Clinical Trials in Ln

8/13/2019 Clinical Trials in Ln

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CLINICAL TRIALS IN LN02 January 201413:54

NIH TRIAL: compared three re!men" !n #5 pat!ent" $!th a mean "erum creat!n!ne o%appro&!mate'y 1(# to 2(0 m)d'(

A'' rece!*ed ora' predn!"o'one +e!nn!n at a do"e o% 0(5 m), per day and then taper!no*er a per!od o% month" to a'ternate-day ma!ntenance therapy %or contro' o% e&trarena'"ymptom" .m!n!mum do"e 0(25 m), e*ery other day/(

arameter" at 3yr"

Regimen A :I CConth'y & #20 pts

Regimen B:A 3 month'yI* CC %ortota' 24month"20 pts

Regimen C:I* methy'predn!"o'one 1 )mt" month'y 6 # do"e$!thout CC 25 pts

7ou+'!n o% "rcreat!n!ne

Lo$25 8

Lo$258

H!h48%

re'pa"e high Lo$

An e&tended cour"e o% pu'"e cyc'opho"pham!de !" more e%%ect!*e than # month" o% pu'"emethy'predn!"o'one !n pre"er*!n rena' %unct!on !n pat!ent" $!th "e*ere 'upu" nephr!t!"(Add!t!on o% a uarter'y ma!ntenance re!men to month'y pu'"e cyc'opho"pham!de reduce"the rate o% e&acer+at!on"(

pat!ent" $!th re'at!*e'y m!'d d!"ea"e ."erum creat!n!ne 91(3 m)dL 9115 m!cromo')L; and)orprote!n e&cret!on 91(0 )day/ had a %a*ora+'e prono"!"(


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2nd NIH tr!a' :


3/19

()) p(tientsrece!*ed* +(i), p-)ses &. /50 mg &. I meth,)p1e+nis&)&ne%o''o$ed+y ora' 'ucocort!co!d therapy at an !n!t!a' do"ae o%0'5 mg3g3+(, &. p1e+nis&)&ne.or eu!*a'ent/ .&1 4 ees( A do"ae o% 1 m),)day $a" a''o$ed !n cr!t!ca''y !''pat!ent" .tho"e $!th rena' !mpa!rment or "e*ere e&trarena' d!"ea"e/( A%ter 4 $ee,"='ucocort!co!d do"ae" $ere tapered by 2.5 mg of prednisolone (or equivalent)every 2 weeks( Lo$-do"e 'ucocort!co!d therapy 657/'5 mg &. p1e+nis&)&ne pe1 +(,(s m(int(ine+ (t )e(st -nti) m&nth *0 (.te1 in9)-si&n'

A!m m!n!m!e S o% CC( Random!ed pt" to 'o$ do"e CC .B 500 m CC +!$ee,'y 6 #month"/ *" NIH protoco'(A'' pt" rece!*ed predn!"o'one and AA %or ma!nta!nance( 2 $, a%ter 'a"t cyc do"e( 7o"e 2m),)dNI$ p1&t&9&): # motnh'y pu'"e 2 uarter'y7o"e adKu"ted to ma!nta!n nad!r TLC

In!t!a' do"e 0(5 )m2= then !ncrea"e +y 250 m to ach!e*e nad!r TLCA6 1500 m) pu'"ee"na : +a"ed on R& phy"!c!an dec!"!on(en!n rena' %'are" .!(e(= tho"e not meet!n the de%!n!t!on o% "e*ere %'are" "ee +e'o$;/ $eretreated $!th 'o$-do"e 'ucocort!co!d" .915 m o% predn!"o'one per day/ %or a 2-$ee, per!od=hydro&ych'orou!ne .# m),)day/= and)or non"tero!da' ant!!n%'ammatory dru" .NSAI7"/(A "e*ere rena' %'are $a" de%!ned a" 1 o% the %o''o$!n 3 %eature": 1en() imp(i1mentin91e(se in p1&tein-1i( &1 see1e s,stemi9 +ise(se'Ren() imp(i1ment$a" de%!ned a" an SL-re'ated !ncrea"e o% 338 !n the "erum creat!n!ne'e*e' $!th!n a 1-month per!od(

An in91e(se in p1&tein-1i($a" de%!ned a" the recurrence or appearance o% nephrot!c"yndrome .a'+um!nem!a G3(5 m)d' and prote!nur!a M3 m !n a 24-hour "amp'e/( In pat!ent"$!th 'o$-rade prote!nur!a at +a"e'!ne .M0(5 m +ut G1 m !n 24 hour"/= a 3-%o'd !ncrea"e !n24-hour ur!nary prote!n 'e*e'" $!th!n a 3-month per!od $a" a'"o con"!dered a "e*ere %'are=p1&i+e+ th(t it (s (99&mp(nie+ ;, mi91&s9&pi9 hem(t-1i( (n+ (


4/19

The * se9&n+(1, en+ p&ints$ere a" %o''o$":1/the ineti9s &. the 1esp&nse t& the1(p, in the .i1st ,e(1= +a"ed on "er!a'mea"urement" o% "erum creat!n!ne= "erum a'+um!n= 24-hour ur!nary prote!n= and "erum C3'e*e'"= a" $e'' a" the CLA "coreQ 2/ the 1(te &. 1en() 1emissi&n= de%!ned a" G10 red+'ood ce''")h!h-po$er %!e'd and a 24-hour ur!nary prote!n 'e*e' G1 m= !n the a+"ence o% adou+'!n o% the "erum creat!n!ne 'e*e'Q and3the n-m;e1 &. see1e .)(1e"= a" de%!ned a+o*e(

>U 4! m&nth s Lo$ do"e44

NIH protoco'4# TS

R? .(i)-1e ND pr!mary

re"pon"e Stero!d

re"!"tant %'a!r Cr 62

1#8223

208423

Cumu'at!*e do"e 3


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Remissi&n 30 .F18/ 22 . 548/

RENA# >#ARE 12 .2F8/11 dur!n AA R&

13 .2E8/F dur!n I CC R&

Ad*er"e e*ent"

In%ect!on" . SR/

B

5 pt" . F ep!"ode"/

B+ut numer!ca''y h!her!n%ect!on"10 pt" . 1F ep!"ode"/

7eath 2A : 14 yr $!h SI nephrot!c prote!nur!a CH>(2< th day o% R& : D>: 51 yr dropped o "tudy 121 "t $ee, :rea"t cancer-- "udden death $ee, 1E4 :cau"e

0

SR7 1 .$, 20? o% ?RDL??SHou""!au >A= a"conce'o" C= 7PCru 7= et a'( The 10-year %o''o$up data o% the uro-Lupu"Nephr!t!" Tr!a' compar!n 'o$-do"e and h!h-do"e !ntra*enou" cyc'opho"pham!de( Ann

Rheum 7!" 2010Q #E: #1O#4#imit(ti&ns &. the E#NT st-+,: a!n'y done !n Cauca"!an popu'at!on= aKor!ty . B F


6/19

3( Chan T= L! >= Tan CS= et a'( %%!cacy o% mycopheno'ate mo%et!' !n pat!ent" $!thd!%%u"e pro'!%erat!*e 'upu" nephr!t!"( Hon on-@uanhou Nephro'oy Study @roup( N n'J ed 2000Q 343:115#O11#2( 44 pt" = non !n%er!or!ty(!n%ect!on" B4( Chan T= T"e C= Tan CS= et a'( Lon-term "tudy o% mycopheno'ate mo%et!' a"cont!nuou" !nduct!on and ma!ntenance treatment %or d!%%u"e pro'!%erat!*e 'upu" nephr!t!"( JAm Soc Nephro' 2005Q 1#:10F#O10 t& CC :42 pat!ent" random!"ed to > or CC: oth rece!*ed "tero!d"(

RCTs COMPARING MMF TO IV CYC.

Ginzler EM, Dooley MA, Aranow C, et al.Mycophenolate mofetil or intravenous cyclophosphamide

for lupus nephritis. N Engl Med !""#$ %#%&!!'() !!!*.

42 pt" > CC

7DS 2)d 6 #th"

AA 1(5

m),)d 6 #mth"

1)d 6 #mth" Dra'2(5 m),)d6 # mth"

CR U R B B

Re'pa"e B B

C7)SR7 B B

In%ect!on" more


7/19

a mu't!center= open-'a+e'= non!n%er!or!ty tr!a'( DEC ! = "CT 200*

E?9)-si&n 91ite1i($ere creat!n!ne c'earance o% 'e"" than 30 m' per m!nute= "erumcreat!n!ne on repeated te"t!n reater than 3(0 m per dec!'!ter .2#5(2 mo' per '!ter/=

"e*ere coe&!"t!n cond!t!on" prec'ud!n !mmuno"uppre""!*e therapy or cond!t!on"reu!r!n !ntra*enou" ant!+!ot!c therapy= pr!or treatment $!th mycopheno'ate mo%et!'=treatment $!th !ntra*enou" cyc'opho"pham!de $!th!n the pa"t 12 month"= monoc'ona'ant!+ody therapy $!th!n the pa"t 30 day"= or prenancy or 'actat!on(MM> :ycopheno'ate mo%et!' $a" !n!t!ated at a do"e o. 500 mg ti9e +(i),= and the do"e$a" !ncrea"ed to/50 mg ti9e +(i), (t ee 2and ad*anced $ee,'y to ( m(?im-m+&se &. !000 mg th1ee times +(i), un'e"" the $h!te-ce'' count %e'' +e'o$ 3000 percu+!c m!''!meter(I 9,9 : NI$ 1egimen= nad!r TLC 2500 10 day"(

at!ent" rece!*edp1e+nis&ne (t ( +&se &. ! mg pe1 i)&g1(m o% +ody $e!ht perday= $!th taper!n +y 10 to 20 percent at one-$ee, or t$o-$ee, !nter*a'"= on the +a"!"o% c'!n!ca' !mpro*ement(C'!n!ca' deter!ort!on R&ed $!th !ncrea"!n "tero!d(

140 pt" !nc'uded Dra' > . 3 )d/ *" I CC

'ac, and h!"pan!c" repre"ented . race $!th "e*ere d!"ea"e/ r!mary endpo!nt CR 24 $ee," (CR +e.ine+a" the return to $!th!n 10

percento% norma' *a'ue" o% "erum creat!n!ne 'e*e'"= prote!nur!a= and ur!ne "ed!ment(

"econdary endpo!nt PR' +e.ine+a" !mpro*ement o% 50 percent !n a'' a+norma'rena' mea"urement"= $!thout $or"en!n .$!th!n 10 percent/ o% any mea"urement(A++iti&n() se9&n+(1, en+ p&ints!nc'uded chane" !n rena' %unct!on= comp'ementcomponent"= ant!Odou+'e-"tranded 7NA .d"7NA/ ant!+ody t!ter"= and "erum a'+um!n'e*e'"(ARL RSDNS:de%!ned a" an !mpro*ement o% 30 percent !n at 'ea"t t$o mea"ure" o% rena' %unct!on."erum creat!n!ne= prote!nur!a= or ur!ne "ed!ment/ !% a'' three mea"ure" $ere a+norma'

at entry !nto the "tudy= or an !mpro*ement o% 30 percent !n one mea"ure !% one or t$o


8/19

other" $ere a+norma'= pro*!ded no mea"ure" that $ere norma' at +a"e'!ne +ecamea+norma'(

R6 >AIL?R:a cond!t!on reu!r!n h!her do"e" o% cort!co"tero!d" %or d!"ea"e contro'= %a!'ure to eetthe cr!ter!a %or an ear'y re"pon"e= or %a!'ure to reach comp'ete or part!a' rem!""!on at24 $ee,"(

m&nths MM> I CC

CR 22(58 5(?

B B

IN>CTIDNS DR

@I S?pperLo$er

Bore(

B +ut reu!red adm!""!on !n F pt"

7eath 0 2


9/19

a: cere+ra' +'eed= on'y 1 do"e!* cyc+: "ep"!"act!*e LN= 2 do"e !* cyc

BB > non!n%er!or e*en "a%er(#IMITATI"NS:Not +'!nded(I CC do"e $a" adKu"ted +a"ed on @I S= "o 'e"" CR rate Short durat!onNot "tud!ed the %'are rate $!th > !nduct!on= and appropr!ate ma!nata!nance re!men(

Second RCT compar!n > $!th I CC :

ALMS !"#$%&! %'AL: Appe' @= Contrera" @= 7oo'ey A= et a'( ycopheno'atemo%et!' *er"u" cyc'opho"pham!de %or !nduct!on treatment o% 'upu" nephr!t!"( J Am SocNephro' 200EQ 20:1103O1112( JASNA+o*e "tud!e" $ere !n CHINA U ?S( Hence the %o''o$!n "tudy $a" done 'o+a''y(A'"o 2 pha"e tr!a' : Induct!on and ma!ntenance

Random!"ed 3F0 pt"(


10/19

In%ect!on" # e..e9tie in:a! D-62 M2:Radha,r!"hnan J= outour!" 7A= @!n'er = et a'( ycopheno'ate mo%et!' and !ntra*enou"cyc'opho"pham!de are "!m!'ar a" !nduct!on therapy %or c'a"" 'upu" nephr!t!"( !dney Int2010Q FF:152O1#0(ar!m = !"on! CN= >erro L= et a'( Reduct!on o% prote!nur!a $!th mycopheno'ate mo%et!' !npredom!nant'y mem+ranou" 'upu" nephropathy( Rheumato'oy .D&%ord/ 2005Q 44:131FO1321(Spet!e 7N= Tan = Ro*!n H= et a'( ycopheno'ate therapy o% SL mem+ranou"nephropathy( !dney Int 2004Q ##:2411O2415(/! crescentic 82 !Tan = an @= u C= et al.%%ect" o% mycopheno'ate mo%et!' %or pat!ent" $!th cre"cent!c'upu" nephr!t!"(

c! /lac+ hispanics:I"en+er 7= Appe' @= Contrera" @= et a'( In%'uence o% race)ethn!c!ty on re"pon"e to 'upu"nephr!t!" treatment: the ALS "tudy( Rheumato'oy .D&%ord/ 2010Q 4E:12 *"( other !nduct!on therap!e" !nthe conte&t o% eoraph!c %actor"= and %ound that > 'ed to more comp'ete rem!""!on" !npat!ent" out"!de o% A"!a

ST?7IS DN CNI a" !nduct!on aent:C,9)&sp&1ine in #N :3 RCT"(1"t : >u L= an L= Chen = et a'( C'!n!ca' e%%!cacy o% cyc'o"por!n A neora' !n thetreatment o% paed!atr!c 'upu" nephr!t!" $!th hea*y prote!nur!a( r J Rheumato' 1EE


11/19

2nd : NIH !n NAustin HA 3rd, Illei GG, Braun MJ, et al.Randomized, controlled trial of prednisone, cyclophosphamide, andcyclosporine in lupus membranous nephropathy. J Am oc !ephrol "##$% "#&$#'($''.

42 pt" : 3 roup"

C"A red 11mth

I cyc # do"e a'ternatemonth red

A'ernate daypredn!"o'one a'one

1 yr cumu'at!*erem!""!on rate

"tero!d" *" h!h do"e I CC "tero!d"(S!m!'ar CR and cumu'at!*e rem!""!on rate(Rap!d !mpro*ement !n Sr a'+um!n and prote!nur!a !n a+o*e tr!a' $!th TAC(ST?7IS AINL IN CHINS( %%!cacy !n more d!*er"e cohort" not ,no$n(?LTITAR@T THRA : TAC >ao H= L!u H= 6!e HL= et a'( Succe""%u' treatment o% c'a"" Y I 'upu" nephr!t!" $!thmu't!taret therapy( J Am Soc Nephro' 200


12/19

Corte"-Hernande J= Torre"-Sa'!do T= edrano AS= et a'( Lon-term outcome" Omycopheno'ate mo%et!' treatment %or 'upu" nephr!t!" $!th add!t!on o% tacro'!mu" %or re"!"tantca"e"( Nephro' 7!a' Tran"p'ant 2010Q 25:3E3EO 3E4!ne 7= et a'( Com+!nat!on therapy o% mycopheno'ate mo%et!' andtacro'!mu" !n 'upu" nephr!t!"( Lupu" 2010Q 1E:E35OE40(

RITUIMAB IN #N:D%% 'a+e' u"e(

at *+ 'adakrisnan ,. lympo-ytes and lupus nepritis new insigts intopatogenesis and targeted terapies. /idney nt 2001 3426721.889 role of lympo-ytes in L!((1i&-s St-+ies h(e sh&n th(t in Resist(nt #N: ?S o% RIT?6IA I CC predn!"o'one !n re%ractory LN BB r!tu&!ma+ "tero!d(

So= $hether add!n R!tu&!ma+ to pr!mary Induct!on aent !" u"e%u' Th!" $a" "tud!ed !nL?NAR(

L?NAR( The #-p-s Neph1itis Assessment Fith Rit-?im(; St-+, T1i()BB 'are"t ( 144pt"("BECTIE : To e*a'uate the e%%!cacy and "a%ety o% r!tu&!ma+ !n a random!ed= dou+'e-+'!nd= p'ace+o contro''ed pha"e III tr!a' !n pat!ent" $!th 'upu" nephr!t!" treated concom!tant'y$!th mycopheno'ate mo%et!' .>/ and cort!co"tero!d"(

>"tero!d R!tu&!ma+ or p'ace+o(-rimary end point: rena' re"pon"e at 52 $ee,"(R!tu&!ma+ !*en at do"e o% 1 on day 1= 15= 1#< and 1 : 500 m T7S -- +y 4 $ee, 3 )d(-- 9&ntin-e+ .&1 52 ees'MP I 1000 m 71 F 73Dra' predn!"o'one : 0(F5 m), ma& #0 m %or 1# day"= tapered to G 10 m)d +y 1# $ee,(Any pt reu!r!n re"cue therapy -- 'a+e''ed a" non re"ponder and $!thdra$n( D*era'' re"pon"e 5F *" 4#8(


13/19


14/19

The pr!mary end po!nt ."uper!or re"pon"e rate $!th r!tu&!ma+/ $a" not ach!e*ed( !ht p'ace+o-treated pat!ent" and no r!tu&!ma+-treated pat!ent" reu!red

cyc'opho"pham!de re"cue therapy throuh $ee, 52( Stat!"t!ca''y "!n!%!cant !mpro*ement" !n "erum comp'ement C3= C4= and ant!O

dou+'e-"tranded 7NA .ant!-d"7NA/ 'e*e'" $ere o+"er*ed amon pat!ent" treated $!thr!tu&!ma+(

In +oth treatment roup"= a reduct!on !n ant!-d"7NA 'e*e'" reater than the med!an

reduct!on $a" a""oc!ated $!th reduced prote!nur!a(Ad*er"e e*ent" $ere eua'= +ut

RT6 a""oc!ated $!th more neutropen!a= 'eucopen!a and hypoten"!on(

8IMII2!2ot included refractory cases.

8:2) shoed )itu


15/19


16/19

M(inten(n9e the1(p, t1i()s:

NI$ Stud!e" !n 1E $a" a*a!'a+'e(!th e"ta+'!"hed "a%ety and e%%!cacy o% >= !t $a" "tud!ed a" ma!nta!nence aent(

>i1st RCT &n MM>:


17/19

Contrera" @= ardo = Lec'erc = et a'( Seuent!a' therap!e" %or pro'!%erat!*e 'upu" nephr!t!"(N n' J ed 2004Q 350:EF1OE(RS?LT: > U AA to CC> $!th %e$ re'ap"e(Lo$er !n%ect!on $!th > U AA(SD I CC ma!nat!nence $a" d!"cardedTRIA#S 9&mp(1ing MM> ith AHA:MAINTAIN NEP$RITIS TRIA#:Houssiau 2A, 4-ruz , an5le , et al.Azathioprine *ersus mycophenolate mofetil for lon56termimmunosuppression in lupus nephritis& results from the MAI!7AI! !ephritis 7rial. Ann Rheum Dis 2010;8$&"#3("#$.

9:R;+9A! +;+:

Res-)t MM> AHA

Ren() .)(1e

Nephrot!cIncrea"e creatIncrea"e prote!nur!a

10 o% 531E8

BB AA= non "uper!or#imit(ti&n: Cauca"!an Sma'' "amp'e "!e

Non '!nd a!nta!nence R& "tarted pr!or to ach!e*ement o% "!n!%!cant ren' re"pon"e(

A#MS MAINTAINENCE TRIA#:22F pt"( Induct!on 6 # mth" : I CC or >( Tho"e $ho had atta!ned rena' re"pon"e $erenc'uded(


18/19

11# : % 2 )d ma!nata!nence111 AA 2 m),)d ma!nta!nence(The p1im(1, e..i9(9, en+ p&int$a" the t!me to treatment %a!'ure= $h!ch $a" de%!ned a"death= end-"tae rena' d!"ea"e= dou+'!n o% the "erum creat!n!ne 'e*e'= rena' %'are= or re"cuetherapy %or 'upu" nephr!t!"(Se9&n+(1, (ssessments!nc'uded the t!me to the !nd!*!dua' component" o% treatment%a!'ure and ad*er"e e*ent"(

* ,1 .&))& -pm% : 'e"" treatment %a!'ure= and 'oner t!me to re'ap"e(Ad*er"e e*ent" "!m!'ar !n +othSer!ou" ad*er"e e*ent" more !n AA roup(!thdra$a' due to S more !n AA roup(< .(&1 MM> (s m(in(tin(n9e R &. 9h&i9e i11espe9tie &. in+-9ti&n R? 1(9e se?ge&g1(ph,'

7oo'ey A= Jayne 7= @!n'er = et a'( ycopheno'ate *er"u" aath!opr!ne a" ma!ntenancetherapy %or 'upu" nephr!t!"( N n' J ed 2011Q 3#5:1


19/19

The C(n(+i(n $,+1&?,9h)&1&-ine St-+, G1&-pdemon"trated *!a a "ma'' random!ed$!thdra$a' tr!a' that "ta+'e SL pat!ent" $ho cont!nued HCX e&per!enced 'e"" d!"ea"e %'are"o*er a 24-$ee, per!od compared $!th tho"e $ho too, p'ace+o( @/8At 3 year" o% %o''o$-up=there $a" a non"!n!%!cant trend to$ard 'e"" rena' %'are" .re'at!*e r!", 0(2#= E58 con%!dence!nter*a' 0(03O2(54= PB 0(25/ $!th cont!nu!n HCX(#8 pt" ret!nopathy B-- there%ore reu'ar optha'mo'o!ca' e&am!nat!on mu"t(

RAAS +'oc,ade :The Lupu" !n !nor!t!e": Nature *"( Nurture "tudy demon"trated an a""oc!at!on +et$eenACI u"e and 'e"" de*e'opment o% 'upu" nephr!t!" !n tho"e $ho d!d not ha*e rena' d!"ea"e=and an !mpro*ement !n prote!nur!a and decrea"ed r!", o% d!"ea"e act!*!ty !n tho"e $!the"ta+'!"hed 'upu" nephr!t!"(Spe9i() C)ini9() C&nsi+e1(ti&nsomen $!th SL are 5O< t!me" more '!,e'y to ha*e coronary heart d!"ea"e than tho"e !n the

enera' popu'at!on(5

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Clinical Trials in Ln