Anca Associated Vasculitis Clinical Trials
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Goals Of Treatment İn Anca Assocıated Vasculıtıs
• Patient survival
• Induce remission of active state
• Reduce disease relapse• Reduce disease relapse
• Minimize therapeutic toxicity
– Least toxic and most effective therapy
– Prevent and monitor toxicity
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EUVAS approach to trials in renal vasculitis
• Subgroup according to severity
• High intensity treatment to induce remission, low intensity to
prevent relapse
• Agree standard regimen by consensus
• Test against best alternative by RCT
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AAV Clinical Trials Overview
3 - 6 mo.
NORAM: MTX vs CYC
MEPEX: PE vs MP
CYCLOPS: CYC iv vs oral
WEGET: Etanercept vs placebo
SOLUTION: ATG
MYCYC: MMF Vs CYC
RITUXIVAS
ACTIVE
InductionACTIVE
MaintenanceNORAM: MTX vs CYC
CYCAZAREM: AZA vs CYC
IMPROVE: AZA vs MMF
REMAIN: AZA, 24 mo vs 48 mo
Alternative agentsMAINSTIRANRAVEABAVASRATTRAP
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Cyclophosphamide / Steroid
� Mainstay of treatment for both MPA and WG since 1980s
� High rate of remission
� Significant morbidity� Significant morbidity� Hemorragic cystitis
� Bladder cancer
� Myelodysplasia
� Infertility
� infection
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Which is better: Oral or IV CYC?
• Guillevin L et al, Arthritis Rheum, 1997
• RCT of patients with WG
Group A (CYC Group A (CYC
IV) n = 27IV) n = 27
Group B (CYC Group B (CYC
PO) n = 23PO) n = 23
Initial Initial remissionremission
89%89% 78%78%
Infectious side Infectious side effecteffect
41%41% 70% 70% (p < 0.05)(p < 0.05)
RelapseRelapse 60%60% 13% 13% (p = 0.02)(p = 0.02)
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CYC: oral vs pulse IV, meta analysis
•• MetaMeta--analysis analysis
•• 11 non11 non--randomized studies randomized studies
•• N = 202 patients N = 202 patients
•• Pulse vs. daily oral CycPulse vs. daily oral Cyc•• No difference in death / ESRD / remissionNo difference in death / ESRD / remission
•• More relapsesMore relapses OR 1.79* (CI 0.85OR 1.79* (CI 0.85--3.75)3.75)
•• Less infectionsLess infections RR 0.45RR 0.45
•• Lower dose Lower dose 17 g vs. 35 g17 g vs. 35 g
**not statistically significantnot statistically significant
K de Groot et al. Nephrol Dial Transplant 2001
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CYCLOPS – Time to remission
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Cyclops – Time to relapse
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Lessons from CYCLOPS
• PULSE cyc is as effective as daily oral cyc
• Pulse cyc is a/w 50% reduction in total cumulative dose
• Pulse cyc Probably more safer than oral cyc• Pulse cyc Probably more safer than oral cyc
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Iv pulse
cyc
Oral cyc
dose
15 mg/kg
q2-3 wk2 mg/kg
daily
2009
dose q2-3 wk daily
no 76 73
Remission @ 9 mo 67[88%] 64[88]Not significant
Time to remission not different
Relapse 13 6 Not powered
Cyc cumulative dose 8.2 gm 15.9gm P<0.001
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• A retrospective review
• 20 patients with lung hemorrhage(MP 17,WG 2, CSS 1)
• All treated with PE and Prdn/Cyc
• Resolution of lung hemorrhage in 20/20(100%) with6.4(average ) treatments6.4(average ) treatments
• Half of pts who presented with azotemia(7/14) were d/s withimproved renal function
• No complications of PE
• Historical review revealed death in 3/11 patients not receivingPE
Klemmer, Am J Kid Dis 2003
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Induction for severe disease :MEPEX Trial
Design
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MEPEX –significant differences at 3 months
• Surviving patients • dialysis independent on dialysis
• PE 81 % 19% p=0.012
• MeP 61% 39% • MeP 61% 39%
• In the patient group as a whole
• alive and dialysis –independent on dialysis or dead
• PE 69% 31% p=0.023
• MeP 49% 51%
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MEPEX - Renal recovery
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What are the approaches to Achieve remission without CYC?
• Methotrexate –NORAM• Rituximab – RITUXIVAS• MMF• Lefno• TNF alpha inhibitors – WGET • TNF alpha inhibitors – WGET • ATG• IVIG• Cyclosporin• Deoxyspergaulin
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INDUCTION THERAPY
3 - 6 mo.
NORAM: MTX vs CYC
MEPEX: PE vs MP
CYCLOPS: CYC iv vs oral
WEGET: Etanercept vs placebo
SOLUTION: ATG
MYCYC: MMF Vs CYC
RITUXIVAS
Induction
RITUXIVAS
MaintenanceNORAM: MTX vs CYC
CYCAZAREM: AZA vs CYC
IMPROVE: AZA vs MMF
REMAIN: AZA, 24 mo vs 48 mo
Alternative agentsMAINSTIRANRAVE
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NORAM- NonRenal Wegener’s Alternatively
treated with Methotrexate• A non-inferiority trial, MTx vs cyc in early systemic disease
• Exclusion: abnormal creatinine, > 1g proteinuria, myocarditis ,CHF
• randomized 100 patients to receive either standard oral CYC, 2mg/kg/day or oral MTX, 20–25 mg/week for 12 months andthen withdrew therapy.then withdrew therapy.
• both groups received same dose of steroid- 7.5 mg/d by 6months and stop by 12 months
• FU for 18 months
• A third of these patients did have hematuria,may be ?an earlyrenal trial in some of the patients, although none of them hadbiopsy-proven renal vasculitis
de Groot,Rheumatology,2005
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NORAM- Study Design
Stop PRDN by
12 months
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Mtx Cyc Remarks
Remission @ 6 months 90 93 P=0.78 No difference
Months to remission 3 2
Relapse @ 18 months 70 46.5 P=0.02 significant
Median cumulative Prdn dose 8.8 gm 6.2 gm P=0.001 significant
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NORAM results
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Lessons from NORAM
• WITH Mtx there is delayed onset of remission in pts with pulmonary involvement or relatively extensive disease
• With Mtx,there is significantly higher rate of • With Mtx,there is significantly higher rate of relapse than cyc
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How to Maintain remission?
• CYCAZAREM- early remission phase of generalized vasculitis- CYC vs AZA
• WEGENT –AZA vs Mtx
• WGET-role of Ethanercept • WGET-role of Ethanercept
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• Prospective RCT-open label trial by EUVAS
• New pts with WG or MPA
- First EUVAS trial to be published
CYCAZAREM Trial
- First EUVAS trial to be published
- Can exposure to CYC in pts with generalized vasculitis could be reduced by substitution of AZA at remission
• 3-6 months of oral Cyc + PRDN, then either oral CYC or AZA for 12 mo. After 12 months all pts on AZA up to 18 months
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CYCAZAREM trial design
n =144 AZA-73 , CYC-71
Mostly WG, creatinine- < 5.7 mg%
Jayne et al, NEJM, 349;1, 2003
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CYCAZAREM - Results
p=0.65
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Lessons from CYCAZAREM
• Lower dose of Cyc with early conversion to Aza is justified and probably safer long-term
• The relapse rate among MPA was lower than WG (p=0.03)WG (p=0.03)
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• To test that mtx is a/w less serious adverse events than aza
• Primary outcome measure is not relapse rate
WEGENT trial
• Primary outcome measure is not relapse rate but adverse event that causes drug discontinuation or death
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WEGENT Trial design
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AZA MTX
55 pts 59 pts
RELAPSE @18 17.8 13.7
RELAPSE @ 36 50.1 46.7RELAPSE @ 36 50.1 46.7
RELAPSE FREESURVIVAL @ 18 88.9 90.5
RELAPSE FREESURVIVAL @ 36
64.1 69
TOXICITY GRADE ¾@ 18 7.9 17.4
DRUG WITHDRAWL@36 11.1 17.4
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Lessons from WEGENT
• MTX IS not safer than aza
• Both are similar in remission maintenance in mpA AND WG- so choice of drug is best decided on basis of each patients individual decided on basis of each patients individual situation
• A SETBACK TRIAL FOR MTX
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• RCT –ethanercept ys placebo in remission maintemance-180
• Both groups received cyc/ mtx
• Only 49 percent of patients remained in remission
throughout the trial, and etanercept did not result in a
higher rate of sustained remission than placebo
2005
higher rate of sustained remission than placebo
• No difference in remission rates and disease flares
• Why no benefit of ethanercept?
o Insufficient dose
o Inefficacy in granulomatous disorders
• Increased malignancy rate in ethanercept group
• Conclusion- no role of ethanercept in WG
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MMF
• No RCTs till nowStassen et al Langford et al Koukoulaki et al
Ann RD 2007 A&R 2004Nephron clin prac
2007
Refractory aav-induction trial maintenance
Ind -3
Rem.main -29
High response rates but a
high relapse rate ,upto 50% induction trial maintenance 3 29
32 pts 14 wg pts 19-active disease rx
Cr 25(78%) 100%
Pr 19
relapse 61% 6 (43%) 10 pt 14
Median Relapse free 16 mo
17.5 mo 14mo
high relapse rate ,upto 50%
@ 2yrs as well as adverse
effects upto 70 %
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MYCYC trial • RCT of MYC Vs. IV CYC in remission induction in AAV
• Primary endpoint- remission induction by 6 months
• MMF Dose- 2 gram/ day for 3-6 mo ,until remission, thenswitch to AZA
IMPROVE trial International Mycophenolate mofetil Protocol to Reduce Outbreaks of Vasculitis
•Randomised ,open label ,phase 3 ,interventional trial
•Compares MMF with AZA in remission maintenance
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Anti-CD 52 therapy• Alemtuzumab (Campath-1H)
• Walsh et al:
� 71 pts –remission in 60 pts (85%)
� CR in 46 pts
� Severe infections in 27%
� Total deaths – 31(infection in 6)
� Conclusion- grave adverse affect profile- so only
experimental in AAV
Walsh et al,ARD,2007
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15- DeoxySperGualin
• 15 –DSG is a synthetic derivative of SPERGUALIN, a protein from
Bacillus laterosporus that is capable of preventing B and T cell
maturation
• Inhibits NF-κβ translocation into nucleus• Inhibits NF-κβ translocation into nucleus
• Reversibly inhibits T-cell proliferation and monocyte activation
• Marked neutropenia but no neutrophil dysfunction
• SC Injection in 6 cycles of 21 days with a 7 day washout b/w cycles-
dose: 0.5 mg/kg/day
• Cycles stopped if WBC < 4000
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Birck et al Flossmann et al 15-DSG may be a safer
alternative to CYC in
remission
JASN,2003 ARD ,2009
Refractory AAV
Relapsing or refractory AAV
Induction study
Induction Trial
20 pts 44 pts remission induction ,but
not yet approved for
routine clinical use
CR 6 20(45%)
PR 8 22(50%)
Relapses 18(43%)
Median time to relapse
170(44-316days)
Severe adverseeffects
none 24(53%)Leucopenia related
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IVIg
• RCT – IVIG vs. placebo
• 34 pts -24 WG and 10 MPA –refractory AAV
• All pts had received 2 mo of PRDN + CYC or AZA and continued on
these for at least 3 mo after IVIGthese for at least 3 mo after IVIG
• IVIG dose-0.4g/kg/d for 5 days
• @ 3 mo- remission in ivig-14/17(82%) and 6/17(35%)– p=0.015
• Limitation- benefit of IVIG did not last beyond 3 months as
subsequent vasculitic activity ,relapse frequency and IS need were
similar in both groups
Jayne et al,2000, Quarterly Journal Of Medicine
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Anti Thymocyte Globulin(ATG)
• SOLUTION- Anti Thymocyte Globulin for refractory vasculitis trial
• A single arm pilot study by EUVAS
• 15 wg pts • 15 wg pts
• CR- 4 ,PR-9 ,no remission- 2
• Relapse -7 after a mean of 8.4 months
• 2 deaths soon after ATG-pul.infection & pul.hemorrhage
• Conclusion- not supported clinically
Schmitt et al,Kidney International ,2004
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Leflunomide – remission maintenance • An RCT –planned 154 pts ,but stopped after 54 pts
..prematurely
• Reason- very high relapse rate in Mtx arm
• 26 pts -LEf oral daily for 24 mo vs 28 pts - weekly MTX
• Mtx -13/28 –relapse within 6 months;7 relapses were severesevere
• Lef- 6/26 –relapse;1-severe relapse
• Total follow up- 21 months
• High adverse rate of lef leading to stoppage in 4 pts
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Q.Why mtx did not work here unlike in wegent trial?
A Low initial dose of 7.5 mg/week used .wegent-20 mg/wk
• Lesson- higher Mtx dose needed in AAV than in RA
• Positive finding in this study-• Positive finding in this study-• Remission maintenance in lef group similar to aza in
cycazarem,although no.are small
• Conclusion - trial inconclusive, but suggests a possible role for LEF@ 30 mg/day in maintenance therapy for wg,albeit with increased adverse events
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Role of biologics in AAV
• Ethanercept –WGET trial
• Infliximab – ACTIVE trial
• Rituximab
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ACTIVE –INFLIXIMAB in systemic vasculitis
• A pilot study
• 32 pts with 19 WG/ 13 MPA
• 16-acute disease & 16-persistent disease
• Treated with infliximab 5 mg/kg @0,2,6 and 10 weeks
• 88% remission(both groups)• 88% remission(both groups)
• 20% relapse(mainly group 2)
• 21% infection –high incidence
• 6% mortality(pulmonary hemorrhage ,pneumonia)
• Steroid sparing
• Conclusion- no control arms in this study ;may provide a support for larger clinical trial acc.to authors
Booth ,J A S N ,2004
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RATTRAP
• Infliximab Versus Rituximab In Systemic Necrotizing Vasculitis
Compares both in 200 pts with resistant AAV• Compares both in 200 pts with resistant AAV
ABAVAS
• Abatacept in AAV
• a pilot study by EUVAS
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54 pts 35 wg+ 16 mpa,2 rv,1 mc
37 are refractory vasculitis(69%)
43 (81%)Remission 10 no Remission
6-bvas improved1 year
28(85%) sustained
remission
6-bvas improved
1 -died
3 –remission induced
with other agents
1 year
f/u
5(12%) relapses
C mukt\htyar,r luqmani ,ARD 2005;64
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Rituximab
• What is the place of Rituximab in AAV ?
• Induction
• Maintenance
• Relapses• Relapses
• Refractory AAV
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• Aim- efficacy & safety of rituximab
• Retrospectively - 65 pts with refractory AAV
• All pts achieved B cell depletion
• 2 REGIMENS• 2 REGIMENS
• LYMPHOMA regimen-375 mg/m2 weeklyx4
• RA regimen-2 one gram iv 2 weeks apart
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65 Refractory AAV pts
CR -49 (75%)NO RESPONSE-1 (2%)PR -15 (23%)
MEDIAN-11.5 mo
RELAPSE-
28(57%)
MEDIAN-11.5 mo
•B cell return preceded relapse only in 14/27 pts(52%)•Relapse not a/w anca titer rise or positivity•Immunosupressive rx withdrawn in 37/60 (62%)•Type of rx or IS withdrawl dinot effect relapse timing
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Ra-30
Lym-26
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Open label trial-rituximab
• 11 pts with pr3-anca(10 wg,1 mp)
• 10 CR ,1 PR at 6 mo
• B cell depletion in all patients
• Fall in ANCA titer in all pts• Fall in ANCA titer in all pts
• Relapse in 5/11 as B cells returned(5-12 mo)
• However, all responded to retreatment Keogh ,A&R 2005
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Rituximab In AAV remission induction
• RITUXIVAS- Randomized open label trial comparing rituximab vs.cyc/aza in induction in refractory vasculitisvasculitis
• RAVE- RCT, double blind, placebo controlled-Oral cyc vs rituximab in remission induction in severe WG
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Maintenance of remission using Rituximab in
Systemic ANCA associated vasculitis
• Inclusion-remission (first or after a second remission)remission)
• In the first 3 months after starting aza
• Objectives-
• Decrease the relapse rate by 50%
• Increase the tolerance of maintenance treatment
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MAINRITSAN study design
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Ongoing trials at EUVAS• Length of long-term immunosuppressive therapy?
• REMAIN -long-term low dose immunosuppression
versus treatment withdrawal for renal vasculitis
• Clearance of nasal carriage of Staph Aureus with mupirocin in
WG
• MUPIBAC
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Take home messages
• Pulse iv cyc –best induction strategy• Add plasma exchange if severe disease especially renal and
pulmonary • The optimal choice of medication for relapse prevention is not well
established• Azathioprine is the best –validated maintenance therapy to date• Azathioprine is the best –validated maintenance therapy to date• Overall data do not support routine use of Mtx in prevention of
relapse in AAV • Lefno and MMF- good remission induction but a/w high adverse
rates• Tnf alpha inhibitors- so far useless• Rituximab -results are encouraging.. But Needs to wait a liitle more• Ivig –effects not longl asting
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Thank you