n der g o  R T-
P C R a m plific a tio n of  t he T C R -β/I g H,  res pe ctively.  N e xt -Ge nerat io n 
Se q ue ncin g  will  be  us e d  t o  define  t he  diversit y  of  t he  T C R/ B C R re pert oire 
lo n git u dina lly  t o as c ertain h o w a bata c e pt ma y i m pa ct c lo na lit y.  


Brist ol  M yers  S q uib b  
Pr ot oc ol  S yno psis:  A batace pt in  I g G 4 -R D  
Clinica l  St ud y  S yno psis 
C O N FI D E N TI A L  
Pa ge 7  of 6 6  
V 3. 1: O ct 2 8, 2 0 1 8  
 
 
E n d poi nts :  
Pri mar y:  
- C o mplete  re missio n  at  3 6  wee ks.  C o mplete  re missio n  is  define d  as  a n 
I g G 4-R D  Res p o nder  I nde x  Sc ore  of  0  a nd  a  pre d nis o ne  d ose  of  0 
mg/ da y  be yo nd  wee k 4 a nd no flare  since  be ginni n g  treat me nt.  
Sec o ndar y:  
- 
Disease  res p o nse  at 4, 1 2, 2 4, a nd  3 6 wee ks. Disease  res p o nse  will  be 
define d  at 6 mo nt hs as: 1) i mpr o ve me nt  of > 1 p oint in t he I g G 4-R D  RI  
sc ore o ver  baseline;   2) no gluc oc ortic oi d  use follo wi n g  t he wee k 4 visit; 
3) no disease  flares,  as assesse d b y  t he I g G 4 -R D  RI.  Disease  flare  will 
be  define d  as  rec urre nce  of  disease  activit y  or  de mo nstratio n  of  a 
disease  e xacer batio n  s uc h  t hat  a d ditio nal  t hera p y  be yo nd  t he  tr ia l 
pr ot oc ol  is  indicate d.  
S uc h  a d ditio nal  t hera p y  
ma y  incl u d e 
gluc oc ortic oids  or alter nati ve  i m mu nos up pressi ve  a ge nts. 
- 
C o mplete  re missio n  at  3 6  wee ks.  
- 
Ti me  t o disease  re miss io n  (I g G 4 -R D  RI  =  0) 
- 
Re miss io n  rates 
- 
N u mber  of  disease  flares  per s ubject  o ver  ti me 
- 
C u mulati ve  c ortic oster oid  d oses a nd Gluc oc ortic oid  To xicit y  I nde x 
- 
P hysicia n  Glo bal  Assess me nt  ( P G A).  A  P G A  c o nsisti n g  of  a  1 0 -
ce nti meter  vis ual  a nalo g  scale  is  c ollecte d  at  eac h  patie nt  visit.  O nl y 
active  disease  (as  o p p ose d t o  da ma ge)  is c o nsidere d  in  t he  sc oring  of 
t he P G A.  
- 
S y mpt o m  Se verit y  I nde x 
- 
Ser u m   i m mu no gl o b uli n le vels, I g G 4 s ubclass c o nce ntratio ns,  I g E 
le vels, e osino p hils,  a nd ser u m  C 3 a nd C 4  le vels. 
Sec o ndar y  Safet y:  
- 
Safet y:  I ncide nce  of a d verse  e ve nts 
- 
Safet y:  I ncide nce  of c ortic os ter oid-relate d  a d verse e ve nts 
- 
C o mp osite  of  vital  signs  assess me nt  as a meas ure  of  safet y 
- 
C o mp osite  of  clinical  la b orat or y  tests assess me nt  as a meas ure  of  safet y 
 
St atistic al  M et ho ds:  
A nal ysis P o p ul ati o ns  
•  
T he  pri mar y  a nalysis  will  be a n  inte nt io n -t o-treat a nalysis  in  w hic h 
t he  pr o p ortio n of  s ubjects  ac hie vi n g  t he pri mar y  o utc o me  is  assesse d.  
Pri mary  effic ac y a nal ysis: 
T he  pri mar y  a nalysis  will  be base d o n t he pr o p ortio n  of s ubjects  ac hie vi n g  t he 
pri mar y  o utc o me.  


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 7  of 6 6  
 
 
 
2  
T A B L E O F  C O N T E N T S  
1 
TI T L E  P A G E...........................................................................................................  
S T U D Y S Y N O P SI S ................................................................................................  
2 
T A B L E O F C O N T E N T S  ........................................................................................ 
3 
I N T R O D U C TI O N A N D S T U D Y  B A C K G R O U N D..............................................  
Ba c k gr o u n d.................................................................................................  
A bata c e pt ..............................................................................................................  
I g G4-Relate d Dis e as e............................................................................................  
C urre nt Tre at me nt of I g G4 -R D a n d Ratio nal  f or Clinic al  St u d y  .......................... 
D os e  Ra tio na le  
.................................................................................................. 
P ote ntial Ris ks.......................................................................................................  
C o nclusio n  a n d Et hic al  C o nsideratio ns ................................................................. 
4 
S T U D Y O BJ E C TI V E S  ........................................................................................... 
Pri mar y O bje ctives.. ...................................................................................... 
Se c o n dar y O bje ctives....................................................................................  
E x pl orat or y  O bje ctives ................................................................................. 
5 
I N V E S TI G A TI O N A L P L A N..................................................................................  
O verall St u d y D esig n a n d Pla n...................................................................  
D es criptio n ........................................................................................................ .... 
Sc he d ule of Ass ess me nts ......................................................................................  
St u d y Ass ess me nts .......................................................................................... ...... 
Scre e nin g P erio d....................................................................................  
Tre at me nt P erio d ( 1 0 1 w e e ks) ...............................................................  
F ollo w -u p  P erio d ................................................................................... 
Dis c ussio n of St u d y D esig n........................................................................  
Ris k/ Be nefit a n d Et hic al Ass ess me nt ............................................ ........ 
Early Ter minatio n  of t he St u d y .............................................................  
Sele ctio n of St u d y P o p ulatio n  ............................................................... ..... 
I nclusio n  Criteria ................................................................................... 
E xclusio n  Criteria .................................................................. ................ 
Wit h dra w al of S u bje cts..........................................................................  
Ot her S u bje ct Restrictio ns ..................................................... ................ 
St o p pin g  Criteria f or t he Clinic al  St u d y.................................  
D os e D ela y a n d D os e M o dific atio n  in  S u bje cts W h o 
E x perie nc e T o xicit y  ...............................................................  
6 
T R E A T M E N T O F  S U BJ E C T S...............................................................................  
I de ntit y of St u d y Tre at me nt(s) ................................................................... 


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 8  of 6 6  
 
 
 
A d ministratio n  of St u d y Tre at me nt(s)........................................................  
St u d y Tre at me nt P a c ka gin g a n d La bellin g.................................................  
P a c ka gin g a n d La bellin g........................................................................  
St ora ge ...................................................................................................  
S u bje ct C o m plia nc e....................................................................................  
St u d y Tre at me nt A c c o u nta bilit y,  H a n dlin g,  a n d Dis p os al .........................  
C o n c o mita nt T hera p y ................................................................................. 
Pre vio us/ C o nc o mita nt  Me dic atio n ........................................................  
C o ntra c e ptio n......................................................................................... 
7 
A S S E S S M E N T O F E F FI C A C Y  ............................................................................. 
Effic a c y V aria bles ......................................................................................  
Effic a c y Ass ess me nts .................................................................................  
I g G4-R D Res p o n der I n de x ....................................................................  
Dis e as e A ctivit y V A S............................................................................  
P h ysicia n’s G lo bal  Dis e as e A ctivit y V A S ............................. 
S u bje ct’s Glo bal  Dis e as e A ctivit y V A S.................................  
S y m pt o m  Se verit y I n de x ........................................................  
Gluc oc ortic oid  T o xicit y  I n de x ...............................................  
3 6 -Ite m S h ort F or m H e alt h S ur ve y ........................................ 
8 
A S S E S S M E N T O F  S A F E T Y..................................................................................  
La b orat or y Ass ess me nts .............................................................................  
P h ysic al E xa minatio n  .................................................................................  
Vital Sig ns ..................................................................................................  
9 
S T A TI S TI C A L E V A L U A TI O N  ............................................................................. 
Sa m ple Size a n d P o w er ..............................................................................  
A nalysis P o p ulatio n....................................................................................  
E n d p oints....................................................................................................  
Pri mar y Effic a c y E n d p oint  ................................................................. ... 
Se c o n dar y Effic a c y E n d p oints...............................................................  
Safet y E n d p oints.................................................................................. .. 
Q ualit y  of Life Ass ess me nts ..................................................................  
I n de pe n de nt D ata M o nit orin g  C o m mitte e (I D M C) ............................... 
Statistic al  Met h o ds  ..................................................................................... 
Ge neral C o nsideratio ns..........................................................................  
1 0   
DI R E C T A C C E S S T O S O U R C E D A T A/ N O T E S  ................................................. 
1 1  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  ...................................... 
1 5. 1  
D ata Q ualit y Ass ura nc e  .............................................................................. 
1 5. 2  
St u d y  M o nit orin g........................................................................................  


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 9  of 6 6  
 
 
 
1 2  
E T HI C S  ................................................................................................................... 
I n de pe n de nt Et hics C o m mitte e/I nstit utio nal  Re vie w B oar d ...................... Go o d 
Clinic al  Pra ctic e......... ....................................................................... 
Writte n I nf or me d C o ns e nt ..........................................................................  
Pr ot oc ol A p pr o val  a n d A me n d me nt(s).......................................................  
C o nfide ntialit y  D ata Pr ote ctio n ..................................................................  
1 3  
D A T A H A N D LI N G A N D R E C O R D  K E E PI N G  ................................................... 
Cas e Re p ort F or ms/ S o urc e D ata H a n dlin g.................................................  
Rete ntio n of Ess e ntial D oc u me nts............. ................................................. 
1 4  
FI N A N CI N G A N D  I N S U R A N C E.......................................................................... 
1 5  
P U B LI C A TI O N P O LI C Y  ....................................................................................... 
1 6  
SI G N A T U R E O F I N V E S TI G A T O R  ...................................................................... 
1 7  
R E F E R E N C E LI S T  ................................................................................................. 
1 8  
A P P E N DI C E S  ......................................................................................................... 
A.  I g G4-R D Res p o n der I n de x (I g G4 -R D RI)  
B.  P h ysic ia n  Glo bal  Ass ess me nt of Dis e as e A ctivit y ( V A S)  
C.  S u bje ct’s Glo bal  Ass ess me nt of Dis e as e A ctivit y ( V A)  
D.  S F -3 6  H e alt h S ur ve y  
E.  I g G4-Relate d Dis e as e S y m pt o m  Distress I n de x  
F.  T he Gluc oc ortic oid  T o xicit y  I n de x  
G.  A C R/ E U L A R 2 0 1 8 Classific atio n  Criteria f or I g G4 - R D 
 
 


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 1 0  of 
 
 
 
3  
I N T R O DU C TI O N  A N D S T U D Y  B A C K G R O U N D  
 
3. 1 A bat ace pt 
 
A batace pt  is  a selective  c osti mulati o n  mo d ulat or  t hat  c o nsists  of  a fusio n  pr otein  of hu ma n 
I g G 1  a nd  t he  e xtracell ula r  d o main  of  C T L A 4,  w hic h  inhib its  T  cell  ( T  ly mp hoc yte )  activatio n 
b y bindin g  t o C D 8 0 a nd C D 8 6 , t here b y  bloc king  interactio n  wit h  C D 2 8. This  bloc ks t he  a bilit y 
of a ntige n  prese ntin g  cells  t o deliver  t he  c o -sti mulat or y  signal  nee de d t o activate  T cells.  It is 
c urre ntl y  indicate d  for  use in  a d ult  r he u mat oid  art hritis,  j uve nile  idio pat hic  art hritis.  I t is not 
c urre ntl y  indicate d  for  use  in  I g G 4 -R D.  
 
3. 2 I g G 4- R el ate d Dis e as e  
 
I g G 4-R D  is  a c hr o nic  fibr o -infla  m mat o r y  c o nditio n  t hat  ca n  affect  virt ua ll y  e ver y  or ga n 
s yste m  includi n g  t he pa ncreas,  biliar y  tract,  salivar y  a nd  lacri mal  gla nds,  or bits,  lungs,  k id ne ys, 
me nin ges,  pit uita r y  gla nd,  pr ostate  a nd  t hyr oid  a mo ng  ot hers.  It  ma y  als o  invol ve  t he 
retr o perit o ne u m.  T his  multi-or ga n  i m m u ne -me diate d  c o nditio n  was pre vio usl y  re gar de d  as a 
gr o up  of  is olate d  single  or ga n  diseases  b ut has rece ntly  bee n rec o gnize d as  a unif yi n g  e ntit y 
linke d  b y c o m mo n  hist o pat holo gical  a nd i m m u no hist oc he mical  feat ures.  The  hist o pat holo gical 
feat ures  include  a de nse ly mp ho plas mac ytic  infiltrate  c o nsisti n g  of T cells  a nd I g G 4 +  plas ma 
cells,  st orifor m  fibr osis  a nd  o bliterat i ve  p hle bit is.  I m muno per o xidase  stainin g  of  affecte d 
tiss ues  ge nerall y  de mo nstrates  a ratio  of ≥4 0 % I g G 4/I g G +  plas ma  cells  ( Des hpa nde  et al. 
2 0 1 2). Ser u m  I g G 4  c o nce ntratio ns  are ele vate d  in  at least  5 0 -6 0 % of  cases before  t he  initiati o n 
of treat me nt  ( Wallace  et al.  2 0 1 5). 
 
T he  fre q ue nc y  of  I g G 4 -R D  is  unk no w n  in  most  c o untries  ot her  t ha n  Ja pa n,  w here  it  is 
t ho ught  t o affect  at least  8 0 0 0 individ uals  ( Uc hida  et al.  2 0 1 2). H o we ver,  beca use t his  disease 
has o nly  bee n rec o gnize d  a nd describe d  in  t he  last  1 0 years,  rec o gnitio n  of t he  disease  is 
gr o wing  in  ot her  parts  of  t he  w orld,  includ i n g  t he  U S  a nd  Eur o pe.  I g G 4 -R D  a p pears t o ha ve  a 
mo dest  pre dilectio n  for affecti n g  me n  more  ofte n  t ha n  w o me n  a nd te nds  t o afflict  mid dle -a ge d 
t o elderly  individ uals.  Alt ho u g h  I g G 4-R D  ca n affec t  a single  or ga n  at  prese ntatio n,  it  is  not 
unc o m mo n  for  patie nts  t o prese nt  wit h  or de velo p  multi -or ga n  disease.  As t he  disease 
pr o gresses,  a d ditio nal  or ga ns  de velo p  lesio ns  a nd  t he cellular  infla m matio n  c haracterizi n g  early 
disease  mo ves  t o war d a more fibr otic  sta ge, ca using  maj or  tiss ue  da ma ge,  d ysfuncti o n  a nd 
ulti mate l y  or ga n  fail ure.  
 
It is unclear  w het her  I g G 4  itself  is  invol ve d  in  t he  pat ho ge nesis  of  t he disease.  T cells 
c o mprise  t he maj or  infla m mat or y  cell  in  t his  disease.  I n fact,  t w o C D 4 + T cells  are belie ve d  t o 
pla y  cr ucial  r oles  in  t his  c o nditio n:  1) A C D 4 + c yt ot o xic  T ly mp hoc yte  bearing  S L A M F 7 o n its 
s urface,  secreting  pr ofibr otic  c yt o kines  I L-1 B a nd T G F -B 1 a nd I F N -ga m ma,  as well  as 
c yt ot o xic  molec ules  s uc h  as perforin  a nd gra nzy me  B. 2) A C D 4 + T  follic ular  helper  cell, 
k no w n  t o drive  t he  class  s witc h  wit hi n  ly mp h  no des  a nd  e xtra -no dal  ger minal  ce nters  ( Matt o o 
et al. 2 0 1 6) 
  
A d ditio nall y,  se veral  B cell  s ubsets  ha ve  rece ntly  bee n describe d  b y flo w  c yt o metr y  t o 
be ele vate d  in  t he perip heral  blo o d of  I g G 4 -R D  patie nts.  Circ ulati n g  I g G 4 +  plas ma blasts 
( C D 1 9lo w C D 3 8 + C D 2 0-C D 2 7 +)  ha ve  bee n s ho w n  t o be ele vate d  in  active  disease  as c o mpare d 
t o indivi d ua ls  wit h  ot her  diseases  a nd  nor mal  c o ntr ols,  e ve n  in  I g G 4-R D  patie nts  wit h  nor mal 
I g G 4  ser u m  le vels.  T otal plas ma blasts  ca n t herefore  be utilize d  as a dia gnostic  feat ure  of I g G 4 - 
R D ( Wallace  et al. 2 0 1 4, Matt o o et al. 2 0 1 4).  
 


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 1 1  of 
 
 
 
T his  st ud y  will  e nr oll  male  a nd  fe male  s ubjects  a ge  1 8 or older  w ho  fulfil l  t he 
A C R/ E U L A R  2 0 1 8 C lassificat i o n  C riteria  for  I g G 4 -R D  wit h  a  mini m u m  I g G 4 -R D  Res p o nder 
I nde x  sc ore of  2 S ubjects  are not  re q uire d  t o ha ve  faile d  prior  t hera p y  for  t heir  disease  t o be 
eligib le  for  t his  st ud y.  
 
3. 3 C urre nt  Tre at me nt  of I g G 4- R D a n d  R ati o nale   f or  t he   Cli nic al  St u dy  
 
I g G 4-R D  is  c urre ntl y  inc ura ble.  The goals  of  treat me nt  are t o re d uce  infla m mati o n  a nd 
s welli n g  in  t he or ga ns,  pre ve nt  or re verse  (if  p ossible)  fibr osis  a nd  increase  gla nd ular  secretio n. 
A ggressi ve  treat me nt  is  warra nte d  t o pre ve nt  or ga n  failure  w he n  vital  or ga ns  are invol ve d.  F or 
e xa mple,  c hola ngitis  d ue  t o I g G 4- R D  ca n lea d t o he patic  failure,  I g G 4 -relate d  (t ype  2) 
a ut oi m m u ne  pa ncreatitis  ca n lea d  t o failure  of eit her  or b ot h t he  e nd ocrine  a nd e xocrine 
pa ncreas,  a nd I g G 4 -relate d  a ortitis  ca n  lea d t o a ne ur ys ms  a nd/ or  a ortic  dissectio n.  At t he 
prese nt  ti me,  gluc oc ortic oids  at daily  d oses of 0. 6 mg/ k g  daily  for 2 t o 4  8  wee ks follo we d  b y 
ta pering  t o lo w  d oses ( or disc o nti n ui n g  alt o get her)  o ver 3-6 mo nt hs  is  t he  first  line  of  t hera p y. 
Alt ho ug h  t his  a p pr oac h  is  effecti ve  initia ll y  in  most  patie nts,  t he  rela pse  rate up o n  ta pering  or 
disc o nti n uati o n  is high  ( K hosr os ha hi  et al. 2 0 1 5). I n a d ditio n,  t he  lo ng  ter m  use of 
gluc oc ortic oid s  in  older  p o p ulatio ns  s uc h  as t hat  affecte d  b y I g G 4 -R D  ca n  lea d t o ma ny 
unt o war d  side  effects  s uc h  as oste o p or osis,  high  blo o d  press ure  a nd dia betes. 
I m munos up pressi ve  me dicatio ns  s uc h  as azat hio pri ne,  myc o p he nolate  mofetil  a nd met hotre xate 
ha ve  bee n use d  as gluc oc ortic oi d -s pari n g  a ge nts,  wit h  no clear  indicatio n  of efficac y  ( St o ne  et 
al.  2 0 1 2, Ya ma mot o  et al.  2 0 1 4, K hosr os ha hi  et al.  2 0 1 5). A high  disease  res p o nse  rate has 
bee n o bser ve d  in  o ne  s mall  o pe n -la bel  trial  wit h  rit uxi ma b,  utilizi n g  a n  I g G 4- R D Res p o nder 
I nde x  ( RI)  as a meas ure  of disease  res p o nse  ( K hosr os ha hi  et al.  2 0 1 0, C arr ut hers  et al.  2 0 1 5). 
M ore rece ntly,  a sin gle  case re p ort fr o m  Ja pa n  has describe d  dra matic  efficac y  in  a patie nt  wit h 
mult i -or ga n  I g G 4 -R D  w hose  s y mpt o ms  a nd signs  of disease  were refract or y  t o B cell  de pletio n 
wit h  rit uxi ma b  ( Ya ma mot o  et al. 2 0 1 6). A strate gy  tar getin g  C D 4 + T cells  ma y  indee d  be 
s uccessful  in  c o ntr olli n g  I g G 4-R D.  We see k t o c o nfir m  t his  hyp ot hesis  in  a pr os pective,  single 
ce nter,  o pe n-la bel,  1 0-patie nt  pr o of- of-c o nce pt  st ud y.  S ubjects  will  receive  wee kly 
s ubc uta ne o us  d oses of a batace pt  ( 1 2 5 mg)  for 2 5 d oses. 
 
3. 4 D os e R ati o nale  
 
T h e  d ose a batace pt  1 2 5 mg  s ubc uta ne o usl y  wee kly  is  c urre ntl y  a p pr o ve d for  use in  a d ult 
r he u mat o id  art hritis,  j uve nile  idio pat hic  art hrit is 
  
3. 5 P ote nti al  Ris ks 
 
Base d o n e xperie nce  in  hu ma n  st udies  t o date a nd class  effects  of i m m u no mo d ulati n g 
me dicatio ns,  s ubjects  receivin g  S C a batace pt ma y  be at ris k  for a d verse  e ve nts.  
 
T he  follo wi n g  a d verse  effects  are base d o n a batace pt a d ministere d  intra ve no usl y  in 
patie nts  wit h  active  R A  in  place b o - c o ntr olle d  st udies  ( 1 9 5 5 patie nts  wit h  O R E N CI A, 9 8 9 wit h 
place b o).  T he s ubc uta ne o us  data is  base d o n a ra nd o mize d,  d o uble- bli nd,  d o uble -d u m m y,  no n- 
inferiorit y  st ud y  t hat  c o mpare d  t he efficac y  a nd safet y  of a batace pt  a d minister e d 
s ubc uta ne o us l y  ( S C) a nd  intra ve no us l y  (I V)  in  1 4 5 7 s ubjects  wit h  r he u mat o id  art hritis  being 
treate d  wit h  bac k gr o und  met hotre xate.  I n patie nt’s  receivin g  intra ve no us  a batace pt for  active 
R A in  place b o -c o ntr olle d  trials,  t he most  c o m mo n  a d verse  e ve nts  re p orte d  in  greater  t ha n  te n 
perce nt  of patie nts  were hea dac he,  up per res pirat or y  infectio n,  nas o p har yngitis  a nd na usea. 
A d verse  e ve nts  t hat  occ urre d  in  at least  3 % of patie nts  a nd at least  1 % more  fre q ue ntl y  in 
a batace pt-treate d  patie nts  t ha n  place b o-treate d  patie nts  were hea dac he,  nas o p har yn gitis, 


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 1 2  of 
 
 
 
dizzi ness,  c o ugh,  bac k pain,  hyperte nsio n,  d ys pe psia,  urin ar y  tract infectio n,  ras h,  a nd pain  in 
e xtre mit y.  T he  most  serio us  a d verse  e ve nts  were infectio n  a nd malig na nc y.  
 
I. 
I nfectio ns 
I nfectio ns  were re p orte d in  5 4 % of  patie nts  receivi n g  a batace pt a nd 4 8 % of t hose  receivin g 
place b o.  T he  most  c o m mo n  infectio ns  were  up per  res pirat or y,  nas o p har yn gitis,  sinusitis, 
urinar y  tract  infectio n,  infl ue nza,  a nd  br o nc hitis.  Ot her  infectio ns  re p orte d  in  fe wer  t ha n  5 % of 
patie nts  were  r hinit is,  her pes  si mple x,  a nd  p ne u mo nia.  The  most  c o m mo n  serio us  infect io ns 
re p orte d were p ne u monia,  cellulitis,  urinar y  tract infectio n,  br o nc hitis,  divertic ulitis,  a nd ac ute 
p yelo ne p hr itis.  
 
II. 
Maligna nc ies  
I n place b o-c o ntr olle d  p ortio ns  of  clinica l  trials,  t he  fre q ue nc y  of  mali g na nc ie s  are si mila r  in  t he 
t w o gr o ups  wit h  1. 3 % in  t hose  receivin g  a batace pt  a nd 1. 1 % o n place b o.  H o we ver,  more cases 
of lung  ca ncer  were o bser ve d in  a batace pt -treate d  patie nts  ( 4, 0. 2 %) t ha n  place b o-treate d 
patie nts  ( 0). I n  t he c u mulati ve  a batace pt  clinic al  trials  ( place b o -c o ntr olle d  a nd unc o ntr olle d, 
o pe n- la bel)  a t otal  of  8 cases of lung  ca ncer  ( 0. 2 1 cases per 1 0 0 patie nt -years)  a nd  4 ly mp ho  ma s 
( 0. 1 0 cases per 1 0 0 patie nt- years)  were o bser ve d in  2 6 8 8 patie nts  ( 3 8 2 7 patie nt- years).  The  rate 
o bser ve d  for ly mp ho ma  is  a p pr o xi matel y  3. 5 -fold  higher  t ha n  e xpecte d  in  a n  a ge- a nd  ge nder -
matc he d  ge neral  p o p ulatio n  base d o n t he  N atio nal  C a ncer I nstit ute’s  S ur veilla nce, 
E pide mio l o g y,  a nd  E nd  Res ults  Data base.  Patie nts  wit h  R A,  partic ular l y  t hose  wit h  highl y 
active  disease,  are at a higher  ris k  for t he  de velo p me nt  of  ly mp ho ma.  Ot her  malig na nc ies 
include d  s kin,  breast, bile  d uct,  bla d der,  cer vical,  e nd o metrial,  ly mp ho ma,  mela no ma, 
myelo d ys plastic  s yndr o me,  o varia n,  pr ostate,  re nal,  t hyr oid,  a nd uterine  ca ncers.  
 
III. 
H yperse nsiti vit y  Reactio ns  
 
A na p hyla xis  was o bser ve d  in  patie nts  d ose d wit h  O R E N CI A  a d minis tere d  intra ve no us l y  in 
c o ntr olle d  a nd o pe n-la bel  clinical  trials,  a nd t he occ urre nce  was rare ( < 0. 1 %). Ot her  reactio ns 
p ote ntiall y  ass ociate d  wit h  dr ug  hyperse ns iti vit y,  s uc h  as hyp ote nsio n,  urticaria,  a nd  d ys p nea 
t hat  occ urre d  wit hi n  2 4 ho urs  of  O R E N CI A  infus io n,  were  unc o m mo n  ( < 1 %). 
 
I V. 
A d verse  Reactio ns  in  Patie nts  wit h  C O P D  
 
C O P D patie nts  treate d  wit h  O R E N CI A de velo pe d  a d verse  e ve nts  more  fre q ue ntl y  t ha n  t hose 
treate d  wit h  place b o  ( 9 7 % vs  8 8 %, res pectivel y).  Res pirat or y  dis or ders  occ urre d  more 
fre q ue ntl y  in  O R E N CI A-treate d  patie nts  c o mpare d  t o place b o-treate d  patie nts  ( 4 3 % vs 2 4 %, 
res pectivel y)  includi n g  C O P D e xacer batio n,  c o ugh,  r ho nc hi,  a nd d ys p nea.  A greater  perce nta ge 
of O R E N CI A -treate d  patie nts  de velo pe d  a serio us  a d verse  e ve nt  c o mpare d  t o place b o -treate d 
patie nts  ( 2 7 % vs  6 %), includi n g  C O P D e xacer batio n  ( 3 of 3 7 patie nts    [ 8 %]) 
a nd p ne u mo nia  ( 1 of 3 7 patie nts  [ 3 %]).  
 
V.  
I njectio n  Site  Reactio ns  in  A d ult  R A Patie nts  Treate d  wit h  S ubc uta ne o us  Ore ncia 
 
T he  o verall  fre q ue nc y  of  injectio n  site  rea ctio ns  was 2. 6 % ( 1 9/ 7 3 6) a nd 2. 5 % ( 1 8/ 7 2 1) for t he 
s ubc uta ne o us  a batace pt  gr o up  a nd t he  intra ve no us  a batace pt  gr o up  (s ubc uta ne o us  place b o), 
res pectivel y.  All  t hese  injectio n  site  reactio ns  (includi n g  he mat o ma,  pr urit us,  a nd er yt he ma) 
were mild  ( 8 3 %) t o mo d erate  ( 1 7 %) in  se verit y,  a nd no ne  necessitate d  dr ug  disc o ntin uatio n.  
 
 
 


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 1 3  of 
 
 
 
VI.  
I m muno ge nic it y  in  A d ult  R A  Patie nts  Treate d  wit h  S ubc uta ne o us  O R E N CI A 
 
T he  o verall  i m m u no ge nicit y  fre q ue nc y  t o a batace pt was 1. 1 % ( 8/ 7 2 5)  a nd 2. 3 % ( 1 6/ 7 1 0) for 
t he  s ubc uta ne o us  a nd  intra ve no us  gr o ups,  res pectivel y.  There  was no c orrelatio n  of 
i m mu no ge nicit y  wit h  effects  o n p har mac o ki netics,  safet y,  or efficac y. 
 
VII.  
I m muno ge nic it y  a nd  Safet y  of  S ubc uta ne o us  O R E N CI A  A d minis tra tio n  as 
M o not hera p y  wit ho ut  a n  I ntra ve no us  Loa ding  D ose  
 
I n  a st udy  t hat  was c o nd ucte d  t o deter mine  t he  effect  of  mo not hera p y  use of  O R E N CI A o n 
i m mu no ge nic it y  follo wi n g  s ubc uta ne o us  a d minis trati o n  wit ho ut  a n  intra ve no us  loa d  in  1 0 0 R A 
patie nts,  w ho ha d not  pre vio usl y  receive d  a batace pt or ot her  C T L A 4I g,  w ho receive d  eit h er 
s ubc uta ne o us  O R E N CI A  plus  met hotre xa te  ( n = 5 1)  or  s ubc uta ne o us  O R E N CI A  mo not hera p y 
( n = 4 9).  N o patie nts  in  eit her  gr o up  de velo pe d  a nti-pr o d uct  a ntib o dies  after  4 mo nt hs  of 
treat me nt.  T he  safet y  o bser ve d  in  t his  st ud y  was  c o nsiste nt  wit h  t hat  o bser ve d  in  t he  ot her 
s ubc uta ne o us  st udies. 
 
VIII.  
I m muno ge nic it y  a nd  Safet y  of  S ubc uta ne o us  O R E N CI A  up o n  Wit hdra wa l  ( Three 
M o nt hs)  a nd Restart  of Treat me nt  
 
I n  a st ud y  c o nd ucte d  t o investi ga te  t he  effect  of  wit hdra wal  (t hree  mo nt hs)  a nd restart of 
O R E N CI A s ubc uta ne o us  treat me nt  o n  i m mu no ge nic it y  in  R A  patie nts  treate d  c o nc o mita ntl y 
wit h  met hotre xa te,  o ne  hundre d  sixt y -se ve n  patie nts  were e nr olle d  in  t he  first  3-mo nt h 
treat me nt  perio d  a nd res p o nders  ( n = 1 2 0)  were ra nd o mize d t o  eit her  s ubc uta ne o us  O R E N CI A or 
place b o  for t he  sec o nd 3 -mo nt h  perio d  ( wit hdra wal  perio d).  Patie nts  fr o m  t his  perio d  t he n 
receive d  o pe n-la bel  O R E N C I A  treat me nt  in  t he  fina l  3-mo nt h  perio d  of t he  st ud y  ( perio d  3). At 
t he  e nd of t he  wit hdra wal  perio d, 0/ 3 8 patie nts  w ho c o ntinue d  t o receive  s ubc uta ne o us 
O R E N C I A de velo pe d  a nti-pr o d uct  a ntib o dies  c o mpare d  t o 7/ 7 3 ( 9. 6 %) of patie nts  w ho  ha d 
s ubc uta ne o us  O R E N CI A  wit hdra w n  d uring  t his  perio d.  Half  of  t he  patie nts  receivin g 
s ubc uta ne o us  place b o  d uring  t he  wit hdra wa l  perio d  receive d  a  single  intra ve no us  infus io n  of 
O R E N CI A at t he start  of perio d  3 a nd half  receive d  intra ve no us  place b o.  At t he e nd of  perio d  3, 
w he n  all  patie nts  a gain  receive d  s ubc uta ne o us  O R E N CI A, t he i m m u no ge nicit y  rates were  1/ 3 8 
( 2. 6 %)  in  t he  gr o up  receivi n g  s ubc uta ne o us  O R E N CI A  t hr o ugho ut,  a nd  2/ 7 3 ( 2. 7 %) in  t he 
gr o up  t hat  ha d receive d  place b o d uring  t he  wit hdra wal  perio d.  U p o n reinitiati n g  t hera p y,  t here 
were no injectio n  reactio ns  a nd no differe nces  in  res p o nse  t o t hera p y  in  patie nts  w ho  were 
wit hdra w n  fr o m  s ubc uta ne o us  t hera p y  for  up  t o 3 mo nt hs relative  t o t hose w ho  re maine d  o n 
s ubc uta ne o us  t hera p y,  w het her  t hera p y  was  reintr o d uce d  wit h  or wit ho ut  a n  intra ve no us  loa ding 
d ose. T he  safet y  o bser ve d  in  t his  st ud y  was c o nsiste nt  wit h  t hat  o bser ve d  in  t he  ot her  st udies.  
 
3. 6 C o ncl us i o n  a n d  Et hic al  C o ns i de rati o ns 
 
T he  design  of t he  pr o p ose d trial  c o ntains  meas ures  a p pr o priate  t o t he  miti gati o n  of ris k 
fact ors  for A Es.  F urt her more,  fre q ue nt  safet y  mo nit ori n g  is a n inhere nt  part of t he  pr ot oc ol.  I n 
s u m mar y,  t he be nefits  a nd ris k  assess me nt  for  t he a p plicatio n  of  a batace pt a p pears fa vora ble 
a nd s up p ortive  for initiatio n  of  t he pr o p ose d clinical  trial.  
 
T his  st ud y  will  be perfor me d  in  t he  follo w i n g  ma nner :  
• I n  acc or da nce   wit h  G o o d  Cli nic al  Practice   ( G C P),  as  de fi ne d  by  t he  
I nte r nati o nal  C o nfe re nce   o n  H ar mo niza ti o n  (I C H),  W H O  a n d  a ny l oc al 
dire cti ves.  
• I n  c o m pli a nce   wit h  t he  prot oc ol. 


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 1 4  of 
 
 
 
• T he   prot oc ol,  a ny  a me n d me nts ,  a n d  t he   s u bje ct  i nf or me d  c o ns e nt will 
re ce i ve  I ns tit uti o nal  R e vie w B o ar d/I n de pe n de nt  Et hics   C o m mitte e  
(I R B/I E C)  a p pro v al/f a v ora ble  o pi ni o n  bef ore i nitiati o n  of  t he  s t u dy.  
• Wit h  pe rs o n ne l  w ho  are  q ualifie d  by e d uc ati o n,  trai ni ng,  a n d  e x pe rie nce  t o 
pe rf or m  t he ir  re s pe cti ve  t as ks  a n d  t hat  t he   s t u dy  will  not  us e  t he   s e rvice s  of 
s t u dy  pe rs o n ne l  f or  w ho m  s a ncti o ns   ha ve  be e n  i nv o ke d  or  w he re   t he re  has  
be e n s cie n tific  mis c o n d uct  or  fra u d 
• Wit h  s i g ne d, date d  I nf or me d  C o ns e nt  fro m  e ac h of  t he  partici pa nts
 
• I nve s ti g at ors / S po ns ors   m us t  e ns ure   t hat  s u bje cts --or,  i n  t hos e sit uati o ns 
w he re   c o ns e nt c a n not  be  gi ve n by  s u bje cts ,  t he ir  le g all y acce pt a ble  
re pres e nt ati ves --are   c le arl y  a n d  f ull y  i nf or me d  a bo ut  t he   p ur pos e ,  pote nti al 
ris ks , a n d  ot he r  critic al  is s ue s  re g ar di ng  cli nic al  s t u die s  i n  w hic h  t he y 
v ol u nte e r  t o partici pate .  T he   a p pro ve d  i nf or me d  c o ns e nt f or m  will  a d he re  
t o t he   e t hic al  pri nci ple s   t hat  ha ve  t he ir  ori gi n  i n  t he D e cl arati o n  of Helsi n ki.  
• I ncl u de   re le v a nt  s afe t y i nf or mati o n  re g ar di ng  dos e /s c he d ule  of  I P  a n d  a ny 
ot he r  dr ugs / proce d ure s  
• B M S a n d  he alt h a ut horit y  t o ha ve dire ct  access t o st u dy re c or ds  B M S will 
pro vi de   t he   s t u dy  dr ug  a n d  f u n di ng  f or  t his   s t u dy.  
4  
 S T U D Y   OB J E C TI V E S  
4. 1  
Pri mary  O bje cti ves  
• T o e valuate  t he  effect  of wee kly  s ubc uta ne o us  ( S C) a d ministrati o n  of a batace pt o n 
c o mplete  re missio n  of  I g G 4 -R D  at 2 4  wee ks  
4. 2  
Se c o n dary  O bje cti ves  
• T o  e valuate t he effect  of a batace pt o n disease  res p o nse at 4, 1 2 a nd 2 4 wee ks  a nd c o mplete 
re missio n  at  3 6 wee ks  
• T o e valuate  t he  effect  of a batace pt  o n ti me  t o disease  re missio n  (I g G 4 -R D  RI  = 0), 
re missio n  rates, nu mber  of  disease  flares  per s ubject  o ver ti me 
• T o e valuate  t he  effect  of a batace pt  o n p hysicia n  glo bal  assess me nt  ( P G A),  S y mp t o m 
Se verit y  I nde x,  a nd c u mulati ve  c ortic oster oid   d oses 
• T o  e valuate  t he  effect  of  a batace pt  o n  ser u m  i m mu no gl o b uli n  le vels,  I g G 4  s ubclass 
c o nce ntratio ns, I g E le vels,  e osino p hils,  a nd  ser u m  C 3  a nd  C 4 le vels  at  4,  1 2, 2 4  a nd  3 6 
wee ks  
4. 3  
E x pl orat ory O bje cti ves  
T o e valuate  t he  effect  of a batace pt  o n C D 4 + T cells  a nd B cell  s ubsets,  s pecificall y:  
- C D 4 + c yt ot o xic  T ly mp hoc yte s 
- C D 8 + c yt ot o xic  T ly mp hoc yt es 
- C D 4 + T  follic ula r  helper  cells 
- C D 4 + perip heral  helper  T  cells 
- Plas ma blast s  
- Activate d  B  cells 


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 1 5  of 
 
 
 
 
 
5  
I N V E S TI G A TI O N A L  P LA N 
O ve rall  St u dy  D e s i g n a n d  Pl a n 
D es cri pti o n  
T his  is  a  P hase  2, pr os pective,  o pe n -la bel,  single  ce nter  clinical  trial  in  s ubjects  wit h  active 
I g G 4-R D.  A p pr o xi matel y  1 0 s ubjects  wit h  active  I g G 4 -R D  will  be e nr olle d.  After  scree ni n g 
a nd e nr oll me nt,  eligib le s ubjects will  receive a n init ia l s ubc uta ne o us  d ose of a batace pt ( 1 2 5 mg) 
follo we d  b y wee kly  s ubc uta ne o us  d oses of  a batace pt ( 1 2 5 mg)  for  a t otal  of up t o 2 4 d oses ( 2 4 
wee ks). S ubjects will  be follo we d  o n st ud y  for 1 2 wee ks follo wi n g  t he last  d ose for a t otal  st ud y 
perio d  of up t o 3 6  wee ks.  
After   o btaini n g infor me d c o nse nt,  all scree ning pr oce d ures  a nd tests esta blis hi n g eligib i l i t y 
will  be  perfor me d  o n  t he  initia l  scree ning  visit.  S ubjects  deter mine d  t o  be  eligib le  at 
scree ning  will  receive  a n  init ia l  s ubc utane o us  d ose  of  a batace pt  ( 1 2 5 mg),  w hic h  will  be 
c o ntinue d  wee kly  for  a t otal  of up t o 2 4 d oses ( 2 4 wee ks). Ster oid  t hera p y  must  be ta pere d 
off  a nd disc o nti n ue d  o ver a 4 wee k perio d  (ta per  must  be c o mplete d  no later  t ha n  wee k 4). 
S ho uld  patie nts  be dee me d  t o  ha ve  w orse ning  disease  or faili n g  t hera p y  at 4 wee ks t he n  a 
trial  of ster oids  ca n be c o nsidere d.  
S ubjects  will  ret ur n  o n  wee ks  1,  2, 4,  8, 1 2,  1 6, 2 0,  a nd  2 4  w hile  o n  treat me nt  for  t heir 
injectio ns,  a nd  for t he  sc he d ule d  safet y  a nd  disease  res p o nse  assessme nts.  S ubjects  will  be 
allo we d  t o  self-a d mi nister  t heir  injectio ns  at ho me.  The  full  treat me nt  perio d  is 2 4 d oses 
give n  wee kly  for  2 4 wee ks.  S ubjects  w ho  are not  a ble  t o be ta pere d  off  c ortic oster oids  or 
w ho  re q uire  reinstit uti o n  of  c ortic oster oid  t hera p y  at  a ny  ti me  d uring  t he  st ud y  will  be 
c o unte d  as  treat me nt  failur es  b ut  ma y  c o ntinue  o n  st ud y.  S ho uld  t he  I g G 4 -R D  res p o nder 
inde x  fail  t o  i mpr o ve  b y 8 wee ks  or w ho  de velo p  ne w  or ga n  invol ve me nt  b y  wee k 4  will 
be  dee me d  a  treat me nt  failure,  patie nt’s  will   be dee me d  treat me nt failure a nd ca n  be gi n 
c ortic oster oid   or alter nati ve  i m mu nos up pr essi ve  t hera p y  at  t he  I nvestigat or’s  discreti o n. 
T hose  w ho re q uire  rit uxi ma b  or w ho re q uire  a d ditio n  of ot her oral  i m mu nos up pressi ve  will 
be c o unte d  as treat me nt  failures  a nd  will  ter minate  t he  st ud y. 
All  s ubjects  c o mpleti n g  t he  treat me nt  perio d  will  ha ve  follo w  up  visits  off  pr ot oc olize d 
treat me nt  at  2 8  a nd  3 6 wee ks.  All  A E(s)  (includi n g  serio us  A Es  a nd  deat hs)  a nd  use  of 
c o nc o mita nt  me dicatio n  infor ma t io n  will  be  c ollecte d  t hr o ugho ut  t he  st ud y  fr o m scree ni n g 
t hr o ugh  st ud y  ter mina tio n.  S ubjects  de velo pin g  treat me nt-e mer ge nt  A Es  or  clinic a l l y 
significa nt safet y la b a b nor malities will   be follo we d until res olutio n  or until sta biliza t io n of 
t he A Es/a b nor ma l it ies.  
Signs  a nd  s y mpt o m s  of  I g G 4-R D  activit y  will  be meas ure d  perio dicall y  t hr o ugho ut  t he  st ud y 
using  a mo dificati o n  of t he  I g G 4 -R D  RI ( C arr ut hers  et al. 2 0 1 2, Wallace  et al. 2 0 1 6 ). The  I g G 4-
R D  RI  is  base d o n  t he  Bir mi n g ha m  Vasc ulitis  Activit y  Sc ore  for  We ge ner’s  Gra nulo mat os is 
(St o ne  et al.  2 0 0 1 )  utilize d  for  t he  e valuatio n  a nd  lice ns ure  of  rit uxi ma b  in  A N C A-ass ociate d  
vasc ulit is   (St o ne  et al.  2 0 1 0). T he  I g G 4-R D  RI  is a n instr u me nt designe d  t o  detect  c ha nge  i n   
disease   activit y  a nd  ide ntif y  i mpr o ve  me nts   a nd  w orse nin g  in   t he  s a me   or 


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 1 6  of 
 
 
 
 
differe nt  or ga n  s yste ms  a nd  has  bee n  use d  in  prior  clinica l  trials  t o  mo nit or  I g G 4 -R D  diseas e 
activit y  (K hosr os ha hi  et al. 2 0 1 0, C arr ut hers  et al. 2 0 1 5, St o ne  et al.  2 0 1 6 ). 
Assess me nts  will  include A E  assess me nt,  p hysica l e xa minat io n,  vital signs, clinica l  la b orat or y 
testing  (clinica l  c he mistr y,  he mat olo g y,  ser u m  i m mu no gl o b uli ns,  ser u m  I g G 4  s ubclass e s ,  
c o mple me nts,  a nd  urinal ys is)  a nd  c o nc o mita nt  me dicat io ns.  A d ditio na l  ser olo gic  indicat ors  of 
res p o nse  will  include  i m mu no gl o b uli n  le vels,  I g G 4  s ubclasses,  I g E,  Eosino p hil  le vels,  C 3 a nd 
C 4  le vels. 
A d ditio na l  
mec ha nis tic  st udies  
will  be  c o nd ucte d  t hr o ugh  t he  M G H  NI H -fund e d  
A ut oi m m u nit y  C e nter  of  E xcelle nce  for  I g G 4 -R D,  w hic h  has  esta blis he d  tra nslati o na l 
c olla b oratio ns  bet wee n  t he  M G H  Clinic  a nd  t he  R a go n  I nstit ute  of  Har var d,  M G H,  a nd  MI T 
(t he  la b orat or y  of  Dr.  S hiv  Pilla i). 
Briefl y,  perip heral  blo o d  mo no nuclear  cells  ( P B M Cs)  a nd  plas ma  will  be is olate d  a nd fr o ze n 
fr o m eac h s ubject at wee ks  0, 1, 4, 1 2 a nd 2 4 c orres p o ndin g wit h  clinica l  blo o d dra ws.  PB M Cs 
a nd  plas ma  will  be st ore d  in  liq uid  nitr o ge n  for  preser vatio n.  The  follo wi n g  e xperi me nts  will 
be carrie d  o ut in  batc hes  of  1 0 patie nt  ti me  p oints  per  e xperi me nt: 
1. Flo w  c yt o metric  q ua ntificatio n  of  plas ma blasts,  activate d  B  cells,  ter mina l l y 
differe nt ia te d  C D 4 +  c yt ot o xic  T  cells  ( C D 4 + C T Ls),  ter minall y  differe ntiate d  C D 8 + 
c yt ot o xic  T cells ( C D 8 + C T Ls), activate d  follic ular helper   T ( T F H) cells a nd perip her al 
helper  T  ( T P H)  cells.  Ter mina l  differe nt iat i o n  will  be  define d  b y  t he  loss  of  C D 2 8 
s urface  e xpressio n  a nd gain  of  C D 5 7 s urface  e xpressio n  wit hi n  t he  res pective  effect or 
( C D 4 5 R A-C C R 7 -) T cell  p o p ulatio n.  These  cell  p o p ulatio ns  will  be assesse d  at wee ks 
0,  1,  4,  1 2  a nd  2 4  t o  deter mine  t he  treat me nt  effect  o n  t he  a bs olute  nu mbers  a nd 
pr o p ortio ns  of t hese  c ell t ypes. 
2. Q ua ntifie d  cell  p o p ulatio ns  will  be a nalyze d  for  c orrelatio n  wit h  o ne  a not her,  disease 
activit y,  plas ma  I g G 4  le vels  a nd clinical  res p o nsive ness  t o  a batace pt.  
3. Fr o m  5 of  t he e nr olle d  s ubjects  wit h  k no w n  e xpa nsio ns  of t he  res pective  cell  t ype  a nd 
clinical  res p o nsive ness  t o  a batace pt,  ter minall y  differe ntiate d  C D 4 + C T Ls,  ter mina l l y 
differe ntiate d  C D 8 + C T Ls  a nd activate d  B cells  will  be s orte d b y F A C S at wee ks 0, 1 2 
a nd  2 4.  R N A  will  be  is olate d  t o  under go  R T-P C R  a mplificati o n  of  t he  T C R -β/I g H,  
res pectivel y.  N e xt-Ge neratio n  Se q ue ncing  will  be  use d  t o  de fine  t he  diversit y  of  t he 
T C R/ B C R  re pert oire  lo ngit udi nall y  t o ascertain  ho w  a batace pt ma y  i mpact  clo nalit y.  


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 1 7  of 
 
 
 
 
5. 1 Sc he d ule of As s ess me nts  
T he s c he d ule of ass ess me nts is pres e nte d in  ta ble  f or mat in  t he st u d y  s y n o psis  
 
St u d y P h as e  
Sc re e n
i n g  
Tre at me n
t 
VI S I T N U M B E R 
1 
2  
 
3  
 
 
4  
 
 
5  
 
 
W E E
K  
0 
1
1  
2 
3 
 
4 
5 
6 
7 
8 
9 
1 0  1 1  1 2  1 3  
1 4  
1 5  
I nf or me d c o ns e nt 
X  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
St u d y  dr u g 
d i i 
i
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
St u d y  dr u g I nstr uctio n  
 
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
Me dic a l  hist or y 2  
X 2 
X  
2  
 
X  
2  
 
 
X 2  
 
 
X 2   
 
 
P h ysic al e xa minatio n 3  
X 3 
X  
3  
 
X  
3  
 
 
X 3  
 
 
X 3   
 
 
A d vers e 
E ve nt 
4  
 
X   
 
X   
 
 
X   
 
 
X   
 
 
Re c or d c o nc o mita nt 
me dic atio ns 4  
X  
X   
 
X   
 
 
X   
 
 
X   
 
 
Vita l  sig ns 5  
X  
X   
 
X   
 
 
X   
 
 
X   
 
 
C B C w/ differe ntial, 
platelet  c o u nt  
X  
X   
 
X   
 
 
X   
 
 
X   
 
 
C o m pre he nsive 
Meta b olic P a nel ( C M P)  
X  
X   
 
X   
 
 
X   
 
 
X   
 
 
Urinalysis  a n d Urine 
pr otein/cre atinine 
 
X  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pre g na nc y test 7  
X  
X   
 
X   
 
 
X   
 
 
X   
 
 
H Bs A g, H Bc A b, 
H C V * * N ot re q uire d  if 
c olle cte d  6 m o nt hs 
prior  t o s cre e nin g 
i i * * 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ser u m i m m u n o glo b uli n 
le vels  (I g M, I g E,  I g G) 
X  
X   
 
 
 
 
 
 
 
 
 
 
 
 
 
Ser u m I g G s u bclass es  
X  
X   
 
X   
 
 
X   
 
 
X   
 
 
C 3 a n d C 4  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Me c ha nistic s a m ples  
X  
X   
 
X   
 
 
 
 
 
 
X   
 
 
Fa stin g  lipid  pr ofile  
X  
X  
 
 
X   
 
 
X   
  
X   
 
 
C T c hest, a b d o me n, 
pe lvis 8  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I g G4-R D RI  
X  
X   
 
X   
 
 
X   
 
 
X   
 
 
P h ysicia n  Glo bal 
A ctivit y  V A S  
X  
X   
 
X   
 
 
 
X  
 
 
 
X   
 
 
S y m pt o m  Se verit y I n de x  
X  
X   
 
X   
 
 
X   
 
 
X   
 
 
Gluc oc ortic oid 
T o xicit y  I n de x  
X  
X   
 
X   
 
 
X   
 
 
X   
 
 
S F -3 6  H e alt h S ur ve y  
X  
X   
 
X   
 
 
X   
 
 
X   
 
 


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 1 8  of 
 
 
 
 
 
 
St u d y P h as e  
 
V I SI T N U M B E R 
6  
 
 
7 
 
 
 
8 
9 
1 0/ E O
S  
W E E
 
1 6  
1 7  
1 8  
1 9  
2 0  
2 1  
2 2  
2 3  
2 4  
2 8  
3 6  
I nf or me d c o ns e nt 
 
 
 
 
 
 
 
 
 
 
 
St u d y  dr u g a d ministratio n  
X  
X  
X  
X  
X  
X  
X  
X  
X   
 
Me dic a l  hist or y 2  
X  
 
 
 
X 2   
 
 
X  
X 2  
X 2  
P h ysic al e xa minatio n 3  
X  
 
 
 
X 3   
 
 
X  
X 3  
X 3  
A d vers e E ve nt ass ess me nt 4  
X   
 
 
X   
 
 
X  
X  
X  
Re c or d c o nc o mita nt  me dic atio ns 4  X   
 
 
X   
 
 
X  
X  
X  
Vita l  sig ns 5  
X   
 
 
X   
 
 
X  
X  
X  
C B C w/ differe ntial,  platelet 
 
X   
 
 
X   
 
 
X  
X  
X  
C he mistr y  P a nel  
X   
 
 
X   
 
 
X  
X  
X  
Urinalysis  a n d Urine 
pr otein/cre atinine 
i 6  
 
 
 
 
 
 
 
 
 
 
X  
Urine Pre g na nc y test 7  
X   
 
 
X   
 
 
X  
X  
X  
H Bs A g, H Bc A b, H C V 8  
 
 
 
 
 
 
 
 
 
 
 
Ser u m i m m u n o glo b uli n  le vels 
(I g M, I g E, I g G) 
 
 
 
 
 
 
 
 
X   
X  
I g G s u bclass es 
X   
 
 
X   
 
 
X   
X  
C 3 a n d C 4  
 
 
 
 
 
 
 
 
 
 
X  
Fa stin g  lipid  pr ofile  
X   
 
 
X   
 
 
X  
 
X  
Me c ha nistic s a m ples  
 
 
 
 
 
 
 
 
X   
 
I g G4-R D RI  
X   
 
 
X   
 
 
X   
X  
P h ysicia n  Glo bal  A ctivit y  V A S  
X   
 
 
X   
 
 
X   
X  
S y m pt o m  Se verit y I n de x  
X   
 
 
X   
 
 
X   
X  
Gluc oc ortic oid  T o xicit y  I n de x  
X   
 
 
X   
 
 
X   
X  
S F -3 6  H e alt h S ur ve y  
X   
 
 
X   
 
 
X   
X  
1 T he Scre e nin g visit  ( Visit  1) a n d t he Tre at me nt We e k 1 ( Visit  2) visit  c o uld  p ote ntially  be o n t he s a me 
da y  
2 I nclu des prior  hist or y  a n d tre at me nt of I g G4 - R D 
3 C o m plete  p h ysic al  e xa minatio ns  will  be  perf or me d  at  Scre e nin g,  o n  D a y  1  (c o uld 
p ote ntially  be  t he  s a me  visit)  a n d  at  E O S.  A b bre viate d,  s y m pt o m 
dire cte d  P E  will  be  perf or me d  at  all  ot her  visits.  I nclu de  heig ht  at 
s cre e nin g  o nly  a n d  w eig ht  at  visits  1,  2,  4,  8,  1 2,  1 6,  2 0,  2 4,  2 8,  a n d 
E O S.  
4 A d vers e e ve nts a n d c o nc o mita nt  me dic atio ns  t o be c olle cte d  b y site pers o n nel  via p h o ne  or e mail.  
5 S u pine  blo o d  press ure a n d he art rate, b o d y  te m perat ure, res pirat or y rate. Vital sig n 
ass ess me nts will  be ma de i m me diately  prior  t o inje ctio n.  
6 Urinalysis  a n d urine  pr otein/cre atinine  ratios,  at s cre e nin g or bas eline  a n d E O S, 
a n d at e a c h st u d y visit  if  re nal in v olve me nt  
7 Pre g na nc y test o nly  f or w o me n of c hild -be arin g  p ote ntial  ( urine)  
7 If t he patie nt  has a d oc u me nte d ne gative  res ult wit hin  6 0  da ys bef ore t he first d os e 
of a bata c e pt, t his ite m ma y be o mitte d  
8 All  patie nts  will  ne e d t o ha ve a s cre e nin g C T c hest, a b d o me n a n d pelvis  wit h  he a d 
a nd/ or or bits  if  t here is he a d a n d ne c k or e xtra oc ular m us cle 
in v olve me nt.  If a b n or mal,  it  will  be re pe ate d at a p pr o xi mately  6 
m o nt hs  or e arlier bas e d o n dis e as e a ctivit y.  
* N ot re q uire d  if c olle cte d  6 m o nt hs  prior  t o s cre e nin g visit  


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 1 9  of 
 
 
 
 
5. 2 St u dy  Ass ess me nts  
 
Scree ning  Visit  
T he  follo wi n g  pr oce d ures  will  be perfor me d:  
1.  
O btain  writte n  infor me d  c o nse nt  after  c o nse nt  prese ntatio n  
2.  
O btain  Me dical  hist or y  
a) I ncludi n g  de mo gra p hics 
b)  I ncludi n g  hist or y  of  I g G 4-R D  
3.  
P hysical  e xa mina t io n  
4.  
Rec or d c o nc o mita nt  me dicatio n  
5.  
Vital  sign s  includ i n g;  B P, P, R,  T,  weight,  a nd  height. 
a. 
Weight  will  be meas ure d  wit h  o uter wear  a nd s hoes  re mo ve d  
b.  
Height  will  be  meas ure d  wit h  s hoes  re mo ve d  (scree nin g  visit  o nly)  
c. 
Blo o d  press ure  a nd  p ulse  rate o btaine d  after  t he s ubject  has bee n 
s upine  ≥ 5 minutes 
6.  
A d verse  E ve nt  mo nit or i n g  (fr o m  ti me  of  st ud y  dr ug  a d ministrati o n)  
7.  
La b orat or y  tests:  
a. 
C B C wit h  cell  differe ntial  a nd platelets  
b.  
C he mistr y  pa nel  
c. 
Urinal ysis  a nd urine  pr otein/creati ni ne  ratio  
d.  
Urine  pre gna nc y  test  ( o nly  for  w o ma n  of  c hild  bearing  a ge)  
e. 
He patitis  B a nd  C tests  ( not  re q uire d  if  c ollecte d  3 0 da ys  prior  t o 
scree ning  visit) 
f. 
Ser u m  I m muno glo b uli n  le vels  (I g M,  I g E,  I g G)  
g.  
Ser u m  I g G 4  s ubclasses  
h.  
C o mple me nt  le vels  
i. 
Fasting  lipid  pr ofile  
j. 
Mec ha nistic  sa mples  will  be c ollecte d  fr o m  s ubject  at wee ks 0, 1, 
4, 1 2 a nd 2 4 st udies)  
8.  
I ma gin g  tests:  C T c hest,  a b d o me n,  pelvis 
9.  
P hysicia n  re p orte d  o utc o mes  
a. 
I g G 4  Res p o nder  I nde x  (I g G 4-R D  RI)  
b.  
P hysicia n  Glo bal  Activit y  V A S  
1 0.  
Patie nt  re p orte d  o utc o mes  
a. 
S y mpt o m  Se verit y  I nde x  
b.  
Gluc oc ortic oid  To xicit y  I nde x  
c. 
S F -3 6 Healt h  S ur ve y  
d.  
Patie nt  Glo ba l  Activit y  V A S 
 
Baseline  Visit :  Visit  2 ( wee k  1)  
 
T he  scree ning  ( visit  1) a nd  baseline  visit  ( visit  2) c o uld  p ote ntiall y  be c o mbine d  a nd c o mplete d 
o n t he  sa me da y  
T he  follo wi n g  pr oce d ures  will  be perfor me d:  
1.  
Verify  eligib i lit y  criteria.  
2.  
Re vie w  ge neral  me dic al  a nd  I g G 4  hist or y 
3.  
Brief  p hysical  e xa mina t io n  
4.  
Rec or d c o nc o mita nt  me dicatio n  
5.  
Vital  signs  includ i n g;  B P, P, R,  T,  weight,  a nd  height.  


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 2 0  of 
 
 
 
a. 
Weight  will  be meas ure d  wit h  o uter wear  a nd s hoes 
re mo ve d 
b.  
Blo o d  press ure  a nd  p ulse  rate o btaine d  after  t he s ubject 
has bee n s upine  ≥ 5 minutes 
6.  
A d verse  E ve nt  mo nit or i n g  
7.  
La b orat or y  tests:  
a. 
C B C wit h  cell  differe ntial  a nd platelets  
b.  
C he mistr y  pa nel  
c. 
Urinal ysis  a nd urine  pr otein/creati ni ne  ratio  
d.  
Urine  pre gna nc y  test  ( o nly  for  w o ma n  of  c hild  bearing 
a ge) 
e. 
Ser u m  I m muno glo b uli n  le vels  (I g M ,  I g E,  I g G) 
f. 
Ser u m  I g G 4  s ubclasses  
g.  
Fasting  lipid  pr ofile  
h.  
Mec ha nistic  sa mples  will  be c ollecte d  fr o m  s ubject  at 
wee ks 0, 1, 4, 1 2 a nd 2 4 st udies) 
8.  
Patie nt -re p orte d  o utc o mes: 
a. 
S y mpt o m  Se verit y  I nde x  
b.  
Gluc oc ortic oid  To xicit y  I nde x  
c. 
S F -3 6 Healt h  S ur ve y  
d.  
Patie nt  Glo b al  Activit y  V A S  
9.  
P hysicia n -re p orte d  o utc o mes 
a. 
Gluc oc ortic oid  To xicit y  I nde x  
b.  
P hysicia n  glo bal  activit y  V A S  
c. 
I g G 4-R D  RI  
1 0.  
St ud y  dr ug  a d minis tra tio n  a nd  teac hin g  
1 1.  
St ud y  me dicatio n  dis pe nse  
 
Visit  3 ( wee k 4)- visit  1 0 ( wee k 3 6)  
 
Patie nts  will  ha ve  visits  at Wee ks 4, 8, 1 2, a nd t he n  e ver y  4 wee ks per t he  sc he d ule  of 
assess me nts  s ho w n  in  Ta ble  1  
1.  Brief  p hysical  e xa m  includ i n g  vital  signs  ( F ull  p hysical  e xa m  at E O S)  
2.  Assess me nt  of signs  a nd s y mpt o ms  of I g G 4 -R D  
3.  C o nc o mita nt  Me dicatio ns  re vie w  
4.  A d verse  E ve nts  Assess me nts  
5.  Asses s me nt  of  signs  a nd  s y mpt o ms  of  I g G 4-R D  activit y  
6.  A batace pt  a d ministratio n  ( baseline,  w 4, w 1 2, w 2 0, w 2 8, w 3 6, w 4 4)  
7.  La b orat or y  tests  (t o be dra w n  before  st ud y  pr o d uct  a d ministr atio n).  See sc he d ule  of 
e ve nts.  
i. Mec ha nistic  sa mples  will  be c ollecte d  fr o m  s ubject at wee ks 0, 1, 4, 1 2 
a nd 2 4 st udies) 
8.  Patie nt -re p orte d  o utc o mes  ( per sc he d ule  of  e ve nts,  ta ble  1) 
9.  P hysicia n  re p orte d  o utc o mes  ( per sc he d ule  of e ve nts,  ta ble  1)  
1 0.  St ud y  me dicatio n  acc o unta bilit y  a nd dis pe nse  
 
Safet y  follo w  up  visit  (if  nee de d)  
D uring  t he  safet y  follo w  up t he follo wi n g  pr oce d ures  will  be c o mplete d  
1.  Vital  signs  a nd  P hysical  e xa m  
2.  C o nc o mita nt  Me dicatio ns  re vie w  


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 2 1  of 
 
 
 
3.  A d verse  E ve nts  Assess me nts  
4.  Assess me nt  of signs  a nd s y mpt o ms  of I g G 4 -R D  
 
5. 3 Disc ussio n  of  St ud y  Design  
 
N o t hera pies  for  I g G 4 -R D  ha ve  bee n a p pr o ve d  b y  re gulat or y  a ut horities  a nd  t hus  t here  are no 
esta blis he d  st ud y  designs  for  t his  disease  indicatio n.  This  st ud y  design  is  c o nsiste nt  wit h  t he 
foc us  of t his  trial  o n pr o of- of-c o nce pt  a nd mec ha nistic  st udies  a nd  will  be s uita ble  t o ac hie ve 
t his  goal  base d o n t he  strict  pri mar y  o utc o me  criteria.  There  is  no c o ntr ol  gr o up  in  t his  pr o of  of 
c o nce pt  st ud y.  T he  design  will  be a ble  t o assess w het her  a batace pt ca n  ha ve  a n effect  o n disease 
res p o nse  as has  bee n s ho w n  in  a prior  case re p ort as disc usse d  a b o ve.  The  design  of  t his  trial  is 
a p pr o priate  t o o ur  c urre nt  understa ndi n g  of t he  p ote ntial  r ole  of a batace pt in  I g G 4 -R D,  w hic h  is 
prese ntly  t o o li mite d  t o j ustif y  a ra nd o mize d  trial.   S ho uld  patie nts  fail  t o res p o nd  t o t he  st ud y 
dr ug  a batace pt  or s ho uld  t he y de velo p  e nd -or ga n  ma nife sta t io ns,  t he y  will  be a ble  t o o btain 
sta ndar d  of  care gluc oc ortic oi d  treat me nt. 
 
A was ho ut  perio d  is b uilt  int o  t he st ud y  pr ot oc ol.  Exclusio n  criteria  include  t he prior  use  of 
rit uxi ma b  ( or  ot her  B cell  de pleting  a ge nts)  wit hi n  6 mo nt hs  of  e nr oll me nt  unless  B  cells  ha ve 
bee n  de mo nstrate d  t o  ha ve  re p o p ulate d  or t he  use  of  a ny  investi ga tio na l  a ge nt  wit hi n  5 half -
lives  of  t he  a ge nt  ( or 6 mo nt hs  if  t he  half-life  is unk no w n)  prior  t o e nr oll me nt.  This  s ho uld  be 
s uffic ie nt  in  ide ntif yi n g  any  a d verse  effects  d ue t o t he  investi gati o nal  pr o d uct  a batace pt. 
H o we ver,  patie nt’s  ma y  ha ve  bee n  o n  gluc oc ortic o ids  d uring  trial  e ntr y,  b ut  must  be willi n g  t o 
ta per off  of gluc oc ortic oid s  wit hi n 4  8 wee ks of be ginni n g  a batace pt. This  is  necessar y  in  or der 
to s uffic ie nt l y recr uit  patie nts  for  t he  st ud y. 
 
T he  investi gati o nal  me dicatio n  a batace pt  is d ose d wee kly  b y s ubc uta ne o us  r o ute  w hic h  is 
c o nsiste nt  wit h  its  p har mac o kinetic  a nd p har mac o d y na mic  pr ofile.  It is  a p pr o ve d for  t he 
treat me nt  of  r he u mat oid  art hritis  at  t his  d osing  inter va l.  These  me dicatio ns  ma y  be c o ntinue d 
indefi nitel y  for c o ntr ol  of t he  disease  a nd a ny  effect  s ho uld  be seen  wit hi n  2 4 wee ks of 
treat me nt. 
 
5. 4 Early  Ter minati o n  of  t he  St ud y  
 
If  t he I nvesti gat or  or t he  S p o ns or bec o mes  a ware of  c o nditio ns  or  e ve nts  t hat  s uggest  a p ossible 
hazar d  t o s ubjects  if  t he  clinical  st ud y  c o ntinues,  t he n  t he clinical  st ud y  ma y  be ter minate d  after 
a p pr o priate  c o ns ultatio n  a mo ng  t he invol ve d  parties.  The  clinic al  st ud y  ma y  be ter minate d  at 
t he  S p o ns or’s  discretion  als o  in  t he  a bse nce  of  s uc h  a findi n g.  
C o nditio ns  t hat  ma y  warra nt  ter minati o n  of  t he  clinica l  st ud y  include,  b ut  are not  li mite d  t o:  
• 
T he  disc o ver y  of a n  une xpecte d,  rele va nt,  or unacce pta ble  ris k  t o t he 
s ubjects  e nr olle d  in  t he  clinica l  st ud y; 
• 
Failure  t o e nr oll  s ubjects  at t he  re q uire d  rate;  
• 
A decisio n  of t he  S p o ns or t o s us pe nd  or disc o ntin ue  de velo p me nt  of t he 
I M P. 
 
S ho uld  t he  st ud y  be ter minate d, a nd/ or  t he  site  close d  for w hate ver  reas o n,  all  d oc u me ntatio n 
pertaini n g  t o t he  st ud y  a nd  I M P must  be ret ur ne d  t o t he  S p o ns or. A ny  actio ns  re q uire d  for 
assessing  or maintai ni n g  st ud y  s ubject  safet y  will  c o ntinue  as re q uire d,  des pite  ter minatio n  of 
t he  st ud y  b y  t he  S p o ns or. 
 
E nd - of-St ud y  is  define d  as c o mpletio n  of  t he  End - of-St ud y  Visit  o n Wee k 3 6.  
 
 


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 2 2  of 
 
 
 
 
5. 5 Selec tio n  of St ud y  P o p ulatio n 
 
Male  a nd fe male  s ubjects  w ho  meet  t he A C R/ E U L A R  2 0 1 8 Classificatio n  Criteria  for  I g G 4 - 
R D A N D active  disease  ( define d  b y I g G 4 -R D  RI ≥2 at scree ning  wit h  disease  ma nifestati o n  in 
at  least  o ne  or ga n  s yste m  e xcludi n g  ly mp h  no des  at  s cree ning).  S ubjects  are not  re q uire d  t o 
ha ve  faile d  prior  t hera p y  for t heir  disease  t o be eligible  for t his  st ud y.  
 
I nclus io n  C riteria 
S ubjects  w ho  meet  t he follo wi n g  criteria  will  be c o nsidere d  eligible  t o participate  in  t he clinical 
st ud y  if  t he y: 
2.  
Are  ma le  or fe male  1 8 years  of a ge or older 
3.  
Meet t he A C R/ E U L A R  2 0 1 8 Classificatio n  Criteria  for  I g G 4 -R D  (see 
a p pe ndix) 
4.  
Ha ve  active  disease  base d o n a n I g G 4 -R D  RI ≥2 at scree ning  wit h  disease 
ma nife sta tio n  in  at least  o ne  or ga n  s yste m  e xcludi n g  ly mp h  no des  at 
scree ning 
5.  
Ma y or ma y  not  ha ve  receive d  prior  I g G 4 -R D  t hera p y  
6.  
M ust  be willi n g  t o ta per off  a ny  s yste mic  c ortic oster oid  t hera p y  wit hi n 
4   8 
wee ks of first  d ose of  trial  dr ug.  
7.  
M ust  be a ble  a nd willi n g  t o disc o ntin ue  a ny  i m mu nos up pr essi ve  a ge nt  at 
scree ning  (e. g.  met hotre xate,  myc o p he nolate  mofetil,  6-merca pt o p uri ne, 
tacr oli m us,  c yclo p hos p ha mid e  or azat hio pri ne). 
8.  
N o hist or y  of se vere  aller gic  reactio ns  t o mo noclo nal  a ntib o dies.  
9.  
Are a ble  a nd willi n g  t o c o mplete  t he  e ntire  st ud y  acc or ding  t o t he st ud y 
sc he d ule. 
1 0.  
Are wil li n g  t o  fore go  ot her  for ms  of  e xperi me nta l  treat me nt  d uring  t he  st ud y. 
1 1.  
Are a ble  t o pr o vide  writte n  infor me d  c o nse nt.  
 
E xclus io n  C riteria  
S ubjects  w ho  meet  o ne or more  of  t he follo wi n g  criteria  will  not be c o nsidere d  eligible  t o 
participate  in  t he  clinical st ud y: 
1.  Hist or y  or e vide nce  of a clinicall y  unsta ble/ u nc o ntr olle d  dis or der,  c o nditio n  or diseas e 
(includi n g  b ut  not  li mite d  t o  car dio p ul mo nar y,  o nc olo gic,  re nal,  he patic,  meta b olic, 
he mat olo gic  or  ps yc hiatric)  ot her  t ha n  I g G 4 -R D  t hat,  in  t he  o pinio n  of  t he  
I nvesti gat or,  w o uld  p ose a ris k  t o patie nt  safet y  or interfere  wit h  t he st ud y  e valuati o n, 
pr oce d ures  or c o mpletio n.  
2.  Maligna nc y  wit hin  5 years (e xce pt s uccessfull y  treate d in sit u  cer vical  ca ncer, resecte d 
s q ua mo us cell  or basal cell carcino ma  of t he s kin,  or pr ostate  ca ncer wit h  no  rec urre nc e 
≥3 years  follo wi n g pr ostatect o my).  
3.  Liver  disease:  Ac ute  or c hr o nic  no n -I g G 4-relate d  liver  disease  dee me d s ufficie ntl y 
se vere  t o i mpair  t heir  a bilit y  t o  participate  in  t he trial. 
4.  U nc o ntr olle d  disease:  e vide nce  of a not he r  unc o ntr o lle d  c o nditio n,  includ i n g  dr ug 
a nd alc o hol a b use,  w hic h  c o uld interfere wit h  participatio n in t he trial acc or ding t o t he 
pr ot oc ol. 
5.  Prese nce  of rec urre nt  or c hr o nic  infectio ns,  define d  as ≥3 infectio ns  re q uirin g 
a nti micr o bials  o ver t he  past 6 mo nths  prior  t o  scree nin g. 


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 2 3  of 
 
 
 
6.  Active  infectio n  re q uirin g  hos pitalizatio n  or treat me nt  wit h  pare nteral  a nti micr o bials 
wit hi n  t he 3 0 da ys  prior  t o  ra nd o miza t io n. 
7.  Prior  use  of  rit uxi ma b  ( or  ot her  B  cell  de pletin g  a ge nts)  wit hi n  6 mo nt hs  of 
e nr oll me nt  unless  B  cells ha ve  bee n de mo nstrate d  t o ha ve  re p o p ulate d. 
8.  Use  of  a ny  investi ga tio na l  a ge nt  wit hi n  5 half -li ve s  of  t he  a ge nt  ( or  6 mo nt hs  if  t he 
half- life  is  unk no w n)  prior  t o e nr oll me nt.  
9.  W hite  blo o d  cell  c o unt  < 2. 5 x 1 0 3 / µ L. 
1 0.  A bs olute  ne utr o p hil  c o unt  ( A N C) < 1. 0 x 1 0 3 / µ L. 
1 1.  I g G 4-relate d  re nal  disease  wit h  ser u m  creatini ne  > 2. 0 mg/ d L.  
1 2.  He mo glo bi n  < 1 0 g/ d L.  
1 3.  Platelet  c o unt  < 7 5 x  1 09 / L. 
1 4.  K no w n  p ositive  res ult  for  HI V  I or II  a ntib o d y,  he patitis  B  s urface  a ntige n,  he patitis 
B c ore a ntib o d y  or he patitis  C  a ntib o d y. 
1 5.  Has receive d  live  vaccines  wit hi n  4 wee ks o k  e nr oll me nt.  
1 6.  I na bilit y  t o  c o m munica te  relia bl y  wit h  t he investi ga t or. 
1 7.  Patie nt  is  pre gna nt  or breast  fee ding,  or pla nni n g  t o bec o me pre gna nt  w hile  e nr olle d 
in  t he  st ud y,  up  t o E O S visit.  
1 8.  P ositive  pre gna nc y  test at scree ning or  d uring  t he  st ud y. 
1 9.  S ubjects  of  c hild beari n g  p ote ntial  w ho d o not  a gree t o use me dicall y  acce pta ble 
met ho ds  of  c o ntrace ptio n.  
2 0.  K no w n  or s us pecte d se nsiti vit y t o ma m ma lia n  cell-derive d   pr o d ucts  or a ny 
c o mp o ne nts  of  t he st ud y dr ug.  
2 1.  Hist or y  of alc o hol  a nd/ or s ubsta nce  a b use  wit hi n  1 2 mo nt hs  prior  t o scree ning. 
2 2.  U na ble  or un willi n g  t o parta ke in  follo w -up  assess me nts  or re q uire d  pr ot oc ol 
pr oce d ures.  
5. 6 Wit hdra wal  of S ubjects 
S ubjects  are e nc o ura ge d  t o c o mplete  all  st ud y  e valuatio ns.  H o we ver,  t he y  ma y  wit hdra w  fr o m 
t he  st ud y  at  a ny  ti me  a nd  for  a ny  reas o n.  Ever y  effort  will  be ma de  t o  deter mine  w hy  a n y 
s ubject wit hdra ws  fr o m t he st ud y pre mat urel y.  All  s ubjects w ho  wit hdra w  fr o m t he st ud y wit h 
a n o ngoin g  A E must  be follo we d  until  t he  e ve nt  is  res olve d  or dee me d  st a ble.  At t he  ti me  t hat 
a  s ubject  wit hdra ws  pre mat urel y  for  a ny  reas o n,  all  assess me nts  as  liste d  for  t he  E O S  visit 
s ho uld  be perfor me d.  If  a s ubject  wit hdra ws  pre mat urel y  after  d osing,  all  data t o be c ollect e d 
prior  t o  disc har ge  fr o m  t he  clinica l  site  will  be  c ollecte d  at  t he  ti me  of  pre mat ur e 
disc o nti n uati o n   or at t he sc he d ule d e nd- of-st ud y visit.  S ubject  participat io n ma y   be ter mina t e d  
prior  t o c o mpleti n g  t he st ud y  a nd t he  reas o n rec or de d as  follo ws : 
1.  A d verse  e ve nt 
2.  Pr ot oc ol violat io n 


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 2 4  of 
 
 
 
3.  L oss t o  F ollo w -up  
4.  S ubj ect  wit hdre w c o nse nt 
5.  I nvesti gat or  wit hdre w  s ubject  t o give  resc ue  t hera p y  ot her  t ha n ster oids 
6.  Ot her  
A c o mpre he nsi ve  effort  must  be ma de  t o deter mine  t he  reas o n(s)  w hy  a s ubject  fails  t o ret ur n 
for  t he  necessar y  visits  or  is  disc o ntin ue d  fr o m  t he  st ud y.  If t he  s ubject  is  unreac ha ble  b y 
tele p ho ne,  a re gistere d  letter,  at mini m u m,  s ho uld  be se nt  t o t he  s ubject  re q uesting  hi m/ her  t o 
c o ntact  t he  st ud y  site.  
S ubjects  wit hdra w n  d ue  t o  A Es  c o nsidere d  t o  ha ve  a p ossible  relatio ns hi p  t o st ud y  dr ug  will 
not  be re place d.  S ubjects  wit hdra w n  for  a no n -dr ug  relate d  reas o n  will  be re place d  if  dee me d 
necessar y  b y  t he  S p o ns or.  T he  decisio n  re gar ding  t he  re place me nt  of  s ubjects  will  be 
d oc u me nte d.  
If  a  s ubject  wit hdra ws  pre mat urel y,  all  assess me nts  as  liste d  for  t he  E O S  visit s ho uld  be 
perfor me d  a nd rec or de d o n a n unsc he d ule d  visit  e C R F  pa ge.  I n a d ditio n, t he s ubject s ho uld be 
sc he d ule d  for  a  follo w-up  visit  4  wee ks  fr o m  t he  ti me  of  t he  last  injectio n  of  st ud y  dr ug,  at 
w hic h  ti me  all  assess me nts  as liste d  for  t he  E O S visit  s ho u ld  be perfor me d. 
5. 7 Ot he r  S u bje ct  R e s tricti o ns  
S ubjects  must  ha ve  signe d  a nd  date d a n  I R B/I E C -a p pr o ve d  writte n  infor me d  c o nse nt  for m  i n 
acc or da nce  wit h  re gulat or y a nd instit uti o na l guideli nes   before t he perfor ma nce   of a ny pr ot oc ol-  
relate d  pr oce d ures.  Pris o ners  or s ubjects  w ho  are c o mp uls or y  detaine d  will  not  be eligible  t o 
participate.  
5. 8 St o p pi ng  Crite ri a  f or  t he  Cli nic al  St u dy  
Participatio n  for  a ny  indivi d ual  s ubject  will  be  st o p pe d  if  t he  s ubject  e xperie nces  a  p ossibl y 
dr ug-relate d  S A E  or a p ossibly  dr ug-relate d  significa nt  no n-serio us  A E,  w hic h  in  t he  o pini o n 
of  t he  PI or  S p o ns or’s  me dical  re prese ntati ve,  warra nts  disc o nti n uati o n  of  t he  s ubject  in  t he 
st ud y  in  t he  interest  of t hat  s ubject’s  well-bei n g.  Disc o nti n uatio n  of  t he s ubject  fr o m  t he st ud y 
wil l  be disc usse d  wit h  t he S p o ns or. 
T he  I nvestigat or  will  ma ke  all  a p pr o priate  safet y  assess me nts  o n  a n  o ngoing  basis.  The 
S p o ns or’s  me dical  re prese ntati ve  will  re vie w  individ ua l  safet y  infor ma t io n  as  it  bec o me s  
a vaila b le  t hr o ugho ut  t he  st ud y.  
A n  I D M C  will  be  use d  t o e valuate  interi m  safet y  a nd  efficac y  res ults  a nd  t o deter mine  if  t he 
trial  s ho uld  be st o p pe d early.  All  unbli nde d  a nalyses  for  I D M C re vie w  will  be pre pare d b y  a n 
inde pe nde nt  Data  C o or dinatin g  C e nter  (I D C C). Me mbers  of t he  I D M C will  be e xter nal  t o t he  
S p o ns or’s  st ud y  tea m  a nd  will  follo w  a  c harter  t hat  o utli nes  t heir  r oles  a nd  res p o nsibilitie s. 
Prior  t o  t he  pla nne d  interi m  a nalyses  of  t he  pri mar y  e nd p oint,  t he  I D M C  will  meet 
a p pr o xi matel y  t wice  a nnuall y  t o re vie w  safet y.  


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 2 5  of 
 
 
 
 
6. T R E A T M E N T  O F  S U B J E C T S    
6 . 1 I de ntit y  of St u dy  Tre at me nt(s) 
O R E N CI A (a batace pt)  is  a s oluble  fusio n  pr otein  t hat  c o nsists  of  t he e xtracell ular  d o main  of  
hu ma n  c yt ot o xic  T -ly mp hoc yte-ass ociate d  a ntige n  4  ( C T L A-4)  linke d  t o  t he  mo difie d  Fc 
( hinge,  C H 2, a nd  C H 3 d o mains)  p ortio n  of  huma n  i m mu no glo b uli n  G 1  (I g G 1).  A batace pt  is 
pr o d uce d  b y  rec o mbina nt  D N A  tec hnolo g y  in  a  ma m malia n  cell  e xpressio n  s yste m.  The 
a p pare nt  molec ular  weight  of a batace pt is  9 2 kilo dalt o ns.  
 
O R E N C I A  s olutio n  for  s ubc uta ne o us  a d minis tra t io n  is  s up plie d  as a steril e,  preser vative -free, 
clear,  c olorless  t o  pale -yello w  s olutio n  wit h  a  p H  of  6. 8  t o  7. 4.  Eac h  single  d ose  of 
s ubc uta ne o us injectio n  pr o vides  1 2 5 mg  a batace pt,  dibasic   s o diu m  p hos p hate a nhydr o us  ( 0. 8 3 8 
mg),  mo no basic  s o diu m  p hos p hate  mo no hydrat e  ( 0. 2 8 6 mg), p olo xa mer  1 8 8 ( 8 mg),  s ucr os e 
( 1 7 0  mg),  a nd  q ua ntit y  s uffic ie nt  t o  1  m L  wit h  water  for  injectio n.  U nlike  t he  intra ve n o us  
for mulati o n,  O R E N CI A  s olutio n  for  s ubc uta ne o us  a d ministrati o n  c o ntains  no malt ose.  
A ctive  s u bsta nc e:  a bata c e pt 
Teste d  in dic atio n:  I g G4 - R D 
Stre n gt h:  1 2 5. 0  m g/s yrin ge  
D os a ge f or m:  prefille d  glass s yrin ge 
R o ute of a d ministratio n:  S C inje ctio n  
T he d osin g  a n d s c he d ule are s u p p orte d b y  P has e I or later res e arc h.  
 
6. 2  A d mi nistrati o n  of St u dy  Tre at me nt(s)  
All  s u bjects  will  receive  a batace pt.  
6. 3 Tre at me nt   Prot oc ol 
•A batace pt ( Ore ncia):  O ne  1 2 5 mg/ m L  single -d ose  prefille d  glass  s yringe  will  be a d minis t e r e d  
b y  s ubc uta ne o us  ( S C)  injectio n  wee kly  b y  t he  pati e nts  or care givers.  Patie nts  a nd  care gi vers 
will  be traine d  o n  ho w  t o a d minis ter  t he  me dicatio n  b y  t he  st ud y  investi gat o rs  or a  designa t e d  
st ud y  staff  me mber  d uring  baseline  a nd  wee k 1 visits.  A batace pt  interr upti o ns  or wit hdra w a ls 
will  be as per t he c urre nt  U. S. pr o d uct  insert  ( See Attac he d  Pac ka ge I nsert).  
•Pre d nis o ne  ta per :  S ubjects  w ho  are  o n  pre d nis o ne  at  baseline  will  be gin  a n  investi gat o r-
directe d  c ortic oster oid  ta per designe d  t o disc o ntin ue  pre d nis o ne  not later  t ha n  8 wee ks after  t he 
baseline  visit.    
6. 4 St u dy  Tre at me nt  P ac k a gi ng  a n d  L a belli ng  
O R E N CI A (a batace pt)  injectio n  s olutio n  for  s ubc uta ne o us  a d ministrati o n  is s up plie d  eit her  as 
a single-d ose  dis p osa ble  prefille d  glass  s yringe  wit h  Ultra Safe  Passive  nee dle guar d  wit h  fla n ge 
e xte nders  or as a single-d ose  dis p osa ble  prefille d  glass  s yrin ge  wit h  fla nge  e xte nder.  The  Type 
I glass  s yringe  has  a  c oate d  st o p per  a nd  fixe d  stainless-steel  nee dle  ( 5  be vel,  2 9- ga uge  t hi n 
wall,  ½ -inc h  nee dle)  c o vere d wit h  a rigid  nee dle  s hield.  The  prefille d  s yrin ge  pr o vides  1 2 5 m g 


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 2 6  of 
 
 
 
of a batace pt  in  1 m L  a nd  is pr o vide d  in  t he follo wi n g  pac ka ges:  
• 
N D C 0 0 0 3- 2 1 8 8- 1 1: pac k of  4 s yringes  wit h  a passive  nee dle  safet y  guar d  
• 
N D C 0 0 0 3- 2 1 8 8- 3 1: pac k of  4 s yringes  wit ho ut  a passive  nee dle  safet y  guar d  
6. 5 St ora ge 
O R E N CI A  s olutio n  s up p lie d  in  a prefille d  s yringe  s ho uld  be refrigerate d  at 2 C t o 8 C ( 3 6 F t o 
4 6 F). T he  me dicatio ns  s ho uld  not  be use d be yo nd  t he  e xpiratio n  date o n t he  prefille d  s yringe.  
It s ho uld  be pr otecte d fr o m  light  b y st oring  in  t he origi nal  pac ka ge until  ti me  of use. The prefille d 
s yringe  s ho uld  not be allo we d  t o freeze. 
 
T he  I nvestigat or /I ns tit uti o n  is  res p o nsible  for  t he  follo wi n g.  
o  I nvesti gati o nal  pr o d uct  is  t o be st ore d  in  a sec ure  area acc or ding  t o local  re gulat i o ns 
a nd  st ore d  under  t he  a p pr o priate  e nvir o n me ntal  c o nd itio ns  (te mperat ure,  light,  a nd  
hu midit y).  If  mar kete d  pr o d uct  is  use d,  it  s ho uld  be  st ore d  in  acc or da nce  wit h  t he 
pac ka ge  insert, S u m mar y   of Pr o d uct C haracteristics  ( S m P C), U nite d  States  prescri bi n g 
infor mat i o n  ( U S PI),  or si mila r guida nce.  
o  T he  investi ga t io nal  pr o d uct  will  be  dis pe nse d  o nly  t o  st ud y  s ubjects  a nd  o nly  fr o m 
official  st ud y  sites  b y a ut horize d  pers o nnel,  as dictate d  b y local  re gulatio ns 
o  C urre nt  dis p ositio n  rec or d  of  I P (s up plie d  b y B M S)  is  t o be maintai ne d  at eac h  st u d y 
site  w here  st ud y  dr ug  is  inve nt or ie d  a nd dis pe nse d  
o  Pr oce d ures  for  pr o per  dis p osal  ha ve  bee n  esta blis he d  acc or ding  t o  a p plica ble 
re gulatio ns,  guideli nes,  a nd  instit utio na l pr oce d ures  
6. 6 S u bje ct  C o m pli a nce  
D osing  will  be perfor me d  b y traine d,  q ualifie d  pers o nnel  designate d  b y  t he  PI.  The  date  a nd 
ti me  of d osing will   be d oc u me nte d   o n eac h d osing da y.  C o m me nts  will   be rec or de d if t here are 
a ny  de viatio ns  fr o m  t he  pla nne d  d osing pr oce d ures.  
6. 7 St u dy  Tre at me nt  Acc o u nt a bilit y,  H a n dli ng,  a n d  Dis pos al  
T he  I nvesti gat or  or designee  is  res p o nsible  for  maintai ni n g  acc urate  acc o unta bilit y  rec or ds of 
t he  I M Ps t hr o ugho ut  t he  clinica l  st ud y.  The  dr ug  acc o unta bilit y  lo g  includes  infor  mati o n  s uc h 
as a mo unt  dis pe nse d  a nd  a mo unt  ret ur ne d  t o t he  p har mac y  (if  a ny).  
All  dis pe nsi n g  a nd  acc o unta bilit y  re c or ds  will  be a vaila ble  for  S p o ns or  re vie w  after  data base 
loc k. T he  site p har macist  ( or designee  under  t he directio n  of t he p har macist)  will  dis pe nse  I M P 
for  eac h s ubject  acc or ding  t o t he pr ot oc ol  a nd p har mac y  ma nual,  if a p plica ble.  
After  receivi n g  S p o ns or  a p pr o val  in  writin g,  t he  site  is  res p o nsible  for  eit her  ret ur ni n g  all 
unuse d  or partiall y  use d I M P t o t he  S p o ns or  or designate d  t hir d  part y  or for  t he  destr uctio n  of 
t he  I M P acc or ding  t o locally  c o mplia nt  pr oce d ures. 
6. 8 C o nc o mit a nt  T he ra py  
Pre vio us/ C o nc o mita nt  Me dicatio n  
C o nc urre nt  a d ministr atio n  of  a T N F a nta go nist  wit h  a batace pt  has bee n ass ociate d  wit h  a n 
increase d  ris k  of  serio us  infectio ns  a nd no signific a nt  a d ditio nal  efficac y  o ver use of  t he T N F 


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 2 7  of 
 
 
 
a nta go nists  alo ne.  C o nc urre nt  t hera p y  wit h  a batace pt a nd  T N F a nta go nis ts  is  not 
rec o m me nde d.  
 
Dis all o we d  pre vi o us or  c o nc o mit a nt  me dic ati o ns:  
• Prior  use of  rit uxi ma b  ( or ot her B cell  de pletin g  a ge nts)  wit hi n  6 mo nt hs  of e nr oll me nt 
unless  B cells  ha ve  bee n de mo nstrate d  t o ha ve   re p o p ulate d. 
• Use  of  a ny  investi g a tio na l  a ge nt  wit hi n  5 half-li ve s  of  t he  a ge nt  ( or  6 mo nt hs  if  t he  half- 
life  is  unk no w n)  prior  t o e nr oll me nt 
• Receive d  live  vaccines  wit hi n  4 wee ks of  e nr oll me nt.  
 
Fro m  A bat ace pt  P ac k a ge I ns e rt (s e cti o n 5. 1): C o nc o mit a nt  Us e wit h  T N F A nt a g o nists  
•  I n  c o ntr olle d  clinica l  trials  in  patie nts  wit h  a d ult  R A,  patie nts  receivi n g  c o nc o mita nt 
O R E N CI A a nd T N F a nta go nist  t hera p y  e xperie nce d  more  infectio ns  ( 6 3 %) a nd serio us 
infectio ns  ( 4. 4 %) c o mpare d  t o patie nts  treate d  wit h  o nly  T N F a nta go nists  ( 4 3 % a nd 
0. 8 %, res pectivel y)  [see A d verse  Reactio ns  ( 6. 1) fr o m  pac ka ge insert].  These  trials 
faile d  t o de mo nstrate  a n i mp orta nt  e nha nce me nt  of efficac y  wit h  c o nc o mita nt 
a d ministr atio n  of  O R E N CI A  wit h  T N F  a nta go nist;  t herefore,  c o nc urre nt  t hera p y  wit h 
O R E N CI A  a nd  a T N F  a nta go nist  is  not  rec o m me nde d.  W hile  tra nsit io ni n g  fr o m  T N F 
a nta go nist  t hera p y  t o O R E N CI A t hera p y,  patie nts  s ho uld  be mo nit ore d  for signs  of 
infect io n. 
o  E nbrel  (eta nerce pt)  
o  Kineret  (a na kinra)  
o  C i mzia  (cert oliz u ma b  pe gol)  
o  H u mira  (a dali m u ma b )  
o  Rit uxa n  (rit uxi ma b )  
o  Acte m ra  (t ociliz u ma b) 
o  Re mica de  (infli xi ma b)  
o  Si mp o n  ( goli m u ma b)  
•  
D e ta ils  of  a ll prior  a n d c o nc o mita nt me dic atio n  m ust  be  re c or de d at st u d y e ntr y (i. e., at t he first 
visit)  inclu din g  prior  tre at me nt f or I g G4 -R D, prior I g G4 -R D c linic a l  tria l  pa rtic ipa tio n  a n d prio r 
m o n oclo nal  a ntib o d y  us e. All  t hera pies ( pres criptio n  or o ver -t he-c o u nter me dic atio ns,  inclu di n g 
vita mins  a n d her bal s u p ple me nts) differe nt fr o m t he st u d y dr u g m ust be re c or de d. A n y me dicin a l 
pr o d uct,  pres cribe d or O T C,  inclu din g  her bal  a n d ot her  n o n -tra ditio nal  re me dies,  is  c o nsidere d 
a  c o nc o mita nt  me dic atio n.  A n y  c ha n ges  in  c o nc o mita nt  me dic atio n  m ust  be re c or de d  at e a c h 
visit. If t he c ha n ge influe nc es  t he s u bje ct’s eligibilit y  t o c o ntin ue  in  t he st u d y,  t he S p o ns or  m ust 
be  inf or me d.  C o nc o mita nt  me dic atio n  us e ma y  be  w arra nte d f or  t he  tre at me nt of  A Es.  I n t he 
interest of  s u bje ct s afet y a n d a c c e pta ble  sta n dar ds of  me dic al  c are  t he  I n vestigat or  will  be 
per mitte d  t o pres cribe tre at me nt(s) at his/ her dis cretio n.  All  tre at me nts m ust be  re c or de d in t he 
s u bje cts’ c as e  re p ort f or m ( C R F); me dic atio n,  d os e,  tre at me nt d uratio n  a n d  in dic atio n. 
•  
T he  inf or matio n c olle cte d f or e a c h c o nc o mita nt me dic atio n  inclu des, at a mini m u m,  start date, 
e n d date or o n g oin g,  d os e a n d u nit,  fre q ue nc y, r o ute of a d ministratio n  a n d  in dic a tion.  


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 2 8  of 
 
 
 
6. 9  C o ntr ac e pti o n  
•  
W o me n  of  c hild be arin g  p ote ntial  m ust  ha ve a ne gative  pre g na nc y  test d urin g  s cre e nin g  a n d  at 
bas eline  ( D a y 1)  a n d  m ust  us e 1 hig hly  effe ctive met h o d  of birt h  c o ntr ol  d urin g  t he  st u d y  a n d 
f or  3  m o nt hs  f ollo win g  t he  last  d os e  of  a bata c e pt. Hig hly  effe ctive  met h o ds  of  birt h  c o ntr ol 
inclu de  h or m o nal  birt h  c o ntr ol,  intra uterine  de vic es (I U Ds),  or  a n y  barrier  met h o ds  (s p o n ges, 
fe male c o n d o ms) us e d b y t he w o ma n in  a d ditio n  t o c o ntra c e ptio n us e d b y t heir male part ner s uc h 
as a vas e ct o m y or a c o nd o m  s u p ple me nte d  wit h s per micide.  
•  
W o me n of n o n -c hild be arin g  p ote ntial  m ust ha ve a d oc u me nte d re as o n (i. e., p ost me n o pa us al  b y 
hist or y  wit h  n o  me ns es f or  o ne ye ar a n d c o nfir me d  b y  F S H [ usin g  loc al  refere nc e ra n ges], O R 
hist or y  of  h ystere ct o m y,  O R  hist or y  of bilateral  t u bal  ligatio n,  O R  hist or y  of  bilatera l 
o o p h ore ct o m y).  
•  
Male s u bje cts of c hild be arin g  p ote ntial  m ust  be willin g  t o pra ctic e a hig hly  effe ctive met h o d  of 
birt h  c o ntr ol  f or  t he  d uratio n  of  t he  st u d y  a n d  c o ntin uin g  f or  3  m o nt hs  after t he  last  d os e  of  
a bata c e pt.  Hig hly  effe ctive  met h o ds  of  birt h  c o ntr ol  inclu de  a  vas e ct o m y  or  a  c o n d o m  in 
c o m binatio n  wit h  barrier met h o ds,  h or m o nal  birt h  c o ntr ol  or I U D us e d b y  t he w o ma n.  
 
6. 1 0 Tre at me nt  C o m pli a nce   
 
Patie nts  will  be as ke d t o maintai n  diaries  t o rec or d me dicatio n  ta ke n at ho me.  These  diaries 
will  be re vie we d  b y t he c o or dinat ors  at eac h visit  t o assess c o mplia nce.  
 
7.  A S S E S S M E N T O F E F FI C A C Y  
7. 1  Effic ac y  Vari a ble s  
Efficac y  will  be  meas ure d  b y  t he  a bilit y  of  a batace pt  t o  s ustain  t he  disease  i mpr o ve me nt. 
Disease  activit y  will  be  follo we d  using  t he  follo wi n g  assess me nts  t o  be  rec or de d  b y  st ud y 
investi gat o rs : 
• 
I g G 4-R D  RI will  be t he  pri mar y  efficac y  varia ble  
• 
T he  follo w i n g  assess me nts  will  als o  be  o btaine d: 
• 
P hysicia n  Glo bal  Assess me nt  of  Disease  Activit y  ( Vis ual  Acti vit y Sc ore)  
• 
S ubject’s  Glo bal  Disease  Activit y  V A S  
• 
S y mpt o m  Se verit y  I nde x 
• 
Gluc oc ortic o id  T o xicit y  I nde x 
• 
S F -3 6 Healt h S ur ve y  
7. 2  Effic ac y As s ess me nts  
T he  follo wi n g  efficac y  assess me nts  will  be perfor me d  acc or ding  t o t he  ti me  p oints  define d  in 
t he  Sc he d ule  of Assess me nts  ( Ta ble  1).  
• I g G 4-R D R e s po n de r  I n de x 
Disease  activit y will   be meas ure d  per  sc he d ule  of assess me nts.   F or deter minati o n   of t he I g G 4-  
R D  res p o nder inde x as describe d  in t he sc he d ules  of assess me nts (I g G 4-R D  RI),  t he follo wi n g 
criteria  will  be  use d ( mo difie d  after  C arr ut hers  et al.  2 0 1 2):  Or ga n  site,  s y mpt o matic,  ur ge nt 
disease  (as per I g G 4 -R D  RI)  o ver  t he  pre vio us  2 8  da ys.  
T he  origina l  I g G 4 -R D  RI  has  bee n  mo difie d  t o includ e  t he  full  s pectr u m  of  or ga ns  affect e d 


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 2 9  of 
 
 
 
most  fre q ue ntl y  b y  I g G 4 -R D  a nd  t o  eli m i nat e  ser u m  I g G 4  c o nce ntratio ns  as  part  of  t he 
instr u me nt.  I n  a d ditio n,  a n  assess me nt  of  da ma ge  ca use d  b y I g G 4-R D  in  eac h  affecte d  or ga n 
is  include d.  A sa mple  assess me nt  for m  is  include d  in A p pe ndix.  
• P hysici a n  Gl o bal  Dis e as e Acti vit y  V A S  
T he  p hysicia n’s   o verall assess me nt  of t he s ubject’s c urre nt disease  activit y will   be rec or de d o n 
a 1 0 0 m m  linear  horizo nt al  V A S,  w here  t he  left  ha nd  e xtre me  of  t he  line  is  c o nsidere d  “ Ver y 
G o o d”  (s y mpt o m  free  a nd  no  I g G 4 -R D  s y mpt o ms)  a nd  t he  right -ha nd  e xtre me  is  c o nsider e d  
“ Ver y  Ba d”  ( ma xi m u m  I g G 4 -R D  activit y).  
Details  o n t he  efficac y  assess me nts  ca n be fo und  in A p pe ndix.  
• S u bje ct’s  Gl o bal  Dis e as e Acti vit y  V A S  
T he  s ubject’s  o verall  assess me nt  of t he  s ubject’s  c urre nt  disease  activit y  will  be rec or de d o n a 
1 0 0  m m  linear  horiz o ntal  V A S,  w here  t he  left  ha nd  e xtre me  of  t he  line  is  c o nsidere d  “ Ver y 
G o o d”  (s y mpt o m  free  a nd  no  I g G 4 -R D  s y mpt o ms)  a nd  t he  right  ha nd  e xtre me  is  c o nsider e d  
“ Ver y  Ba d”  ( ma xi m u m  I g G 4 -R D  activit y).  
• S y m pt o m  Se ve rit y  I n de x 
T he  S y mpt o m  Se verit y  I nde x  is  a  no vel  instr u me nt  for  assessing  patie nt-re p orte d  diseas e 
se verit y. It has  not  yet  bee n  validate d  in  a  lo ngit ud i na l  st ud y  of  patie nts  wit h  I g G 4 -R D  b ut  is  
base d  o n  si milar  instr u me nts  use d  in  ot her  c o nditio ns  like  dia betes  mellit us,  hyperte ns io n,  a nd 
be nign  pr osta te  hypertr o p h y.  T he  instr u me nt  q ueries  patie nts  o n  s y mpt o ms  t hat  ca n  be 
ass ociate d  wit h  differe nt  ma nifestatio ns  of  I g G 4 -R D.  F or  eac h  or ga n,  t he  patie nt  sc ores  t he 
se verit y  of his/ her  s y mpt o ms a nd a t otal sc ore is t he n derive d.  I n a d ditio n t o helpin g assess t he  
efficac y  of treat me nt, data  c ollecte d  t hr o ugh t he use  of t his instr u me nt in t his trial will   be use d  
t o assess  t he  valid it y  of  t he instr u me nt. 
• Gl uc oc ortic oi d  T o xicit y  I n de x 
T he  gluc oc ortic oi d  t o xicit y  inde x  is  a  c o mpre he nsi ve  assess me nt  of  t he  c ha nge 
i n 
gluc oc ortic oid  t o xicit y  o ver  ti mes.  It  fact ors  in  a  nu mber  of  varia bles  includi n g  b o d y  mass 
inde x,  gluc ose  t olera nce,  blo o d press ure,  lipids,  b o ne  de nsit y,  ster oid  myo pat hy,  s kin  t o xicit y, 
ne ur o ps yc hiatric  t o xicit y,  infectio n,  a nd  e nd ocrine  (a dre nal  ins uffic ie nc y),  gastr ointes ti na l,  
musc ulos k e le ta l,  a nd  oc ular  t o xicit ies.  
• 3 6- Ite m S hort  F or m  He alt h S urve y  
T he  S F - 3 6 is  a set of  ge neric,  c o here nt,  a nd  easily  a d minister e d  q ualit y- of-life  meas ures.  It has  
bee n use d in  ma ny  diseases  t o assess t he  s ubject’s  per s pective  of  t he effect  t hat  t he disease  pla ys 
in  t heir  activit ies  of  daily  life. T hese  meas ures  rely  up o n  patie nt  self -re p orti n g  a nd are no w wi d el y 
utilize d


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 3 0  of 
 
 
 
 
 
7. 3 P O S T - S T U D Y  A C C E S S  & A D V E R S E  E V E N T 
R E P O R TI N G I N F O R M A TI O N F O R 
I N T E R V E N TI O N A L  P R O T O C O L S 
 
At t he  e nd of t he  st ud y  perio d,  Brist ol-M yer s  S q uib b  C o mpa ny  will  not  c o ntinue  t o  s up pl y 
st ud y dr ug t o s ubjects/i n vesti gat ors unless  t he S p o ns or-I nvesti ga t or c ho oses t o e xte nd t heir 
st ud y.  T he  investi gat or  is  res p o nsible  t o  e ns ure  t hat  t he  s ubject  receives  a p pr o priat e 
sta ndar d  of care or ot her   a p pr o priate treat me nt in t he inde pe nde nt me dical  j ud ge me nt  of t he  
I nvesti gat or  t o  treat  t he  c o nditio n  under st ud y. 
• All  Serio us  A d verse  E ve nts  ( S A Es)  t hat  occ ur  follo wi n g  t he s ubject’s  writte n  c o nse nt  t o 
participate  in  t he  s t ud y  t hr o ugh  3 0 da ys  of disc o nti n uati o n  of d osing  must  be re p orte d  t o 
B M S  W orld wide Safet y,  w het her  relate d  or not  relate d t o st ud y dr ug.  If a p plica ble,  S A Es 
must  be  c ollecte d  t hat  relate  t o  a ny  later  pr ot oc ol -s pecifie d  pr oce d ure  (e g,  a follo w - u p 
s kin  bio ps y). 
• F ollo wi n g  t he  s ubject’s  writte n  c o nse nt  t o  participate  in  t he  st ud y,  all  S A Es,  w het her 
relate d  or not  relate d t o st ud y dr ug,  are c ollecte d,  includ i n g t hose t ho ught t o be ass ociate d 
wit h  pr ot oc ol -s pecifie d  pr oce d ures.  The  investi gat or  s ho uld  re p ort  a ny S A E  occ urri n g 
after  t hese  afore me ntio ne d  ti me  perio ds,  w hic h  is  belie ve d  t o be relate d  t o st ud y  dr ug  or 
pr ot oc ol- s pecifie d pr oce d ure.  
• A n  S A E  re p ort  s ho uld  be  c o mplete d  for  a ny  e ve nt  w here  d o ubt  e xists  re gar ding  its  
serio us ness; 
• If  t he  investi ga t or  belie ves  t hat  a n  S A E  is  not  relate d  t o  st ud y  dr ug,  b ut  is  p ote ntiall y 
relate d  t o  t he  c o nditio ns  of  t he  st ud y  (s uc h  as  wit hdra wal  of  pre vio us  t hera p y  or  a 
c o mplicati o n  of  a st ud y  pr oce d ure),  t he  relatio ns hi p  s ho uld  be s pecifie d  in  t he  narrati ve 
sectio n  of  t he S A E Re p ort F or m.  
• If  t he  B M S  safet y  a d dress  is  not  include d  in  t he  pr ot oc ol  d oc u me nt  (e g,  multice nt er 
st udies  w here  e ve nts  are re p orte d  ce ntrall y),  t he  pr oce d ure  for  safet y  re p orting  must  be 
re vie we d/a p pr o ve d  b y  t he  B M S  Pr ot oc ol  Ma na ger.  Pr oce d ures  for  s uc h  re porting  mus t  
be re vie we d  a nd a p pr o ve d b y B M S prior  t o st ud y  activatio n.  
A n  a p pr o priate  S A E  for m  (e. g. e x - U S = CI O M S for m  or U S A = Me d watc h  for m)  will  be use d 
t o re p ort  S A Es t o B M S. 
o  T he  CI O M S for m  is a vaila ble  at:  htt p:// w w w.ci o ms.c h/i nde x. p hp/cio ms -for m-i 
o  T he  Me d Watc h  for m  is  a vaila ble  at: Me d Watc h  3 5 0 0  F or m  
• F or st udies  wit h  lo ng -ter m  follo w-up  perio d s  in  w hic h  safet y  data are being  re p orte d, 
include  t he  ti min g  of  S A E c ollectio n.  
• T he  S p o ns or  will  rec o ncile  t he clinical  data base S A E cases (case le vel  o nly)  tra ns mitt e d 
t o  B M S  Glo bal  P har mac o vi gila nce  (W orld wide. Safet y @ b ms .c o m).  Fre q ue nc y  of 
rec o nciliatio n  s ho uld  be  e ver y  3  mo nt hs  a nd  prior  t o  t he  data base  loc k  or  final  data 
s u m mar y.  B M S  G P V & E  will  e mail,  up o n  re q uest  fr o m  t he  I nvesti gat or,  t he  G P V & E 
rec o nciliatio n  
re p ort.  
Re q uests  
for  
rec o nciliati o n  
s ho uld  
be  
se nt  
t o 


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 3 1  of 
 
 
 
ae p b usiness pr ocess @ b ms.c o m.  The  data  ele me nts  liste d  o n  t he  G P V & E  rec o nciliat i o n 
re p ort will  be use d for  case ide ntific atio n  p ur p oses.  If  t he I nvesti gat or  deter mines  a case 
was  not  tra ns mitte d  t o B M S  G P V & E,  t he  case  s ho uld  be  se nt  i m me diatel y  t o  B M S.I n 
acc or da nce  wit h  local  re gulatio ns,  B M S  will  notify  investi gat ors  of  all  re p orte d  S A Es 
t hat  are  s us pecte d  (relate d  t o  t he  investi gati o nal  pr o d uct)  a nd  une xpecte d  (ie,  not 
pre vio usl y  describe d  in  t he  I B).  A n  e ve nt  meeting  t hese  criteria  is  ter me d  a  S us pecte d, 
U ne xpecte d  Serio us  A d verse  Reactio n  ( S U S A R). I nvestiga t or notifica t io n  of t hese e ve nts  
will  be in  t he  for m  of  a  S U S A R  Re p ort. 
o  Ot her  i mp orta nt  findi n gs  w hic h  ma y  be re p orte d  b y  B M S as  a n  Expe dite d  Safet y 
Re p ort ( E S R) include : increase d fre q ue nc y  of a clinica ll y signif ica nt e xpecte d  S A E,  
a n S A E  c o nsidere d  ass ociate d  wit h  st ud y  pr oce d ures  t hat  c o uld  mo dify  t he  c o nd uct 
of t he st ud y, lac k of efficac y t hat  p oses signific a nt hazar d  t o st ud y s ubjects, clinica l l y 
significa nt  safet y  find i n g  fr o m  a  no ncli nical  (e g,  a ni mal)  st ud y,  i mp orta nt  safet y 
rec o m me ndati o ns  fr o m  a  st ud y  data  mo nit ori n g  c o m mittee,  or  s p o ns or  decisio n  t o 
e nd or te mp oraril y  halt  a clinical  st ud y  for  safet y reas o ns. 
o  U p o n receivi n g a n E S R  fr o m B M S,  t he investi ga t or must  re vie w a nd retain t he E S R 
wit h  t he I B. W here re q uire d  b y local  re gulatio ns  or w he n  t here  is  a ce ntral  I R B/I E C 
for  t he  st ud y,  t he  s p o ns or  will  s ub mit  t he  E S R  t o  t he  a p pr o priate  I R B/I E C.  T he 
investi gat or  a nd I R B/I E C  will  deter mine  if  t he  infor me d  c o nse nt  re q uires  re visio n. 
T he in vestigat or  s h o uld  als o  c o m ply  wit h  t he I R B/I E C pr oc e d ures f or re p ortin g  a n y ot her 
s afet y inf or matio n. 
o  I n  a d ditio n  t o  t he  S p o ns or  I n vestigat or’s  res p o nsibilit y  t o  re p ort  e ve nts t o  t heir loc a l  H A, 
s us pe cte d s erio us a d vers e re a ctio ns ( w het her e x pe cte d or u ne x pe cte d) s hall  be  re p orte d b y 
B M S  t o  t he  rele va nt  c o m pete nt  he alt h  a ut h orities  in  all  c o nc er ne d c o u ntries  a c c or din g  t o 
loc al  re g ulatio ns  (eit her as e x pe dite d  a n d/ or in  a g gre gate re p orts). 
S A Es,  w het her relate d  or n ot  relate d  t o st u d y  dr u g,  a n d pre g na ncies  m ust  be re p orte d  t o  B M S  wit hin 
2 4  h o urs \ 1 B usiness D a y of be c o min g  a w are of t he e ve nt. S A Es m ust  be re c or de d o n  eit her CI O M S, 
Me d Watc h, or a p pr o ve d  site S A Ef or m.  
Pre g na ncies m ust be re p orte d a n d s u b mitte d  t o B M S o n a n y of t he f ollo win g  f or m(s):  
1.  Me d Wa tc h or, CI O M S or  
2.  B M S Pre g na nc y S ur veilla nc e  F or m  or , 
3.  A p pr o ve d site S A E  f or m 
S A E E m ail A d dre s s :  W orld wide. Safet y @ B M S. c o m  
S A E F acsi mile  N u m be r:  + 1 6 0 9 -8 1 8 -3 8 0 4  
If o nly  li mite d  inf or ma tio n  is  initia lly  a va ila ble ,  f ollo w -u p  re p orts are re q uire d. ( N ote: F ollo w - u p S A E 
re p orts s h o uld  inclu de  t he s a me in vestigat or  ter m(s) initially  re p orte d.) 
If a n o n g oin g  S A E c ha n ges in  its  inte nsit y  or relatio ns hip  t o st u d y dr u g  or if ne w inf or matio n  be c o mes 
a vaila ble,  a f ollo w-u p  S A E  re p ort s h o uld be  s e nt wit hin  2 4  h o urs  \ 1 B usiness  D a y  t o  B M S usin g  t he 
s a me pr oc e d ure us e d f or tra ns mittin g  t he initial  S A E re p ort. 
All  S A Es s h o uld  be f ollo w e d  t o res olutio n  or sta bilizatio n.  
 


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 3 2  of 
 
 
 
D E FI NI TI O N S  
T he pr ot oc ol  m ust inclu de  a definitio n  f or  Serio us A d vers e E ve nts ( S A E) . 
S E RI O U S A D V E R S E E V E N T S  
A S eri o us A dverse E ve nt ( S A E) is  a ny  unt o war d  me dical  occ urre nce  t hat  at a ny  d ose: 
• res ults  in deat h 
• is  life-t hre ate ni n g  ( define d  as a n e ve nt  in  w hic h  t he  participa nt  was at ris k  of deat h  at t he 
ti me  of t he  e ve nt;  it  d oes  not  refer  t o  a n  e ve nt  w hic h  hyp ot hetica ll y  might  ha ve  ca use d  
deat h  if  it  were more  se vere) 
• re q uires  inpatie nt  hos pitali zati o n  or  ca uses  pr olo ngatio n  of  e xistin g  hos pitalizati o n ( see 
N O T E belo w) 
• res ults  in  persiste nt  or significa nt  disa bilit y/i nc a pacit y 
• is  a c o nge nita l  a no mal y/ b irt h defect  
• is  a n i mp orta nt  me dical  e ve nt  ( define d  as a me dical  e ve nt(s)  t hat  ma y  not be i m me diat e l y 
life-t hr eate ni n g  or res ult  in  deat h or hos pitalizatio n  b ut,  base d up o n  a p pr o priate  me dic al 
a nd  scie ntific  j ud g me nt,  ma y  je o par dize  t he  s ubject  or  ma y  re q uire  inter ve nti o n  [e g, 
me dical,  s ur gical]  t o pre ve nt  o ne  of  t he  ot her  serio us  o utc o mes  liste d  in  t he  definit i o n 
a b o ve.)  E xa mples  of  s uc h  e ve nts  inclu de,  b ut  are not  li mite d  t o, inte nsi ve  treat me nt  i n 
a n  e mer ge nc y  r o o m or  at  ho me  for  aller gic  br o nc hos pas m;  blo o d  d yscrasias  or 
c o nvuls io ns  t hat  d o  not  res ult  in hos pitalizatio n.)  
• S us pecte d  tra ns missi o n  of  a n  infectio us  a ge nt  (e g,  pat ho ge nic  or  no npat ho ge nic)  via  t he 
st ud y  dr ug  is  a n S A E.  
Alt ho ug h  pre gna nc y,  o ver d ose,  p ote n tial  dr ug-ind uce d  liver  inj ur y  ( DI LI),  a nd  ca ncer  are not 
al wa ys  serio us  b y  re gulat or y  definiti o n,  t hese  e ve nts  must  be ha ndle d  as S A Es.  
A ny  c o mp o ne nt  of  a  st ud y  e nd p oint  t hat  is  c o nsidere d  relate d  t o  st ud y  t hera p y  s ho uld  be 
re p orte d as a n S A E  (e g, deat h is a n e nd p oint, if deat h occ urre d  d ue  t o a na p hyla xis,  a na p hyla x is  
must  be  re p orte d). 
N O T E :  ( PI deter mines  if  t his  infor matio n  re gar din g  hos pitalizati o ns  are c o nsidere d  S A Es  a nd 
s ho uld  be include d  in  t he  pr ot oc ol.  T his  is  s up ple me nta l  infor ma t io n  t hat  is  inc l ude d  in  B M S-
s p o ns ore d  trials) 
T he  follo wi n g  hos pitalizatio ns  are not  c o nsidere d  S A Es in  B M S clinical  st udies:  
• a visit  t o t he e mer ge nc y  r o o m or ot her  hos pital de part me nt   < 2 4 ho urs,  t hat d oes not  res ult 
in  a d missio n  ( unless  c o nsidere d  a n  i mp orta nt  me dical or life -t hreate ni n g e ve nt) 
• elective  s ur ger y,  pla nne d  prior  t o signi n g c o nse nt 
• a d missio ns  as per pr ot oc ol  for  a pla nne d  me dical/s ur gical   pr oce d ure 
• r o utine  healt h  assess me nt  re q uiri n g  a d missio n  for  baseline/tr e nd i n g  of  healt h  stat us  (e g,  
r o utine  c olo nosc o p y) 
• Me dical/s ur gical  a d missio n ot her  t ha n t o re me d y ill healt h a nd pla nne d   prior t o e ntr y int o  
t he  st ud y.  A p pr o priate  d oc u me ntatio n  is re q uire d  in  t hese cases. 


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 3 3  of 
 
 
 
• A d missio n  e nc o untere d  for  a not her  life  circ u msta nce  t hat  carries  no  bearing  o n  healt h 
stat us  a nd  req uires  no  me dical/s ur gical  inter ve ntio n  (e g,  lac k  of  ho usin g,  ec o no mic 
ina de q uac y,  care giver  res pite,  fa mil y  circ u msta nces,  a d ministrati ve reas o n). 
• A d missio n  for  a d ministratio n  of  a ntica ncer  t hera p y  in  t he  a bse nce  of  a ny  ot her  S A Es 
(a p plies  t o o nc olo gy pr o t oc ols) 
 
A D V E R S E  E V E N T S  
A n  A d verse  E ve nt  ( A E) is define d  as a ny ne w  unt o war d  me dical  occ urre nce   or w orse ning   of a 
pree xisti n g  me dical  c o nditio n  in  a  clinica l  invest i ga t io n  participa nt  a d minis tere d  st ud y  dr u g 
a nd  t hat  d oes  not  necessaril y  ha ve  a  ca usal  rela tio ns hip  wit h  t his  treat me nt.  A n  A E  ca n 
t herefore  be a ny unfa vora b le  a nd uninte nde d  sign (s uc h as a n a b nor mal  la b orat or y  findi n g), 
s y mpt o m,  or disease  te mp orall y  ass ociate d  wit h  t he  use  of investi gati o nal  pr o d uct,  w het her  or 
not c o nsidere d  relate d  t o t he investi ga tio na l  pr o d uct.  
T he  ca usal relatio ns hi p t o st ud y dr ug is deter mine d   b y a p hysicia n a nd s ho uld  be use d  t o assess 
all  a d verse  e ve nts  ( A E).  T he  cas ual  relatio ns hip  ca n be o ne of t he  follo wi n g: 
Relate d:  T here  is  a reas o na ble  ca usal  relatio ns hip  bet wee n  st ud y  dr ug  a d minis tra tio n  a nd  t he  
A E.  
N ot relate d:  T here  is  not  a reas o na ble  ca usal  relatio ns hip  bet wee n  st ud y  dr ug  a d ministra t i o n 
a nd  t he  A E.  
T he  ter m  "reas o na ble  ca usal  relatio ns hip "  mea ns  t here  is  e vide nce  t o  s uggest  a  ca usal 
relatio ns hi p. 
A d verse  e ve n ts  ca n  be  s p o nta ne o usl y  re p orte d  or  elicite d  d uring  o pe n-e nde d  q uestio ni n g, 
e xa mina t io n,   or e valuatio n  of a s ubject. (I n or der t o pre ve nt  re p orting bias,  s ubjects s ho uld not 
be q uestio ne d  re gar din g  t he s pecific  occ urre nce  of  o ne or more  A Es.)  
N O N S E RI O U S A D V E R S E  E V E N T  
• N o n- serio us  A d verse  E ve nts  ( A E)  are  t o be pr o vide d  t o B M S  in  a ggre gate  via  interi m 
or final  st ud y  re p orts  as s pecifie d  in  t he  a gree me nt  or, if  a re gulat or y  re q uire me nt  [e g, 
I N D U S trial]  as part of  a n a nnual  re p orting re q uire me nt. 
• N o n- serio us  AE infor mati o n  s ho uld  als o be c ollecte d  fr o m  t he start  of a place b o lea d - i n 
perio d  or  ot her  o bser vatio nal  perio d  inte nde d  t o  esta blis h  a  baseline  stat us  for  t he 
s ubjects. 
A n o n- seri o us a dverse eve nt is  a n A E not  classifie d  as serio us. 
N o n- s e ri o us A dve rs e Eve nt  C olle cti o n  a n d  R e porti ng  
T he  c ollectio n  of no n -serio us  A E  infor ma tio n  s ho uld  be gin  at initia tio n  of  st ud y  dr ug.  All  no n-
serio us a d verse e ve nts ( not o nly t hose dee me d  t o  be treat me nt-relate d) s ho uld  be c ollect e d 
c o ntinuo us l y d uring t he treat me nt  perio d a nd for a mini m u m   of 3 0 da ys  follo wi n g t he last  d ose 
of st ud y treat me nt. 
N o n-serio us  A Es  s ho uld  be follo we d  t o res olutio n  or sta bilizati o n,  or re p orte d as S A Es if  t he y 
bec o me  serio us.  F ollo w -up  is  als o  re q uire d  for  no n -serio us  A Es  t hat  ca use  interr upti o n or 
disc o nti n uati o n   of st ud y dr ug a nd for t hose prese nt  at t he e nd of st ud y treat me nt as a p pr o priate. 


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 3 4  of 
 
 
 
L a borat ory  Test A b nor malities  
All  la b orat or y  test res ults  ca pt ure d  as part of t he st ud y  s ho uld  be rec or de d follo wi n g 
instit uti o na l  pr oce d ures.  Test  res ults t hat  c o nstit ute  S A Es  s ho uld  be d oc u me nte d  a nd re p orte d 
t o B M S as s uc h. 
T he  follo wi n g  la b orat or y  a b nor malities  s ho uld  be d oc u me nte d  a nd re p orte d  a p pr o priately:  
• a ny  la b orat or y  test res ult  t hat  is clinicall y  significa nt  or meets  t he  definitio n  of a n  S A E  
• 
a n y la b orat or y  a b n or malit y  t hat re q uire d  t he participa nt  t o ha ve st u d y  dr u g dis c o ntin ue d  or 
interr u pte d 
• 
a n y la b orat or y a b n or malit y t hat re q uire d t he s u bje ct t o re c eive s pe c ific c orre ctive  t hera p y. 
It is e x pe cte d t hat w here ver  p ossible,  t he c linic a l rat her t ha n la b orat or y ter m w o uld  be  us e d  b y  t he 
re p ortin g  in vestigat or  (e g, a ne mia  vers us lo w he m o glo bin value).  
P ote nti al D r u g I n d uc e d Li v e r I nj ur y ( DI LI)  
P ote ntial  dr u g in d uc e d  liver  injur y  is define d  as:  
1)  A T ( A L T or A S T) ele vatio n  > 3 ti mes u p per li mit  of n or mal  (U L N)  
A N D  
2)  T otal  bilir u bin  > 2 ti mes U L N, wit h o ut  initial  fin din gs  of c h olestasis (ele vate d s er u m alkaline  
p h os p hatas e)  
A N D  
3)  N o ot her i m me diately  a p pare nt p ossible  c a us es of A T ele vatio n  a n d h y per bilir u bi ne mia, 
inclu din g,  b ut n ot  li mite d  t o,  viral  he patitis, pre -e xistin g  c hr o nic  or a c ute liver  dis e as e, or t he 
a d ministratio n  of ot her dr u g(s) k n o w n  t o be  he pat ot o xic.  
W here ver p ossible,  ti mely  c o nfir matio n  of initial  liver -relate d  la b orat or y  a b n or malities s h o uld  oc c ur 
prior  t o t he re p ortin g  of a p ote ntial  DI LI e v e nt. All  oc c urre nc es of p ote ntial  DI LIs, me etin g  t he 
define d criteria, m ust be re p orte d as  S A Es.  
Pre g n a nc y  
If, f ollo win g initia tio n of  t he in vestigatio nal pr o d uct,  it is s u bs e q ue ntly dis c o vere d  t hat a st u d y 
participa nt  is  pre g na nt or ma y ha ve be e n pre g na nt  at t he ti me  of in vestigatio nal  pr o d uct e x p os ure, 
inclu din g d urin g  at le ast 5 ha lf -live s after pr o d uct  a d ministratio n, t he in vestigatio nal  pr o d uct  will  be 
per ma ne ntly  dis c o ntin ue d  in  a n a p pr o priate  ma n ner (e g, d os e ta perin g  if ne c ess ar y f or  participa nt).  
T he  in vestigat or m ust  i m me dia te ly n otif y  W orld wide. Safet y @ b ms. c o m  of  t his e ve nt via  eit her t he 
CI O M S, Me d Watc h or a p pr o priate Pre g na nc y S ur veilla nc e  F or m in  a c c or da nc e wit h S A E re p ortin g  
pr oc e d ures.  
Pr ot oc o l-re q uire d  pr oc e d ures f or st u d y dis c o ntin uatio n  a n d f ollo w-u p  m ust be perf or me d o n  t he 
participa nt.  
F ollo w -u p  inf or matio n re gar din g t he c o urs e  of  t he pre g na nc y,  inclu din g perinatal a n d ne o natal 
o utc o me a n d,  w here a p plic a ble,  offs prin g  inf or matio n  m ust be re p orte d o n t he CI O M S, Me d Watc h, 
B M S Pre g na nc y S ur veilla nc e  F or m, o r a p pr o ve d site S A E f or m. A B M S Pre g na nc y S ur veilla nc e 
F or m ma y be pr o vide d  u p o n  re q uest. 
A n y pre g na nc y t hat oc c urs in  a fe male part ner of a male  st u d y participa nt  s h o uld  be re p orte d t o  B M S.  
I nf or matio n o n  t his pre g na nc y  will  be  c olle cte d o n  t he Pre g na nc y  S ur ve illa nc e  F or m. I n or der f or 


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 3 5  of 
 
 
 
S p o ns or or designee  t o c ollect  a ny  pre gna nc y  s ur veilla nce  infor mati o n  fr o m  t he fe male 
part ner,  t he  fe male  part ner  must  sign  a n infor me d  c o nse nt  for m  for  discl os ure  of  t his 
infor mat i o n. 
O ve r dos e 
A n  o ver d ose is  define d  as t he  accide ntal  or inte ntio nal  a d ministratio n  of a ny  d ose of a  pr o d uct 
t hat  is  c o nsidere d  b ot h e xcessive  a nd me dicall y  i mp orta nt.  All  occ urre nces  of  o ver d ose must 
be re p orte d as a n  S A E.  
Ot he r  S af et y C o nsi de rati o ns 
A ny  significa nt  w orse nin g  note d  d uring  interi m  or  final  p hysical  e xa mi nati o ns, 
electr ocar dio gra ms,  X-ra ys, a nd a ny  ot her  p ote ntial  safet y  assess me nts,  w het her  or not t hese 
pr oce d ures  are re q uire d  b y t he  pr ot oc ol,  s ho uld  als o  be rec or de d as a no n-serio us  or serio us 
A E, as a p pr o priate,  a nd re p orte d acc or dingl y.  
L a borat ory  Ass ess me nts  
T he  follo wi n g  la b orat or y  varia bles  will  be deter mine d  as o utline d  belo w:  
He mat ol o g y :  T he  follo w i n g  he mat olo g y  para meters  will  be assesse d:  he mo glo b i n, he mat ocr it, 
re d blo o d cell  c o unt,  w hite  blo o d  cell  c o unt  wit h  differe ntial  ( % a nd derive d  a bs olute  values), 
mea n  c or p usc ular  volu me,  mea n  c or p usc ular  he mo glo bi n,  mea n  c or p usc ular  he mo gl o b i n 
c o nce ntratio n,  a nd a bs olute  platelet  c o unt. 
Cli nic al  c o m pre he ns i ve   met a bolic test ( C M P) : The   follo wi n g clinica l c he mistr y para meters 
will  be  assesse d  per  sc he d ule  of  assess me nt:  T otal  pr otein,  s o diu m,  p otassiu m,  calci u m, 
c hloride,  bicar b o nate  ( H C O 3 ), alb u mi n,  gluc ose,  blo o d  urea  nitr o ge n  ( B U N),  creatini ne,  t otal 
bilir ub i n,  
alka line  
p hos p hatase  ( A P),  as partate  a minotra nsferas e  
( A S T),  ala ni n e 
a minotra nsferase  ( A L T),  a nd  he mo glo bi n  A 1 C. He mo glo bi n  A 1 C will  be use d  as a s urr o gat e 
for  pa ncreatic  e nd ocrine functio n. A  fasting  lipid  pa nel  a nd  H b A 1c  will  be perfor me d  d uri n g 
t he  G TI assess me nt  visits. 
I m m u no gl o b uli n:  Ser u m  I g M,  I g G,  a nd  I g E  will  be  assesse d  per  sc he d ule  of  assess me nt. 
Ser u m  I g G s ubclasses  will  be meas ure d  per sc he d ule  of  assess me nt 
C o m ple me nt  le vels: C 3 a nd C 4 le vels  will  be assesse d per sc he d ule  of  assess me nt  
Uri nal ysis a nd  Urine  pr otein/creati ni ne  ratio:  The  follo wi n g  urinal ysis  para meters  will  be 
assesse d  per  sc he d ule  of  assess me nt:  p H,  gluc ose,  ket o nes,  s pecific  gra vit y,  nitrite,  pr otei n, 
bilir ubi n,  ur o bili no ge n,  le uk oc ytes  a nd  blo o d.  Micr osc o pic  urinal ysis  will  be  per for me d  if 
clinicall y  indicate d.  
Se rol o g y :  H Bs A g,  H Bc A b,  a nd  H C V  A b  will  be  perfor me d  at  Scree ning.  N ot  re q uire d  if 
c ollecte d  6 mo nt hs  prior  t o scree nin g  visit. 
Uri ne   Pre g na nc y  Te s t :  Urine  pre gna nc y  testing  will  be  perfor me d  in  fe male  s ubjects  of 
c hild bearin g  a ge (if  not  s ur gicall y  sterilize d)  
M e c ha nistic s a m ples: C orrel ati ve  St u dies  
Perip heral   blo o d mo no nuc lea r  cells ( P B M Cs) a nd plas ma  will   be is olate d a nd fr oze n fr o m eac h 
s ubject  at wee ks  0, 1, 4, 1 2 a nd  2 4 c orres p o nding  wit h  clinical  blo o d  dra ws.  Flo w  c yto metr y 
lo o king  at T cells  will  be assesse d  at wee ks  0, 1, 4, 1 2 a nd 2 4. Fr o m  5 of  t he  e nr olle d  s ubjects 


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 3 6  of 
 
 
 
wit h  k no w n  e xpa nsio ns  of  t he  res pective  cell  t ype  a nd  clinical  res p o nsive ness  t o  a batace pt, 
ter minall y  differe ntiate d  C D 4 + C T Ls,  ter minall y  differe ntiat ed  C D 8 + C T Ls  a nd  activate d  B 
cells  will  be s orte d b y F A C S at wee ks 0, 1 2 a nd 2 4. 
Bl o o d  R e q uire  me nts :  
Blo o d  will  be c ollecte d  for  clinica l  la b orat or y  testing  as  o utline d  belo w: 
He mat olo g y:  Blo o d  ( 3 m L)  will  be c ollecte d  int o  a la ve nder- t o p  ( E D T A)  t ube. 
C he mis tr y:  Blo o d  ( 5. 0 m L)  will  be c ollecte d  int o  a ser u m  gel  ( S S T) t ube. 
He patitis  ser olo gies ( H Bs A g, H Bc A b,  H C V A b):   Blo o d ( 4. 0 m L)  will   be c ollecte d  int o  a ser u m 
gel  ( S S T)  t ube.  I m muno gl o b uli ns  (I g G,  I g M,  I g E,  I g G4 )  a nd C o mple me nt  C 3 a nd  C 4: Blo o d  ( 5 
m L)  will  b e c ollecte d  int o  a ser u m  gel  ( S T T)  t ube.  
Flo w  C yt o metr y  B  C ell  a nd  C D 1 9 R O:  Blo o d  ( 3. 0 m L)  will  be c ollecte d  int o  a la ve nder -t o p 
t ube  a nd blo o d ( 5. 0 m L)  will  be c ollecte d  in  a C yt o-C he x  B C T glass  strec k C E mar ke d  t ube.  
Plas ma blast  a nd  C D 4 +  C T L  Assess me nt: Blo o d  ( 5. 0  m L)  will  be  c ollecte d  in  a  C yt o -C he x 
B C T glass  strec k C E mar ke d  t ube.  
L a borat ory  V al ues O utsi de  N or mal  R a nge:  
A ny  value  o utside  t he  nor mal  ra nge  will  be  fla gge d  for  t he  atte ntio n  of  t he  I nvesti gat o r  or 
designee  at  t he  site.  T he  I nvesti gat or  or d esignee  will  indicate  w het her  or not  t he  value  is  of 
clinica l significa nce.  La b orat or y values  t hat are clinica ll y significa nt a nd t hat are not  e xplai ne d 
b y  t he  s ubject’s  underlyi n g  disease  or  me dicatio ns  s ho uld  be  e ntere d  as  A Es  a nd  t he 
relatio ns hi p  t o  st ud y  dr ug  assigne d.  A  la b orat or y  value  of  clinica ll y  significa nce  t ypica ll y 
re q uires  a dia gnost ic   or t hera pe utic inter ve nti o n ot her  t ha n re peating t he test. A d ditio nal testi n g 
d uring  t he  st ud y  ma y  be  d o ne  if  me dicall y  indicate d.  The  st ud y  s ubject  will  be fol lo we d  until 
t he  test(s)  has ( ha ve)  nor malize d  or sta bilize d. 
P hysic al  E x a mi nati o n  
C o mplete  p hysical  e xa minatio ns  will  be perfor me d  at Scree ning,  o n  Da y  1 (c o uld  p ote ntiall y 
be t he sa me visit)  a nd at E O S.  A b bre viate d  P Es  will   be directe d   t o war ds t he s y mpt o ms  of I g G 4- 
R D t hat  were pre vio usl y  define d  a nd will  be perfor me d  at all  ot her  visits.  
T he  p hysical  e xa minati o n  includes  a n  assess me nt  of  ge neral  a p peara nce  a nd  a  re vie w  of 
s yste ms  ( der mat olo gic,  hea d,  e yes,  ears,  nose,  mo ut h/t hr oat/ nec k,  t hyr oid,  ly mp h  no d es, 
res pirat or y,  car dio vasc ular,  gastr ointesti nal,  e xtre mities,  musc ulos keletal,  ne ur olo gic,  a nd 
ps yc hiatric  s yste ms).  
Vit al  Si g ns  
Vital  signs  will  be  assesse d  at  Scree ning  ( Visit  1)  a nd  at  eac h  visit  t o  t he  PI’s  office.  The 
follo w i n g  vital  signs  will  be meas ure d: 
• Blo o d  press ure  (s yst olic  a nd diast olic  [ m m H g]); 
• Heart  rate ( beats per minute  [ b p m]); 
• B o d y  te mperat ure  (° C); 
• Res pirat or y  rate ( breat hs  per  minute).  
 


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 3 7  of 
 
 
 
 
 
8.  S T A TI S TI C A L  E V A L U A TI O N  
 
8. 1 A nal ysis P o p ul ati o n 
 
T he definitio ns  of st u d y p o p ulatio ns  are as f ol lo ws: 
• 
Effic a c y  P o p ulatio n:  All  s u bje cts. T his  p o p ulatio n  will  be  us e d  f or t he pri mar y effic a c y 
a nalysis a n d ot her effic a c y a nalys es e xc e pt w here ot her wis e  n ote d.  
• 
Safet y  P o p ulatio n:  All  s u bje cts tre ate d wit h  a bata c e pt.  T his  p o p ulatio n  will  be  us e d  f or 
s afety a nalys es.  
• 
P atie nt  Re p orte d  O utc o me  P o p ulatio n   ( P R O): All  ra n d o mize d s u bje cts w h o  ha ve  a n o n - 
missin g  ba s e line  a n d at le ast o ne  p ost -ba s e line  P R O ass ess me nt.  S u bje cts  in t his s u bs et 
will  be  a nalyze d  a c c or din g  t o  t heir  ra n d o mize d  tre at me nt  assig n me nt,  re gar dless  of 
tre at me nt re c eive d, e xc e pt w here ot her wis e n ote d.  
• 
P har ma c o kinetic P o p ulatio n:  S u bje cts wit h  at le ast o ne q ua ntifia ble  tr o u g h  c o nc e ntratio n 
re s ult will  be inc lu de d  in  t his p o p ulatio n.  
• 
P har ma c o d y na mic P o p ulatio n:  S u bje cts wit h a q ua ntifia ble  bas eli ne  a n d at le ast o ne p ost -
bas eline  ass a y res ult will  be inclu de d  in  t his  p o p ulatio n.  
• 
O pe n -la bel P o p ulatio n:  S u bje cts  wit h  c o ntrain dic atio ns  t o or  w h o  ref us e gluc oc ortic oi d 
t hera p y ma y e nter a n o pe n-la bel  st u d y  a n d re c eive X m A b 5 8 7 1  if  t he y ot her wis e me et all 
ot her  inclusio n  a n d  e xclusio n  criteria.  T hes e s u bje cts  will  f ollo w  t he  s a me  s c he d ule of 
ass ess me nts, b ut s afet y a n d effic a c y will  be re p orte d s e parately. 
• 
C o ntin uin g  Gluc ortic oid  P o p ulatio n:  S u bje cts  w h o  c o ntin ue  o n  st u d y  after  a n 
u ns uc c essf ul gluc oc ortic o id ta per or  w h o  c o ntin ue  after re c eivin g gluc oc ortic oid  res c ue 
t hera p y f ollo win g  a s uc c essf ul ta per. 
8. 2 E n d p oi nts  
Pri m ar y  Effic ac y  E n d p oi nt  
T he pri mar y  e n d p oint  is  c o m plete  re missio n  at 2 4  w e e ks. C o m plete  re missio n  is  define d  as a n I g G4 -
R D  Res p o n der  I n de x  Sc ore  of  0  a n d  a  pre d nis o ne  d os e  of  0  m g/ da y  a n d  n o  flare  sinc e  be gin ni n g 
tre at me nt. 
Se c o n d ar y Effic ac y  E n d p oi nts  
•  
Dis e as e res p o ns e at 4, 1 2,  2 4,  a n d 3 6 w e e ks. Dis e as e res p o ns e will be define d  at 6 m o nt hs as: 1) 
i m pr o ve me nt  of > 1  p oint  in  t he  I g G4 -R D  RI  s c ore o ver  bas eline;  2)  n o  gluc oc ortic oid  use 
f ollo win g  t he w e e k 4  visit;  3)  n o  dis e as e flares,  as ass ess e d b y t he I g G4-R D RI. Dis e as e flare 
will  be define d as re c urre nc e of dis e as e a ctivit y or de m o nstratio n of a dis e as e e xa c er batio n s uc h 
t hat  a d ditio nal  t hera p y  be y o n d  t he  trial  pr ot oc ol  is  in dic ate d.  S uc h  a d ditio nal  t hera p y  ma y 
inclu de  gluc oc ortic oids  or alter native i m m u n os u p pressive a ge nts.  
•  
C o m plete  re missio n  at 3 6  w e e ks.  
•  
Ti me  t o dis e as e re missio n  (I g G4 -R D RI =  0)  
•  
Re missio n  rates 


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 3 8  of 
 
 
 
 
•  
N u m ber of dis e as e flares  per s u bje ct  o ver  ti me 
•  
C u m ulative  c ortic oster oid  d os es a n d Gluc oc ortic oid  T o xicit y  I n de x 
•  
P h ysicia n  Glo bal  Ass ess me nt ( P G A). A P G A c o nsistin g  of a 1 0 -c e nti meter vis ual  a nalo g s c ale 
is c olle cte d at e a c h patie nt visit.  O nly a ctive dis e as e (as o p p os e d t o da ma ge) is c o nsidere d in t he 
s c orin g  of t he P G A.  
•  
S y m pt o m  Se verit y  I n de x 
•  
Ser u m i m m u n o glo b ulin  le vels,  I g G4 s u bclass c o nc e ntratio ns,  I g E le vels,  e osin o p hils,  a n d s er u m 
C 3 a n d  C 4 
S afe t y E n d p oi nts  
Safet y a nalys es will  be perf or me d usin g  all tre ate d s u bje cts.  
•  
T he  n u m ber  a n d perc e nt of s u bje cts e x perie ncin g  a tre at me nt -e mer ge nt a d vers e e ve nt will  be 
ta b ulate d  f or e a c h c o de d Me d D R A s yste m-or ga n class a n d preferre d ter m. Tre at me nt -e mer ge nt 
a d vers e e ve nts will  als o be ta b ulate d a c c or din g  t o inte nsit y  a n d c a us alit y.  
•  
All   SA Es,  dis c o ntin uatio ns  d ue  t o A E,  or  de at hs  oc c urrin g  d urin g  t he c o urs e  of  t he tria l  will  be 
pres e nte d in  s u bje ct  listin gs. 
•  
T he n u m ber  a n d perc e nt of s u bje cts e x perie ncin g  a gluc oc ortic oid -relate d  A E will  be ta b ulate d 
f or  e a c h c o de d  Me d D R A s yste m-or ga n clas s a n d preferre d ter m. Tre at me nt-e mer ge nt a d verse 
e ve nts will  als o be ta b ulate d  a c c or din g t o  inte nsit y  a n d c a us alit y.  
•  
Clinic al  la b orat or y  tests ( o bs er ve d  values) will  be s u m marize d  des criptively  in  ta b ular  f or mat. 
S hift  ta bles  will  be  pres e nte d f or s ele ct l a b orat or y  para meters. I n  t he  s u bje ct  listin gs, values  
o utside  of  t he la b orat or y’s refere nc e li mits will  be  ide ntifie d, alo n g wit h  t he  I n vestigat or’s 
ass ess me nt of clinic al  sig nific a nc e.  A list  of all  n or mal  la b orat or y  ra n ges will  als o  be pr o vide d.  
Clinic a l ly  sig nific a nt  la b orat or y  test a b n or malities  t hat w ere c o nsidere d A Es b y t he I n vestigat or 
will  be pres e nte d in  t he A E  listin gs. 
•  
Vital  sig ns ( B P, p uls e,  te m perat ure) will  be s u m marize d  ( o bs er ve d a n d c ha n ge fr o m bas eline)  at 
e a c h visit vital  sig ns are c olle c te d usin g  des criptive  statistics a n d s u bje ct listin gs. 
•  
C o nc o mita nt  Me dic atio ns  will  be s u m marize d  b y t he n u m ber  a n d perc e nta ge of s u bje cts in  e a c h 
t hera pe utic class a n d preferre d ter m as c o de d usin g  t he W H O Dr u g dictio nar y. 
P h ysic al E xa minatio ns  will  be pre s e nte d in  s u bje ct listin gs. 
8. 3 Q u alit y of Life As s ess me nts  
Q ualit y  of  life  ass ess me nts will  inclu de  t he  P h ysicia n  Glo bal  Dis e as e A ctivit y  Ass ess me nt Vis ual 
A nalo g ue Sc ale ( P h G A V A S), t he P atie nt Glo bal  Dis e as e A ctivit y Ass ess me nt V A S ( Pt G A V A S), t he 
S y m pt o m  Se verit y  I n de x a n d t he 3 6 -ite m  s h ort f or m he alt h  s ur ve y ( S F-3 6). U nless ot her wis e s pe cifie d, 
t he  Q O L a nalys es  will  inclu de  all  ra n d o mize d  s u bje cts  w h o  ha ve a n o n-missin g  bas eline  a n d at le ast 
o ne p ost -bas eline Q O L ass ess me nt. S u bje cts in t his  s u bs et 


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 3 9  of 
 
 
 
 
w ill  be a nalyze d a c c or din g t o t heir ra n d o mize d  tre at me nt assig n me nt, re gar dless of tre at me nt re c eive d. 
T he  perc e nta ge  of  participa nts  ra n d o mize d  t o  e a c h  tre at me nt  gr o u p  w h o  c o m plete  t he  Q O L 
q uestio n naires  at e a c h ass ess me nt p oint  after bas eline (i. e., Q O L c o m pletio n rates) will  be c alc ulate d 
a n d c o m pare d. If sig nific a nt  differe nc es in Q O L c o m pletio n  rates are o bs er ve d, a d ditio nal  a nalys es ma y 
be perf or me d t o e valuate t he p ote ntial  f or re p ortin g  bias es.  
F or  e a c h  Q O L  e n d p oint,  des criptive  statistics  will  be  pr es e nte d f or  re c or de d values  at  e a c h  visit, 
inclu din g  me a n,  sta n dar d de viatio n,  me dia n,  mini m u m,  ma xi m u m,  c ha n ge fr o m bas eline a n d  perc e nt 
c ha n ge fr o m bas eline.  
8. 4 St atis tic al M et h o ds Ge ne r al 
C o ns i de r ati o ns  
S u m mar y  statistics  will  be pres e nte d b y  w a y of n,  me a n,  sta n dar d de viatio n  ( S D),  me dia n,  mini m u m 
a n d ma xi m u m  f or c o ntin u o us  varia bles a n d b y w a y of gr o u p fre q ue ncies a n d perc e nta ges  f or c ate g oric al 
varia bles.  P erc e nta ges  will  be  c alc ulate d usin g  t he t otal s u bje cts per  ar m  in  t he  pla n ne d  a nalysis  
p o p ulatio n,  u nless s pe cifie d  ot her wis e.  
F or  listin gs,  in  t he c as es w here a s u bje ct’s re c or d has be e n c o ntin ue d  t o t he  ne xt pa ge,  a n a p pr o priate 
ide ntific atio n  (e. g., t he s u bje ct I D n u m ber)  m ust be pres e nte d at t he be gin nin g  of t hat pa ge. 
U nless ot her wis e s pe cifie d ,  in  s u m mar y  ta bles  of  c o ntin u o us  varia bles,  t he  mini m u m  a n d  ma xi m u m 
values will  be dis pla ye d  t o t he s a me n u m ber of de ci mal  pla c es as t he ra w data, t he me a n a n d me dia n 
will  be pres e nte d t o o ne e xtra de ci mal  pla c e c o m pare d t o t he ra w data, a n d t he sta n dar d de viatio n  will 
be dis pla ye d  t o  t w o e xtra de ci mal  pla c es c o m pare d t o t he ra w  data. W here ver p ossible,  data will  be 
de ci mal alig ne d.  
U nless  ot her wis e  s pe cifie d fre q ue nc y ta b ulatio ns will  be  pres e nte d  b y  n u m ber  a n d perc e nta ge, w here 
t he perc e nta ge is pres e nted in  bra c kets t o 1 de ci mal pla c e.  
P- values, if a p plic a ble,  will  be pres e nte d t o 3 de ci mal pla c es. If a p -value  is less t ha n 0. 0 5 b ut is  gre ater  
t ha n or  e q ual t o 0. 0 1,  t he n a n asteris k ( *) will  be  a d de d ne xt  t o t his value.  If a p-va lue  is  le ss t ha n 0. 0 1  
b ut  is gre ater  t ha n or  e q ual t o 0. 0 0 1,  t he n t w o asteris ks  ( * *) will  be  a d de d ne xt t o  t his  value. Finally,  if 
t he p-value  is  less  t ha n 0. 0 0 1  t he n t hre e asteris ks  ( * * *)  will  be a d de d ne xt  t o t his value  a n d it will  be  
pres e nte d  as  < 0. 0 0 1.  If t he r o u n de d re s ult is a value  of  1. 0 0 0,  it  will  be dis pla ye d  a s > 0. 9 9 9.  
 
9  DI R E C T A C C E S S  T O  S O U R C E  D A T A/ N O T E S  
T he  I nvestiga t or will  e ns ure t he acc urac y,  c o mplete ness,  a nd ti meli ness  of t he data  re p orte d t o 
t he S p o ns or. Data  c ollectio n pr ocesses  a nd pr oce d ures  will   be re vie we d  and  validate d  t o e ns ur e  
c o mplete ness,  acc urac y,  relia bilit y,  a nd  c o nsiste nc y.  
 
T he  I nvestiga t or  or designee  will  pre pare  a nd mainta i n  a de q uate a nd acc urate st ud y  d oc u me nts 
( me dical rec or ds, E C Gs,  A E  a nd c o nc o mita nt me dicatio n  re p orting, ra w data  c ollectio n for ms ,  
etc.)  designe d  t o  rec or d  all  o bser vatio ns  a nd  ot her  pertine nt  data  for  eac h  s ubject  receivi n g 
I M P. 
 
T he  I nvesti gat or  will  allo w  S p o ns or  re prese ntatives,  c o ntract  designees,  a ut horize d  re gulat or y 
a ut horit y ins pect ors, a nd t he I nstit ut io na l Re vie w  B oa r d (I R B)/ I nde pe nde nt Et hics  C o m mit t e e  
(I E C) t o ha ve  direct  access t o all  d oc u me nts  pertaini n g  t o t he st ud y. 
 


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 4 0  of 
 
 
 
 
1 0  Q U A LI T Y  C O N T R O L  A N D Q U A LI T Y  A S S U R A N C E 
D at a Q ualit y  As s ura nce  
T he  I nvesti gat or  must  pre pare a nd  maintai n  a de q uate  a nd  acc urate  rec or ds  of  all  o bse r vati o ns 
a nd  ot her  data  pertine nt  t o  t he  clinical  st ud y  for  eac h  st ud y  participa nt.  Fre q ue nt 
c o m municati o n  bet wee n  t he  clinical  site  a nd t he  S p o ns or  is  esse ntial  t o e ns ure  t hat  t he  safet y 
of  t he  st ud y  is  mo nit ore d  a de q uately.  The  I nvesti gat or  will  ma ke  all  a p pr o priate  safet y 
assess me nts  o n  a n  o ngoing  basis.  T he  S p o ns or’s  me dical  re prese ntative  ma y  re vie w  safet y 
infor  mati o n  as it  bec o mes  a vaila ble  t hr o ugho ut  t he  st ud y. 
All  as pects  of  t he  st ud y  will  be  carefull y  mo nit ore d  wit h  res pect  t o  G C P  a nd  S O Ps  for 
c o mplia nce  wit h  a p plica ble  go ver n me nt  re gulat io ns. 
 
T he  st ud y  ma y  be  a udite d  t o  assess  a d here nce  t o  t he  Clinical  St ud y  Pr ot oc ol.  The 
I nvesti gat or/i n vesti gati o nal  site  will  per mit  st ud y-relate d  mo nit ori n g,  a udits,  I R B/I E C  re vie w 
a nd  re gulat or y  ins pectio ns  b y  pr o vidin g  direct  access t o s o urce  data/ d oc u me nts.  Direct  access 
includes per missio n t o e xa mine,  a nalyze,  verif y,  a nd re pr o d uce a ny rec or ds a nd re p orts t hat are 
i mp orta nt  t o t he e valuatio n  of a clinical st ud y. 
 
D uring  t he  c o nd uct  of  t he  st ud y,  pr ocess -relate d a udits  ma y  be  perfor me d  as well.  A n  a udit 
certificate  will  be pr o vide d  in  t he  final  st ud y  re p ort  o utli ni n g  t he  a udit  perfor me d  a nd  ot her 
relate d  activities. 
 
1 1  E T HI C S  
1 1. 1 I n de pe n de nt  Et hics   C o m mitte e /I ns tit uti o na l  R e vie w B o ar d  
Prior  t o t he  start of  t he st u d y,  t he  investi gat o r  is  res p o nsible  for  e ns urin g  t hat  t he  pr ot oc ol  a nd  
c o nse nt  for m  ha ve  bee n re vie we d  a nd a p pr o ve d  b y a rele va nt  I E C/I R B.  The  I E C/I R B  s hall  be 
a p pr o priately  c o nstit ute d  a nd  perfor m  its  functio ns  in  acc or da nce  wit h  F D A  I C H  G C P  a nd 
local  re quire me nts  as a p plica ble.  
T he  I E C/I R B  s hall  a p pr o ve  all  pr ot oc ol  a me nd me nts  (e xce pt  for  lo gistical  or  a d ministr at i v e 
c ha nges),  writte n  infor me d  c o nse nt  d oc u me nts  a nd  d oc u me nt  up dates,  s ubject  recr uit me nt 
pr oce d ures  (e. g.,  a d vertise me nts),  writte n  infor mati o n  t o  be  pr o vide d  t o  t he  s ubjects, 
investi gat or's  Br oc hure,  a vaila ble  safet y  infor matio n,  infor matio n  a b o ut  pa y me nt  a nd 
c o mpe nsatio n  a vaila ble  t o s ubjects,  t he investi gat or's  c urric ul u m  vitae  a nd/ or ot her  e vide nce  of  
q ualificati o ns  a nd a ny ot her  d oc u me nts   re q ueste d   b y t he I E C/I R B a nd Re gulat or y  A ut hor it y 
( C o mpete nt  A ut horit y)  as a p plica ble.  
1 1. 2 G o o d Cli nic al  Practice 
T he  pr oce d ures  set o ut  in  t his  clinical  st ud y  pr ot oc ol  are  designe d  t o e ns ure  t hat  t he  S p o ns or 
a nd  t he  I nvestiga t or  a bide  b y  t he  princip les  of t he  I C H  guideli nes  o n  G C P  as  o utli ne d  i n 
C P M P/I C H/ 1 3 5/ 9 5 a nd t he Declaratio n   of Helsink i  ( Versio n  2 0 0 8). The  clinica l st ud y als o will 
be carrie d  o ut  in kee ping wit h  natio na l a nd local le gal re q uire me nts (in acc or da nce wit h  U nit e d  
States I nvesti gati o nal  N e w Dr ug  [I N D] re gulatio ns  [ 2 1 C F R Parts 5 0, 5 6 a nd  3 1 2]). 


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 4 1  of 
 
 
 
T he  I nvesti gat o r  will  be  res p o nsible  for  t he  care  of  t he  s ubjects  t hr o ugho ut  t he  st ud y.  If  t he  
I nvesti gat or  is  not  prese nt  at  t he  st ud y  site,  he/s he  will  lea ve  instr ucti o ns  for  t he  staff  a nd  a 
tele p ho ne  nu mber  w here  he/s he  ca n be reac he d.  
1 1. 3 Writte n  I nf or me d  C o ns e nt 
Before  eac h s ubject  is e nr olle d  in  t he clinical  st ud y,  writte n  infor me d  c o nse nt  will  be  o btaine d 
fr o m t he s ubject acc or ding t o t he re gulat or y a nd le gal re q uire me nts  of t he participati n g c o untr y.  
As  part  of  t his  pr oce d ure,  t he  I nvesti gat or  must  e xplain  orally  a nd  in  writin g  t he  nat ure ,  
d uratio n,  a nd  p ur p ose  of  t he  st ud y,  a nd  t he  actio n  of  t he  dr ug  in  s uc h  a  ma nner  t hat  t he  st ud y 
s ubject  is  a ware  of  t he  p ote ntial  ris ks,  inc o nve nie nces,  or  A Es  t hat  ma y  occ ur.  The  s ubject 
s ho uld  be  infor me d  t hat  he/s he  is  free  t o  wit hdra w  fr o m  t he  st ud y  at  a ny  ti me.  He/ S he  will 
receive all infor ma t io n t hat is re q uire d  b y fe deral re gulatio ns a nd I C H guideli ne s.  The  Princi p a l 
I nvesti gat or  or  designee  will  pr o vide  t he  S p o ns or  wit h  a c o p y  of  t he  I R B/I E C -a p pr o ve d  I C F 
prior  t o t he start  of t he  st ud y. 
T he  infor  me d  c o nse nt  d oc u me nt  must  be  signe d  a nd  date d;  o ne  c o p y  will  be  give n  t o  t he  
s ubject,  a nd  t he  I nvesti gat or  will  retain  a  c o p y  as  part  of  t he  clinical  st ud y  rec o r ds.  The 
I nvesti gat or  will  not  underta ke  a ny  investi ga tio n  s pecifica ll y  re q uire d  for  t he  clinica l  st ud y 
until  writte n  c o nse nt  has  bee n  o btaine d.  The  ter ms  of  t he  c o nse nt  a nd  w he n  it  was  o btaine d 
must  als o  be d oc u me nte d.  
If  a  pr ot oc ol  a me nd me nt  is  re q uire d, t he n  t he  infor me d  c o nse nt  d oc u me nt  ma y  nee d  t o  be 
re vise d  t o reflect  t he  c ha nges  t o t he  pr ot oc ol.  If  t he  infor me d  c o nse nt  d oc u me nt  is  re vise d,  it 
must  be  re vie we d  a nd  a p pr o ve d  b y  t he  res p o nsible  I R B/I E C  a nd  signe d  b y  all  s ubjects 
s ubse q ue ntl y  e nr olle d  in t he  clinical  st ud y  as  well  as  t hose  c urre ntly  e nr olle d  in  t he  clinic a l 
st ud y. 
1 1. 4 Prot oc ol  A p pro v al  a n d  A me n d me nt(s) 
Before  t he  start  of  t he clinical  st ud y,  t he  clinical  st ud y  pr ot oc ol  a nd  ot her  rele va nt  d oc u me nts 
will  be a p pr o ve d  b y  t he  I R B/I E C,  in  acc or da nce  wit h  local  le gal  re q uire me nts.  The  S p o ns or 
must  e ns ure  t hat  all  et hical  a nd  le gal  re q uire me nts  ha ve  bee n  met  before  t he  first  s ubject  is 
e nr olle d  in  t he  clinica l  st ud y.  
T his  pr ot oc ol  is  t o be follo we d  e xactly.  A ny  de viatio ns  s ho uld  be a gree d  b y  b ot h t he  S p o ns or 
a nd t he  I nvestigat or,  wit h  t he  a p pr o priate  writte n  a nd a p pr o ve d  pr ot oc ol  a me nd me nts  ma de  t o 
reflect t he c ha nges a gree d  up o n.   Pr ot oc ol a me nd me nts must   be release d  b y t he res p o nsible staff 
a nd  receive  I R B/I E C  a p pr o val  prior  t o i mple me ntati o n  (as a p pr o priate).  W here  t he  de viati o n 
occ urs  for  t he  well-bei n g  of  t he  s ubject,  t he  S p o ns or  must  be  infor me d  of  t he  actio n  a gree d 
up o n.  
A d ministrati ve  c ha nges  ma y  be ma de  wit ho ut  t he  nee d for  a for mal  a me nd me nt  b ut  will  als o 
be me ntio ne d  in  t he  inte grate d  clin ica l  st ud y  re p ort.  All  a me nd me nts  will  be  distrib ute d  t o  a ll 
st ud y  pr ot oc ol  recipie nts,  wit h  a p pr o priate  instr uctio ns. 
1 1. 5 C o nfi de nti alit y  D at a Prote cti o n 


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 4 2  of 
 
 
 
All  clinical  st ud y  findi n gs  a nd  d oc u me nts  will  be re gar de d  as  c o nfide ntial.  St ud y  d oc u me nts 
( pr ot oc ols, I Bs a nd  ot her  material)  will  be st ore d  a p pr o priately  t o e ns ure  t heir  c o nfide ntialit y. 
T he  I nvesti ga t or  a nd  me mbers  of  his/ her  researc h  tea m  (incl ud i n g  t he  I R B/I E C)  must  not 
disclose  s uc h infor ma t io n wit ho ut   prior writte n   a p pr o val fr o m t he S p o ns or, e xcept t o t he e xte nt 
necessar y  t o  o btain  infor me d  c o nse nt  fr o m  s ubjects  w ho  wis h  t o participate  in  t he  trial  or t o 
c o mply  wit h  re gulat or y re q uire me nts. 
T he a no ny mit y  of participati n g  s ubjects must  be maintai ne d.  S ubjects will  be s pecifie d  o n st ud y 
d oc u me nts  b y  t heir  s ubject  nu mber,  init ia l  or  birt h  date, not  b y  na me.  D oc u me nts  t hat  ide ntif y 
t he  s ubject  (e. g., t he  signe d  infor me d  c o nse nt  d oc u me nt)  must  be maintai ne d  in  c o nfide nce  b y 
t he  I nvestiga t or. 
 
1 2  D A T A H A N D LI N G A N D R E C O R D K E E PI N G  
1 2. 1 C as e R e port F or ms/ S o urce  D a t a H a n dli ng  
T he  investi gat or  must  maintai n  s o urce  d oc u me nts,  s uc h  as la b orat or y  re p orts,  X -ra ys,  E C Gs, 
c o ns ultatio n  re p orts,  a nd c o mplete  me dical  hist or y  a nd p hysical  e xa minatio n  re p orts.  
1 2. 2 R ete nti o n of Ess e nti al D oc u me nts 
T he  s p o ns ors  must  retain  all  s t ud y  rec or ds  a nd  s o urce  d oc u me nts  for  t he  ma xi m u m  perio d 
re q uire d  b y  a p plica ble  re gulatio ns  a nd  guideli nes  or  instit uti o n  pr oce d ures,  or  for  t he  perio d 
s pecifie d  b y a gree me nt  wit h  B M S, w hic he ver  is  lo nger. 
 
1 3  P U B LI C A TI O N  P O LI C Y  
B y  signi n g  t he  clinica l  st ud y  pr ot oc ol,  t he  I nvestiga t or  a grees  wit h  t he  use  of  res ults  of  t he  
clinica l  st ud y  for  t he  p ur p oses  of  natio na l  a nd  inter nati o na l  re gistratio n,  p ublicatio n  a nd 
infor mati o n  for  me dical  a nd  p har mace utical  pr ofessio nals.  If  necessar y,  t he  c o mpete nt 
a ut horit ie s  will  be  notifie d  of  t he  I nvesti gat or’s  na me,  a d dress,  q ualificati o ns  a nd  e xte nt  of 
invol ve me nt.  A n  I nvesti gat or  s hall  not  p ublis h  a ny  data  ( p oster,  a bstract,  pa per, etc.)  wit h o ut 
ha vin g  c o ns ulte d  wit h  t he  S p o ns or  in  a d va nce.  


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 4 3  of 
 
 
 
 
 
1 4  
SI G N A T U R E O F  I N V E S TI G A T O R 
I agre e t o c o n d uct t he st u d y o utline d a b o ve in a c c or da nc e wit h t he ter ms a n d c o n ditio ns of  t he pr ot oc ol, 
I C H g uidelines  o n  G C P  a n d wit h  a p plic a ble  re g ulat or y re q uire me nts. All  inf or matio n  pertainin g  t o  t he 
st u d y s hall  be tre ate d in  a c o nfide ntial ma n ner.  
 
 
 
 
 
2 8 O ct o ber 2 0 1 8  
 
Dr. J o h n H St o ne,  M. D., M. P. H 
P rinc ipa l  I n vestigat or 
 
D ate ( da y/ m o nt h/ ye ar)  


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 4 4  of 
 
 
 
 
1 5  
R E F E R E N C E  LI S T  
A bata c e pt P a c ka ge I ns ert. htt ps:// pa c ka geins erts. b ms. c o m/ pi/ pi_ ore ncia. p df.  
 
A n ders o n P. K. a n d Gill  R. D. C o x’s re gressio n m o del  f or c o u ntin g  pr oc e ss es: a lar ge s a m ple st u d y. 
A n nals of Statistics  1 9 8 2;  1 0:1 1 0 0 -1 1 2 0.  
 
Br o w nlie  RJ, La wlor K E, Nie derer H A, C utler AJ, Xia n g  Z, Clat w ort h y  M R et al. 2 0 0 8. Distinct  c ell -
s pe cific c o ntr ol  of a ut oi m m u nit y  a n d infe ctio n  b y Fc g RII b. J E x p Me d 2 0 5:8 8 3- 8 9 5.  
 
Carr ut hers M N, St o ne J H, D es h pa n de V, K h osr os ha hi  A. 2 0 1 2.  D e velo p me nt of a n I g G4 - R D 
res p o n der I n de x.  I nt J R he u m V olu me  2 0 1 2,  Article I D 2 5 9 4 0 8,  7 pa ges. 
 
Carr ut hers M N, T o pa zia n  M D, K h osr os ha hi  A, et al. 2 0 1 5. Rit u xi ma b  f or I g G4 -relate d dis e as e: a 
pr os pe ctive,  o pe n -la be l  tria l.  A n n R he u m  Dis 0:1-7,  d oi:1 0. 1 1 3 6/a n nr he u m dis - 2 0 1 4 -2 0 6 6 0 5.  
 
Car vajal Ale gria G, P oc har d P, P ers J O, C or ne c D. C o uld a bata c e pt dire ctly tar get e x pa n de d 
plas ma blasts  in  I g G4 -relate d dis e as e ? A n n R he u m Dis. 2 0 1 6  N o v; 7 5( 1 1):e 7 3. 
 
 
Cr o wle y J E, Sta da nlic k  J E, Ca m bier J C, Ca ncr o M P. 2 0 0 9. Fc g RII B sig nals  in hibit  B L y S sig nalin g 
a n d B C R-me diate d B L y S re c e pt or u p -re g ulatio n.  Blo o d  1 1 3:1 4 6 4-1 4 7 3.  
 
D es h pa n de V, Ze n Y, C ha n J K C, et al. 2 0 1 2.  C o ns e ns us state me nt o n t he pat h olo g y  of I g G4 - relate d 
dis e as e. M o der n P at h olo g y  2 5:1 1 8 1-1 1 9 2.  
 
H ort o n H M, Ber nett MJ, P o n g E, P eip p M,  K ar ki S, C h u S Y,  Ric har ds J O, V ostiar I, J o yc e P F, Re p p 
R, D esjarlais J R, Z h u k o vs k y  E A. 2 0 0 8.  P ote nt in  vitr o  a n d in  viv o  a ctivit y  of a n Fc e n gine ere d a nti -
C D 1 9 m o n oclo nal  a ntib o d y  a gainst ly m p h o ma  a n d le u ke mia.  Ca nc er Res. 6 8:8 0 4 9 -8 0 5 7.  
 
H ort o n H M, C h u S Y, Ortiz  E C, P o n g E, Ce mers ki S,  Le u n g I W et al. 2 0 1 1. A ntib o d y 
me diate d c oe n ga ge me nt of Fc g RII b a n d B c ell re c e pt or c o m ple x  s u p press es h u m oral 
i m m u nit y  in  s yste mic lu p us  er yt he matos us. J I m m u n ol  1 8 6:4 2 2 3 -4 2 3 3.  
 
I nter natio nal  C o nfere nc e  o n  H ar m o nis atio n  of  Te c h nic al  Re q uire me nts  f or  Re gistratio n  of 
P har ma c e utic als f or  H u ma n  Us e. I C H  H ar m o nis e d  Tripartite  Guideline,  E 6:  Guideline  f or  Go o d 
Clinic al  Pra ctic e ( C P M P/I C H/ 1 3 5/ 9 5), J a n uar y 1 9 9 7.  
 
K a mis a w a T, F u nata N, H a yas hi Y et al. 2 0 0 3. A ne w clinic o pat h olo gic al  e ntit y  of I g G4 - relate d 
a ut oi m m u ne  dis e as e.  J Gastr oe nter ol 3 8:9 8 2-9 8 4.  
 
K a mis a w a T, Ze n Y, Pillai  S, St o ne  J H. 2 0 1 4. I g G4 -relate d dis e as e. La nc et 
htt p:// d x. d oi. or g/ 1 0. 1 0 1 6/ S 0 1 4 0 -6 7 3 6  ( 1 4) 6 0 7 2 0-0.  
 
K h osr os ha hi  A, Bloc h  D B, D es h pa n de V, St o ne J H. 2 0 1 0. Rit u xi ma b  t hera p y le a ds t o ra pid de cline 
of s er u m I g G4  le vels  a n d pr o m pt  clinic al  i m pr o ve me nt  in  I g G4 -relate d dis e as e. 
Art hri tis  R he u mat ol  6 2:1 7 5 5-1 7 6 2.  


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 4 5  of 
 
 
 
 
K h osr os ha hi  A, Walla c e Z S, Cr o w e J L, A ka miz u  T,  A z u mi  A, Carr ut hers M N, C hari S, D ella - T orre 
E, Fr ullo ni  L, Got o H, H art P, K a mis a w a T, K a w a S, K a w a n o M, Ki m M H, K o da ma Y, K u b ota K, 
Lerc h M M, L o hr  M, Mas a ki Y, Mats ui S,  Mi m ori  T, N a ka m ura, N a ka za w a T, O hara A, O ka za ki K, 
R y u J H, Sa e ki T, Sc hleinitz  N, S hi mats u  A, S hi m os e ga w a T, Ta ka has hi H, Ta ka hira M, Ta na ka A, 
T o pa zia n  M,  U me hara H, We bster GJ, Witzig  T, Y a ma m ot o M, Z ha n g  W, C hiba T,  a n d St o ne J H. 
2 0 1 5.  I nter natio nal  C o ns e ns u s Guida nc e  State me nt o n t he Ma na ge me nt a n d Tre at me nt of I g G4-
Relate d Dis e as e. Art hritis  R he u mat ol  6 7:1 6 8 8 -1 6 9 9.  
 
Mats u ba yas hi H, F ur u ka w a H, Ma e da A, Mats u na ga K et al. 2 0 0 9.  Us ef ulness of p ositr o n 
e missio n  t o m o gra p h y  in  t he e valuatio n  of distrib utio n  a n d a ctivit y  of s yste mic lesio ns ass ociate d 
wit h  a ut oi m m u ne  pa ncre atitis. P a ncre at olo g y 9:6 9 4 -6 9 9.  
 
Matt o o H, Ma haja n V S, D ella T orre E, Se kiga mi  Y, Walla c e Z S, Carr ut hers M, D ella T orre E, 
St o ne J H, Pillai  S. 2 0 1 4.  D e n o v o olig oclo nal  e x pa nsio ns  of circ ulatin g  plas ma blasts  in  a ctive a n d 
rela psin g  I g G4-relate d  dis e as e. J o ur nal  of Aller g y  & Clinic al  I m m u n olo g y  1 3 4( 3):6 7 9-8 7.  
 
Matt o o H, Ma haja n V, Ma e hara T, D es h pa n de V, D ella -T orre E, Walla c e Z, K ulik o va  M, Drijvers J, 
Carr ut hers M,  St o ne J R, St o ne J H, Pillai  S.  Clo nal  e x pa nsio n  of  C D 4( +) c yt ot o xic  T ly m p h oc ytes  in 
patie nts wit h  I g G4 -relate d  dis e as e.  J Aller g y  Clin  I m m u n ol.  2 0 1 6  Se p; 1 3 8( 3):8 2 5-8 3 8.  
 
Mc Ga ha T L, S orre ntin o  B, Ra vetc h J V. 2 0 0 5. Rest oratio n  of t olera nc e in  lu p us  b y  tar gete d 
in hibit or y  re c e pt or e x pressio n. Scie nc e 3 0 7:5 9 0-3.  
 
Mc H or ne y C A, Ware J E, L u J F R, S her b o ur ne  C D. 1 9 9 4. T he M O S 3 6 -ite m  s h ort-f or m  he alt h 
s ur ve y ( S F-3 6):  III. Tests of data q ualit y,  s c alin g  ass u m ptio ns,  a n d relia bilit y  a cr oss divers e 
patie nt  gr o u ps. Me dic al  Care 3 2:4 0 -6 6.  
 
Me e ker T C, Miller  R A, Lin k  M P, Bin dl  J, War n ke R, Le v y R. 1 9 8 4.  A u niq ue  h u ma n B 
ly m p h oc yte  a ntige n  define d b y  a m o n oclo nal  a ntib o d y.  H y brid o ma  3( 4):3 0 5-3 2 0.  
 
N a dler L M, A n ders o n K C, Marti  G,  Bates M, P ar k E, D ale y J F, et al. 1 9 8 3.  B 4, a h u ma n B 
ly m p h oc yte-ass ocia te d  a ntige n  e x press e d o n n or mal,  mit o ge n-a ctivate d,  a n d malig na nt  B 
ly m p h oc ytes.  J I m m u n ol  1 3 1:2 4 4-2 5 0.  
 
Ni m merja h n  F, Ra vetc h J V. 2 0 0 8. Fc g re c e pt ors as re g ulat ors of i m m u ne  res p o ns es. N at Re v 
I m m u n ol  8:3 4-4 7.  
 
Reff M E, Car ner K, C ha m bers K S, C hin n P C, Le o nar d J E, Ra a b R, N e w ma n R A, H a n na N, 
A n ders o n D R. 1 9 9 4. D e pletio n  of B Cells  I n Viv o  b y a C hi meric  M o us e H u ma n M o n oclo nal 
A ntib o d y  t o C D 2 0. Blo o d  8 3:4 3 5 -4 4 5.  
 
Sa m ps o n H A, M u n oz -F urlo n g  A, Ca m p bell  R L, A d kins o n  N F, B oc k S A, Bra n u m A, et al. 2 0 0 6. 
Se c o n d s y m p osiu m  o n  t he definitio n  a n d ma na ge me nt of a na p h yla xis:  S u m mar y  re p ort — Se c o n d 
N atio nal  I nstit ute  of Aller g y  a n d I nfe ctio us  Dis e as e/ F o o d Aller g y  a n d A na p h yla xis  N et w or k 
s y m p osiu m.  J Aller g y  Clin  I m m u n ol  1 1 7:3 9 1-7.  
 
S mit h  K G, Clat w ort h y  M R. 2 0 1 0.  Fc ga m ma RII B in  a ut oi m m u nit y  a n d infe ctio n: 
e v olutio nar y  a n d t hera pe utic i m plic atio ns.  N at ure Re v I m m u n ol  1 0:3 2 8 -3 4 3.  


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 4 6  of 
 
 
 
 
 
St o ne J H, H off ma n G S,  Mer kel  P A, Min  YI, U hlfelder M L,  H ell ma n n  D B, S pe c ks U, Alle n  N B, 
S piera R F, Cala bres e L H, Wigle y  F M, D a vis J C, Maide n N, V a le nte R M, Niles J L, F ye K H, 
Mc C u ne J W, St. Clair  E W, L u q ma ni  R A. 2 0 0 1.  A dis e as e -s pe cific a ctivit y  in de x  f or We ge ner’s 
gra n ulo mat osis:  M o dific atio n  of t he Bir min g ha m  V as c ulitis  A ctivit y  Sc ore.  
I nter natio nal  N et w or k f or t he St u d y  of t he S yste mic  V as c ulitides (I N S S Y S). Art hritis 
R he u mat ol  4 4:  9 1 2 -9 2 0.  
 
St o ne J H, Mer kel P A, S piera R et al. 2 0 1 0. Rit u xi ma b  vers us c yclo p h os p ha mide  f or A N C A - 
ass ociate d vas c ulitis.  N EJ M 3 6 3:2 2 1-2 3 2.  
 
St o ne J H, Ze n Y, D es h pa n de V. 2 0 1 2.  I g G4 -relate d dis e as e. N E n gl  J Me d 3 6 6:5 3 9-5 5 1.  
 
Taras e n k o T, D e a n J A, B olla n d  S. 2 0 0 7.  Fc g RII B as a m o d ulat or  of a ut oi m m u ne  dis e as e 
s us c e ptibilit y.  A ut oi m m u nit y  4 0:4 0 9-1 7.  
 
U c hida K, Mas a m u ne A, S hi m os e ga w a T, O ka za ki.  2 0 1 2. Pre vale nc e of I g G4 -relate d dis e as e in 
J a pa n bas e d o n natio n wide  s ur ve y in  2 0 0 9.  I nt J R he u m V olu me,  Article I D 3 5 8 3 7 1,  5 pa ges.  
 
U niz o n y  S H, D as g u pta B,  Fis hele va E,  R o w ell  L, Sc hett G,  S piera  R, Z w erina J, H arari O, a n d 
St o ne J H. 2 0 1 3. D esig n  of t he t ociliz u ma b  in  gia nt  c ell  arteritis  trial. I nt J of R he u m. V olu me 
2 0 1 3,  Article I D 9 1 2 5 6 2,  1 0 pa ges.  
 
va n Eltere n,  P. H. 1 9 6 0. " O n t he c o m binatio n  of in de pe n de nt  t w o -s a m ple tests of Wilc o x o n,"  B ulletin 
of t he I nter natio nal  Statistic al  I nstit ute,  3 7,  3 5 1 -3 6 1.  
 
Walla c e Z S, Matt o o H, Carr ut hers M et al. 2 0 1 4. Plas ma blasts as a bio mar ker f or I g G4 - relate d 
dis e as e, in de pe n de nt  of s er u m I g G4 c o nc e ntratio ns. A n n R he u m Dis  
d oi:  1 0. 1 1 3 6/a n nr he u m dis -2 0 1 4 -2 0 5 2 3 3  [ E p u b a he a d of print].  
 
Walla c e  Z S,  D es h pa n de V,  Matt o o  H,  Ma haja n V S,  K ulik o va  M,  Pillai  S,  St o ne  J H. 2 0 1 5.  I g G4 -
relate d dis e as e: Bas eline clinic al  a n d la b orat or y fe at ures in 1 2 5 s u bje cts wit h bio ps y- pr o ve n dis e as e. 
Art hritis  R he u mat ol  6 7:2 4 6 6 -2 4 7 5.  
 
Walla c e Z S, K h osr os ha hi  A, Carr ut hers M, P er u gin o  C, C h oi  H, et al. 2 0 1 6.  A n I nter natio nal,  M ulti -
S pe cialt y  V alidatio n  St u d y  of t he I g G4 -Relate d  Dis e as e Res p o n der I n de x. Art hritis  R he u mat ol. 2 0 1 6; 
6 8 (s u p pl  1 0),  A bstra ct 9 4 1.  
 
Ware J E, S her b o ur ne  C D. 1 9 9 2. T he M O S 3 6 -ite m  s h ort-f or m  he alt h s ur ve y ( S F-3 6). 
Me dic al  Care 3 0:4 7 3 -4 8 3.  
 
We c hsler M E, A k ut h ota  P, J a y ne D, K h o ur y  P, Klio n  A, La n gf or d C A, et al. 2 0 1 7.  Me p oliz u ma b 
or pla c e b o f or e osin o p hilic  gra n ulo mat osis  wit h p olya n giitis.  N E n gl  J Me d. 3 7 6:1 9 2 1 -1 9 3 2.  
 
W M A D e cla ratio n of H elsin ki  ( 1 8t h W M A Ge neral Ass e m bly  1 9 6 4),  re vis e d at 5 9t h W orld 
Me dic al  Ass ociatio n  Ge neral Ass e m bly Se o ul,  O ct o ber 2 0 0 8.  


Brist ol  M yers S q uib b  Pr ot oc ol: 
A batace pt  in  I g G 4 -R D  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Pa ge 4 7  of 
 
 
 
 
Y a ma m ot o M, Ta ka has hi H, S hin o m ura  Y. 2 0 1 4.  Me c ha nis ms a n d ass ess me nt of I g G4 - relate d 
dis e as e: less o ns f or t he r he u mat olo gist.  N at Re v R he u mat ol  1 0:1 4 8 -1 5 9.  
 
Y a ma m ot o M, Ta ka has hi H, Ta ka n o K, S hi miz u  Y, Sa k urai  N, S uz u ki  C, N ais hir o  Y, Y aji ma  H, 
A w a ka w a T, Hi mi T, N a kas e H. Effic a c y of a bata c e pt f or I g G4 -relate d dis e as e o ver 8 m o nt hs.  A n n 
R he u m Dis. 2 0 1 6  A u g; 7 5( 8):1 5 7 6 -8.  


Pa ge 5 8  of 6 6  
Brist ol  M yers  S q uib b  
Pr ot oc ol  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
1 7  
A P P E N DI C E S 
Effic ac y  Ass ess me nts  
A. I g G 4-R D R e s po n de r  I n de x  (I g G 4 -R D RI)
T he  I g G 4 -R D  RI  is  a  t o ol  designe d  t o  detect  c ha nge  in  disease  activit y  a nd  ide ntif y 
i mpr o ve me nt s a nd w orse ning  in t he sa me or differe nt  or ga n s yste ms ( mo difie d after C arr ut her s ,  
2 0 1 2). 
At eac h assess me nt,  t he p hysicia n  e nters  a 0 -3 sc ore after  t he  or ga n/site  liste d  wit h; 
0 = N or mal  or res olve d 
1 = I mpr o ve d  b ut  still  prese nt 
2 = N e w  or rec urre nt disease  activit y w hile  s ubject is off treat me nt,  or unc ha nge d  fr o m pre vio us 
visit *  
3 = W orse ne d  or ne w  disease  ma nife statio n  des pite  treat me nt 
* U nc ha nge d  fr o m  pre vio us  visit  will  ofte n  refer  t o disease  ma nifestati o ns  t hat  re q uire  follo w -
up i ma gi n g  t o assess acc urately.
T he  sec o nd c olu mn  is  use d t o rec or d s y mpt o matic  disease;  yes = Y,  no = N.
T he  t hir d  c olu mn  rec or ds w het her  t here  is ur ge nt  disease  in  t hat  site;  yes = Y,  no = N.
Da ma ge  in  t he  or ga n/site  is  rec or de d  in  t he  fo urt h  c olu mn;  yes = Y,  no = N.
T he  fift h  c olu mn  rec or ds  w het her  da ma ge  in  t he  or ga n/site  is  s y mpt o matic ;  yes = Y,  no = N.  
P hysicia n   Glo bal Assess me nt   of disease  activit y is de note d  o n a 1 0 0 m m  line as c o vere d  belo w. 


Pa ge 5 9  of 6 6  
Brist ol  M yers  S q uib b  
Pr ot oc ol  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
I g G 4-R D R e s p o n d er I n d e x ( V er si o n 2 5 J ul y 2 0 1 6)  
S c ori n g R ul e s  
S c ori n g  r ef er s  t o m a nif e st ati o n s  of  di s e a s e  a cti vit y pr e s e nt  i n  t h e l a st 2 8  d a y s 
S c ori n g:  0  
N or m al  or r e s ol v e d 
I m pr o ve d  b ut  still pr e s e nt 
N e w  / R e c urr e n c e  w hil e  p ati e nt  i s off  tr e at m e nt or  u n c h a n g e d  fr o m pr e vi o u s  
vi sit*  
W or s e n e d  or n e w  di s e a s e  m a nif e st ati o n  d e s pit e  tr e at m e nt  
* U n c h a n g e d  fr o m  pr e vi o u s  vi sit will  oft e n  r ef er  t o di s e a s e  m a nif e st ati o n s  t h at
r e q uir e f oll o w-u p  i m a gi n g  t o a s s e s s a c c ur at el y
D efi niti o n s  
Or g a n/ Sit e  s c or e: T h e  o ver all  l e vel  of  I g G 4 -R D a cti vit y wit hi n  a s p e cifi c  or g a n  s y st e m  
S y m pt o m ati c:  I s t h e di s e a s e  m a nif e st ati o n  i n a p arti c ul ar  or g a n  s y st e m  s y m pt o m ati c ?  ( Y = 
y e s; N =  n o)  
Ur g e nt  di s e a s e: Di s e a s e  t h at r e q uir e s  tr e at m e nt  i m m e di at el y t o pr e ve nt  s eri o u s or g a n 
d y sf u n cti o n  ( Y = y e s; N = n o)  ( Pr e s e n c e  of ur g e nt  di s e a s e wit hi n  a n or g a n  l e a d s  t o 
D O U B LI N G of t h at or g a n  s y st e m s c or e ) 
D a m a g e:  Or g a n  d y sf u n cti o n  t h at h a s  o c c urr e d  a s  a r es ult  of  I g G 4-R D  a n d  i s c o n si d er e d 
p er m a n e nt  ( Y =  y e s;  N  =  n o)  


Pa ge 6 0  of 6 6  
Brist ol  M yers  S q uib b  
Pr ot oc ol  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
 
 
 
 
 
T otal  activit y  sc ore is calc ulate d  as give n  in  t he  lo wer  left  ha nd  c or ner  = 
S u m  of  or ga n  sc ores  (a ny  t hat  are ur ge nt  are  multip lie d  b y  2).  


Pa ge 6 1  of 6 6  
Brist ol  M yers  S q uib b  
Pr ot oc ol  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
Gl o b a l A sse ssm e nt  o f Di se a se Acti vit y  ( V A S) 
B. P hysici a n’s  Gl o bal  Ass ess me nt of Dis e as e Acti vit y ( 1 0 0 m m- V A S)
Place  a mar k  o n t he line  belo w  t o indicate  disease  activit y  (inde pe nde nt  of  t he s ubject’s  self - 
assess me nt): 
V A S P h y si ci a n Gl o b al  A s s e s s m e nt of  Di s e a s e  A cti v ity = 
m m  
C. S u bje ct’s Gl o bal Ass ess me nt of Dis e as e  Acti vit y  ( V A S)
S u bje ct’s  Gl o bal  Ass ess me nt of Dis e as e Acti vit y ( 1 0 0  m m -V A S)  
Pla ce  a mar k  o n t he line  belo w  t o indicate  disease  activit y: 
V A S S u bj e ct  Gl o b al  A s s e s s m e nt of  Di s e a s e  A cti v ity = 
m m  
Ver y  G o o d  
Ver y  Ba d  
Ver y  G o o d  
Ver y  Ba d  


Pa ge 6 2  of 6 6  
Brist ol  M yers  S q uib b  
Pr ot oc ol  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
D. S F -3 6 He alt h S urve y
S F -3 6 is  a  set  of  ge neric,  c o here nt,  a nd  easily  a d ministere d  q ualit y -of-life  meas ures.  Thes e 
meas ures  rely  up o n  patie nt  self -re p orti n g  a nd  are no w  widely utilize d  for  r o utine  mo nit or i n g 
a nd assess me nt  of care o utc o mes  in  a d ult  patie nts.  The  3 6 -Ite m Healt h  S ur ve y  was de velo pe d 
at R A N D as part of t he  Me dical  O utc o mes  St ud y  ( Ware et al.  1 9 9 2, Mc H or ne y  et al. 1 9 9 4).  
3 6 -Ite m S h o rt F o r m S ur ve y I nstr u me nt ( S F-3 6) 
R A N D 3 6 -Ite m He alt h S ur ve y 1. 0 Q uesti o n n aire Ite ms 
C ho ose o ne o ptio n  for  eac h q uestio nnaire  ite m. 
1. I n ge neral,  w o uld  yo u  sa y  yo ur  healt h  is:
1 - E xcelle nt
2 - Ver y  go o d
3 - G o o d
4  - Fair
5  – P o or
2. C o mpare d  t o o ne y ear  a go,  ho w  w o uld  yo u  rate  yo ur  healt h  in  ge neral  no w?
1 - M uc h  better  no w  t ha n  o ne  year  a go
2 - S o me w hat  better no w  t ha n  o ne  year a go
3 - A b o ut  t he  sa me
4 - S o me w hat  w orse no w  t ha n  o ne year  a go
5 - M uc h  w orse  no w  t ha n  o ne  year  a go
T he  follo w i n g  ite ms are a b o ut  activitie s  yo u  might  d o d uring  a t ypical  da y.  D oes  yo ur  healt h 
no w  li mit  yo u  in  t hese  activities?  If  s o, ho w  muc h?  
3. Vigor o us  activities,  s uc h  as r unni n g,  lifti n g  hea vy  o bjects,  participati n g  in  stre nuo us  s p orts
1) Yes,  li mit e d  a lot   2) Yes,  li mite d  a litt le   3) N o, not  li mite d  at all 
4. M o derate activities,  s uc h  as mo vin g  a ta ble,  p us hin g  a vac uu m  clea ner,  b o wling,  or pla yin g
golf
1) Yes,  li mite d  a lot   2) Yes,  li mite d  a little   3) N o, not  li mite d  at  all 
5. Lifti n g  or  carr ying  gr oceries
1) Yes,  li mite d  a lot   2) Yes,  li mite d  a little   3) N o, not  li mite d  at  all 


Pa ge 6 3  of 6 6  
Brist ol  M yers  S q uib b  
Pr ot oc ol  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
6. C li mbi n g  se veral  flig ht s  of  stairs
1) Yes,  li mite d  a lot   2) Yes,  li mite d  a little   3) N o, not  li mite d  at  all 
7. C li mbi n g  o ne  flig ht   of stairs
1) Yes,  li mite d  a lot   2) Yes,  li mite d  a little   3) N o, not  li mite d  at  all 
8. Be nding,  k neelin g,  or  st o o ping
1) Yes,  li mite d  a lot   2) Yes,  li mite d  a little   3) N o, not  li mite d  at  all 
9. Walking  more  t ha n  a  mile
1) Yes,  li mite d  a lot   2) Yes,  li mite d  a little   3) N o, not  li mite d  at all 
1 0. Walking  se veral   bloc ks
1) Yes,  li mit e d  a lot   2) Yes,  li mite d  a litt le   3) N o, not  li mite d  at  all  
1 1. Walking  o ne  bloc k
1) Yes,  li mit e d  a lot   2) Yes,  li mite d  a litt le   3) N o, not  li mite d  at  all  
1 2. Bat hin g  or dressing  yo urself
1) Yes,  li mit e d  a lot   2) Yes,  li mite d  a litt le   3) N o, not  li mite d  at  all 
D uring  t he  past 4 wee ks, ha ve  yo u  ha d a ny  of  t he follo wi n g  pr o ble ms  wit h  yo ur  w or k or ot her 
re gular  daily  activities  as a res ult  of yo ur  p hysical  healt h? 
1 3. C ut  d o w n  t he  a mo unt  of  ti me  yo u  s pe nt  o n  w or k  or ot her  activities
1) Yes  2) N o
1 4. Acc o mplis he d  less  t ha n  yo u  w o uld  like
1) Yes  2) N o
1 5. Were li mite d  in  t he  kind  of  w or k or ot her  activities
1) Yes  2) N o
1 6. Ha d diffic ult y  perfor mi n g  t he  w or k or ot her  activities  (for  e xa mple,  it  t o o k e xtra  effort)
1) Yes  2) N o
D uring t he  past 4 wee ks, ha ve  yo u  ha d  a ny  of t he  follo wi n g  pr o ble ms  wit h  yo ur  w or k or ot her 
re gular  daily  activities  as  a  res ult  of  a ny  e motio nal  pr o ble ms  (s uc h  as  feelin g  de presse d  or 
a nxio us)? 
1 7. C ut  d o w n  t he  a mo unt  of  ti me  yo u  s pe nt  o n  w or k  or ot her  activities
1) Yes  2) N o
1 8. Acc o mplis he d  less  t ha n  yo u  w o uld  like


Pa ge 6 4  of 6 6  
Brist ol  M yers  S q uib b  
Pr ot oc ol  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
1) Yes  2) N o  
1 9. Did n't  d o w or k or ot her activities  as carefull y  as us ual
1) Yes  2) N o
2 0. D uring  t he  past  4 wee ks,  t o w hat  e xte nt  has  yo ur  p hysical  healt h  or e motio na l  pr o ble ms
interfere d  wit h  yo ur nor mal  s ocial  activit ies  wit h  fa mil y,  frie nds,  neighb ors,  or  gr o ups?
1 - N ot at  all 
2 - Slight l y
3 - M o derately
4 - Q uite  a bit
5 - E xtre mel y
2 1. H o w  muc h  b o dily  pain  ha ve  yo u  ha d  d uring  t he  past  4  wee ks?
1 - N o ne
2 - Ver y  mild
3 - Mild
4  - M o derate
5  - Se vere
6  - Ver y  se vere
2 2. D uring  t he  past  4 wee ks,  ho w  muc h  did  pain  interfere  wit h  yo ur  nor mal  w or k  (includ i n g
b ot h w or k o utside  t he ho me  a nd  ho use w or k)?
1 - N ot at  all 
2 - A  little  bit
3 - M o derately
4 - Q uite  a bit
5 - E xtre mel y
T hese  q uestio ns  are a b o ut  ho w  yo u  feel  a nd  ho w  t hings  ha ve  bee n  wit h  yo u  d uring  t he  past  4 
wee ks. F or eac h  q uestio n,  please  give  t he  o ne  a ns wer  t hat  c o mes  closest  t o t he  wa y  yo u  ha ve 
bee n feeli n g.  
H o w muc h  of t he  ti me  d uring  t he past 4 wee ks...  


Pa ge 6 5  of 6 6  
Brist ol  M yers  S q uib b  
Pr ot oc ol  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
 
 
 
2 3.  Did  yo u  feel  full  of  pe p? 
1) All  of  t he  ti me  2) M ost  of  t he  ti me  3) A  go o d  bit  of  t he  ti me  4) S o me  of  t he  ti me  5) A  little   
of t he  ti me   6) N o ne of  t he  ti me 
2 4.  Ha ve  yo u  bee n  a ver y  ner vo us   pers o n? 
1) All  of  t he  ti me  2) M ost  of  t he  ti me  3) A  go o d  bit  of  t he  ti me  4) S o me  of  t he  ti me  5) A  little   
of t he  ti me   6) N o ne of  t he  ti me 
2 5.  Ha ve  yo u  felt  s o d o w n  in  t he  d u mps  t hat  not hin g  c o uld  c heer  yo u  up?  
1) All  of  t he  ti me  2) M ost  of  t he  ti me  3) A  go o d  bit  of  t he  ti me  4) S o me  of  t he  ti me  5) A  little   
of t he  ti me   6) N o ne of  t he  ti me 
2 6.  Ha ve  yo u  felt  cal m  a nd  peaceful?  
1) All  of  t he  ti me  2) M ost  of  t he  ti me  3) A  go o d  bit  of  t he  ti me  4) S o me  of  t he  ti me  5) A  little   
of t he  ti me   6) N o ne of  t he  ti me 
2 7.  Did  yo u  ha ve  a lot  of  e ner gy? 
1) All  of  t he  ti me  2) M ost  of  t he  ti me  3) A  go o d  bit  of  t he  ti me  4) S o me  of  t he  ti me  5) A  little    
of t he  ti me   6) N o ne of  t he  ti me 
2 8.  Ha ve  yo u  felt  d o w nhearte d  a nd  blue?  
1) All  of  t he  ti me  2) M ost  of  t he  ti me  3) A  go o d  bit  of  t he  ti me  4) S o me  of  t he  ti me  5) A  little   
of t he  ti me   6) N o ne of  t he  ti me 
2 9.  Did  yo u  feel  w or n  o ut?  
1) All  of  t he  ti me  2) M ost  of  t he  ti me  3) A  go o d  bit  of  t he  ti me  4) S o me  of  t he  ti me  5) A  little   
of t he  ti me   6) N o ne of  t he  ti me 
3 0.  Ha ve  yo u  bee n a ha p p y   pers o n? 
1) All  of  t he  ti me  2) M ost  of  t he  ti me  3) A  go o d  bit  of  t he  ti me  4) S o me  of  t he  ti me  5) A  little   
of t he  ti me   6) N o ne of  t he  ti me 
3 1.  Did  yo u  feel   tire d? 
1) All  of  t he  ti me  2) M ost  of  t he  ti me  3) A  go o d  bit  of  t he  ti me  4) S o me  of  t he  ti me  5) A  little   
of t he  ti me   6) N o ne of  t he  ti me 
 
 
3 2.  D uring  t he  past  4 wee ks,  ho w  muc h  of  t he  ti me  has  yo ur  p hysical  healt h  or  e motio na l 
pr o ble ms  interfere d  wit h  yo ur  s ocial  ac tivit ie s  (like  visit i n g  wit h  frie nds,  relatives, etc.)? 
1  - All  of  t he  ti me 
2  - M ost of t he ti me   3 
- S o me  of  t he  ti me  4 - 
A  little  of  t he  ti me 


Pa ge 6 6  of 6 6  
Brist ol  M yers  S q uib b  
Pr ot oc ol  
C O N FI D E N TI A L  
Fe br uar y  2 0 1 8  
 
 
 
5 - N o ne  of  t he  ti me  
 
 
H o w T R U E  or F A L S E  is  eac h of  t he follo wi n g  state me nts  for  yo u.  
3 3.  I see m  t o get sic k  a little  easier  t ha n  ot her   pe o ple 
1) Definitel y  tr ue   2) M ostly  tr ue   3) D o n't  k no w   4) M ostly  false   5) Definitel y  false 
3 4.  I a m  as healt hy  as  a nyb o d y  I k no w 
1) Definitel y  tr ue   2) M ostly  tr ue   3) D o n't  k no w   4) M ostly  false   5) Definitel y  false 
3 5.  I e xpect  my  healt h  t o get w orse  
1) Definitel y  tr ue   2) M ostly  tr ue   3) D o n't  k no w   4) M ostly  false   5) Definitel y  false 
3 6.  M y  healt h  is  e xcelle nt 
1) Definitel y  tr ue   2) M ostly  tr ue   3) D o n't  k no w  4) M ostly  false   5) Definitel y false 


1  
 
D at e  
 
Pill ai  I D  
 
 
 
 
E.  I g G 4-R el at e d  Dis e as e  S y m pt o m  Distr ess I n d ex  
 
 
 
S ur v e y  I nstr ucti o ns 
 
1.  T his s h o ul d r efl ect a n y s y m pt o ms y o u m ay h av e ex p eri e nc e d o v er t h e l ast 3 0 d ays. F or e ac h  s y m pt o m, c h o os e h o w  oft e n, if at all,  
y o u ex p eri e nc e   t h e s y m pt o m. 
2.  If  pr es e nt,  c h o os e h o w  m uc h t h e s y m pt o m c a us es  y o u distr ess.  
3.  Of all t h e s y m pt o ms y o u i d e ntify o n t his s ur v ey, c h o os e u p t o t hr e e w hic h y o u w o ul d s ay ar e t h e m ost b ot h ers o m e, s ev er e, or 
i m p ort a nt t o y o u. R a n k t h es e t hr e e b y m ar ki n g a 1 f or t h e m ost i m p ort a nt, 2 as t h e n ext m ost i m p orta nt, a n d 3 as t h e l e ast 
i m p ort a nt of t h es e  t hr e e. 
4.  D o n ot c alc ul at e  t h e sc or e.  T his  will b e d o n e  b y y o ur  p h ysici a n.  
 
Ex a m pl e:  
 
 
1.) Fr e q u e nc y 
( C h ec k o n e) 
2.) H o w m uc h distr ess d o es t h e s y m pt o m c a us e 
y o u ?   ( C h ec k o n e)  
Sc or e  
S y m pt o m  
N e v er  
 
 
( 0) 
A f e w 
d a ys a 
m o nt h 
( 1) 
A f e w 
d a ys a 
w e e k 
( 2) 
E v er y 
D a y  
 
( 3) 
N o n e  
 
 
( 0) 
A littl e bit 
( 1) 
S o m e - 
w h at  
 
( 2) 
Q uit e a 
bit  
 
( 3) 
V er y 
m uc h  
 
( 4) 
 
S w elli n g of s ali v ar y gl a n ds 
u n d er  or si d e of t h e j a w  
 
 
 
X  
 
 
X  
 
 
8  
Dr y m o ut h  
X  
 
 
 
 
 
 
 
 
 
S w elli n g  ar o u n d  t h e ey es  
X  
 
 
 
 
 
 
 
 
 
C h a n g e  i n visi o n  
 
 
X  
 
 
X  
 
 
 
3  


2  
 
I g G 4-R el at e d Dis e as e S y m pt o m Distr ess I n d e x  
 
 
 
 
Fr e q u e nc y  
( C h ec k o n e) 
H o w m uc h   distr ess d o es t h e s y m pt o mc a us e y o u ?  
( C h ec k o n e) 
Sc or e  
S y m pt o m  
N e v er  
 
 
 
( 0) 
A f e w 
d ays a 
m o nt h  
 
( 1) 
A f e w 
d ays a 
w e e k  
 
( 2) 
E v er y 
D ay  
 
 
( 3) 
N o n e  
 
 
 
( 0) 
A littl e 
bit  
 
 
( 1) 
S o m e - 
w h at  
 
 
( 2) 
Q uit e a 
bit  
 
 
( 3) 
V er y 
m uc h  
 
 
( 4) 
 
S ali v ar y Gl a n ds  
 
 
 
 
 
 
 
 
 
 
S w elli ng of s ali v ary gl a n ds u n d er  or 
si d e of t h e j a w 
 
 
 
 
 
 
 
 
 
 
Dry m o ut h  
 
 
 
 
 
 
 
 
 
 
Or bit ( E y e Ar e a)  
 
 
 
 
 
 
 
 
 
 
S w elli ng ar o u n d   t h e e y es  
 
 
 
 
 
 
 
 
 
 
C h a ng e i n visi o n  
 
 
 
 
 
 
 
 
 
 
Dry e y es  
 
 
 
 
 
 
 
 
 
 
Ot h er H e a d a n d N ec k  
 
 
 
 
 
 
 
 
 
 
Si n us c o ng esti o n/ dis c h arg e  
 
 
 
 
 
 
 
 
 
 
Si n us p ai n 
 
 
 
 
 
 
 
 
 
 
L oss of s e ns e of s mell  
 
 
 
 
 
 
 
 
 
 
C h est  
 
 
 
 
 
 
 
 
 
 
S h ort n ess   of br e at h  
 
 
 
 
 
 
 
 
 
 
C o ug h  
 
 
 
 
 
 
 
 
 
 
A b d o m e n  
 
 
 
 
 
 
 
 
 
 
P ai n i n t h e  a b d o me n  
 
 
 
 
 
 
 
 
 
 
L oss of a p p etit e 
 
 
 
 
 
 
 
 
 
 
N a us e a a n d/ or  v o miti ng  
 
 
 
 
 
 
 
 
 
 
L o os e st o ol a n d/ or  di arr h e a  
 
 
 
 
 
 
 
 
 
 


3  
 
 
Fr e q u e nc y 
( C h ec k o n e) 
H o w m uc h  distr ess d o es t h e s y m pt o mc a us e y o u ? 
( C h ec k o n e) 
Sc or e  
S y m pt o m  
N e v er  
 
 
( 0) 
A f e w 
d ays a 
m o nt h 
( 1) 
A f e w 
d ays a 
w e e k 
( 2) 
E v er y 
D ay  
 
( 3) 
N o n e  
 
 
( 0) 
A littl e 
bit  
 
( 1) 
S o m e - 
w h at  
 
( 2) 
Q uit e a 
bit  
 
( 3) 
V er y 
m uc h  
 
( 4) 
 
G e nit o uri n ar y ( m al e o nl y)  
 
 
 
 
 
 
 
 
 
 
P ai n i n t h e  gr oi n  
 
 
 
 
 
 
 
 
 
 
Diffic ulty st arti ng a uri n ary 
str e a m 
 
 
 
 
 
 
 
 
 
 
Uri n ati ng fr e q u e ntl y  
 
 
 
 
 
 
 
 
 
 
W a ki ng u p at ni g ht t o uri n at e  
 
 
 
 
 
 
 
 
 
 
S ki n a n d E xtr e miti es  
 
 
 
 
 
 
 
 
 
 
Y ell o wi ng of t h e s ki n 
 
 
 
 
 
 
 
 
 
 
S w elli ng of t h e l o w er l e gs  
 
 
 
 
 
 
 
 
 
 
Ot h er S y m pt o ms  
 
 
 
 
 
 
 
 
 
 
1.  
 
 
 
 
 
 
 
 
 
 
2.  
 
 
 
 
 
 
 
 
 
 
3.  
 
 
 
 
 
 
 
 
 
 
T ot al Sc or es  
 
 
 
 
 
 
 
 
 
 
Of all   t h e s y m pt o ms  list e d a b o v e,  w hic h t hr e e d o y o u  c o nsi d er  t o b e t h e m ost  b ot h ers o m e, s e v er e, or  i m p ort a nt  t o y o u ? 
1.  
 
2.  
 
3.  


4  
 
P ati e nt S ur v e y (S u bj ect  s h o ul d c o m pl et e  t his  f or m) 
 
 
I nstr ucti o ns:  Pl e as e r at e y o ur o v er all  h e alt h  r el at e d  t o y o ur I g G 4 -R el at e d  Dis e as e i n t h e p ast w e ek  b y s el ecti n g  a  
w h ol e n u m b er  b el o w, usi n g t h e f oll o wi n g sc al e:  1 = Extr e m el y  P o or a n d 1 0 =  Exc ell e nt . 
 
* H e alt h  pr o bl e ms  d u e t o a  dis e as e ot h er t h a n  I g G 4 -r el at e d  Dis e as e s h o ul d  n ot b e c o nsi d er e d  i n t his ev al u ati o n. 
  P A R TI CI P A N T  GL O B AL  A S S E S S M E N T  
 
T o d ay's  D at e:  |   
|  
|  - |   
|   
|  - |   
|   
|  
| _    |  ( M M-D D -Y Y Y Y)  
  O n a sc al e  of 1- 1 0, H o w w as y o ur o v er all  h e alt h i n t h e l ast  w e e k ?  
 
( Extr e m el y  P o or) 1  2 3 4 5 6 7  8 9 1 0  ( Exc ell e nt)  


F . T he  Gl uc oc ortic oi d  T o xicit y  I n de x  
c he c k if pre s e nt  
C o m p osite G TI  
Ite m Wei g ht 
S pe cific List  
B o dy  mas s  i n de x  
 
 
I mpr o ve me nt  in  B MI 
- 8 
Maj or increase  in 
B MI  
 
N o c ha nge  in  B MI  
0  
 
 
M o derate increase  in 
B MI  
2 1 
 
 
Maj or increase  in 
B MI  
3 6 
 
Gl uc os e t ole ra nce  
 
I mpr o ve me nt  in 
gluc ose  t olera nce  
- 8 
 
Dia betic  retino pat h y  
 
N o c ha nge  in  gluc ose 
t olera nce 
0 
 
Dia betic  ne p hr o pat hy  
 
W orse ning  of 
gluc ose  t olera nce  
3 2 
 
Dia betic  ne ur o pat hy  
 
W orse ning  of  
gluc ose  t olera nce 
des pite  treat me nt  
 
4 4 
 
Bl o o d  pre s s ure  
 
I mpr o ve me nt  in 
blo o d press ure  
- 1 0 
H yperte nsi ve  
e mer ge nc y 
 
 
N o c ha nge  in  blo o d 
press ure  
 
0 
P osterior  re versible 
e nce p halo pat h y 
s yndr o me 
 
W orse ning 
hyperte ns io n  
1 9 
 
 
W orse ning 
hyperte ns io n  des pite 
treat me nt 
 
4 4 
 
Li pi ds  
 
I mpr o ve me nt  in 
lipids 
- 9 
 
 
N o c ha nge  in  lipids 
0  
 
 
W orse ning  hyperlip id 
e mia 
1 0 
 
 
W orse ning  hyperlip id 
e mia  des pite 
treat me nt 
 
3 0 
 
B o ne  de ns it y  
 
I mpr o ve me nt  in  b o ne 
de nsit y 
- 1 
Maj or decrease in 
b o ne de nsit y 


 
N o c ha nge  in  b o ne 
de nsit y 
0 
I ns uffic ie nc y 
fract ure 
 
Decrease  in  b o ne 
de nsit y 
2 9 
 
Ste roi d  my o pat hy  
 
 
N o ster oid  myo pat hy  
0 
Se vere  
ster oid  myo pat hy 
 
Mild  
ster oid  myo pat hy 
9 
 
 
M o derate  
ster oid  myo pat hy  or 
greater  
 
6 3 
 
S ki n t o xicit y  
 
N o s kin  t o xicit y  
0  
Se vere  s kin  t o xicit y  
 
Mild  s kin  t o xicit y  
8  
 
 
M o derate s kin 
t o xicit y  or greater 
2 6 
 
N e uro ps yc hi atric  t o xicit y  
 
N o ne ur o ps yc hiatric 
s y mpt o ms 
0 
 
Ps yc hosis  
 
Mild 
ne ur o ps yc hia tr ic 
s y mpt o ms 
 
1 1 
 
 
G G -ind uce d  viole nce 
 
M o derate 
ne ur o ps yc hia tr ic 
s y mpt o ms  or greater 
 
7 4 
Ot her se vere 
ne ur o ps yc hia tr ic 
s y mpt o ms 
I nfe cti o n 
 
N o significa nt 
infect io n 
0 
 
Gra de 4 infectio n  
 
Oral/ va gi nal  ca ndidia 
sis  or unc o mplicate d 
zoster 
 
1 9 
 
 
Gra de 5 infectio n  
 
Gra de 3 infectio n  or  
greater  
9 3 
 
E n docri ne  
 
 
 
A dre nal  
ins ufficie nc y 
G astroi ntesti nal  
 
 
 
Perforatio n  
 
 
 
Pe ptic  ulcer  disease  
M us c ul os kelet al  
 
 
 
A vasc ular  necr osis  
 
 
 
Te nd o n  r upt ure  
Oc ul ar  


C e ntral  ser o us  
retino pat h y 
I ntra oc ular  press ure 
ele vatio n 
P osterior  s ubca ps ular  
cataract 
T ot al  
-3 6 t o 4 3 9