Anca Associated Vasculitis Clinical Trials

Goals Of Treatment İn Anca Assocıated Vasculıtıs • • • •

Patient survival Induce remission of active state Reduce disease relapse Minimize therapeutic toxicity – Least toxic and most effective therapy – Prevent and monitor toxicity

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

AAV Clinical Trials Overview

Induction 3 - 6 mo.

Maintenance

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 NORAM: MTX vs CYC CYCAZAREM: AZA vs CYC IMPROVE: AZA vs MMF REMAIN: AZA, 24 mo vs 48 mo

Alternative agents MAINSTIRAN RAVE ABAVAS RATTRAP

Cyclophosphamide / Steroid
Mainstay of treatment for both MPA and WG since 1980s
High rate of remission
Significant morbidity






Hemorragic cystitis Bladder cancer Myelodysplasia Infertility infection

Which is better: Oral or IV CYC? • Guillevin L et al, Arthritis Rheum, 1997 • RCT of patients with WG Group A (CYC IV) n = 27

Group B (CYC PO) n = 23

Initial remission

89%

78%

Infectious side effect

41%

70%

Relapse

60%

(p < 0.05)

13% (p = 0.02)

CYC: oral vs pulse IV, meta analysis •

Meta--analysis Meta • •

•

11 nonnon-randomized studies N = 202 patients

Pulse vs. daily oral Cyc • • • •

No difference in death / ESRD / remission More relapses OR 1.79* (CI 0.850.85-3.75) Less infections RR 0.45 Lower dose 17 g vs. 35 g

*not statistically significant K de Groot et al. Nephrol Dial Transplant 2001

CYCLOPS – Time to remission

Cyclops – Time to relapse

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

2009

Iv pulse cyc Oral cyc

dose

15 mg/kg q2-3 wk

2 mg/kg daily

no

76

73 Not significant

Remission @ 9 mo

67[88%]

64[88]

Time to remission not different Relapse

13

6

Not powered

Cyc cumulative dose

8.2 gm

15.9gm

P<0.001

• • • •

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%) with 6.4(average ) treatments • Half of pts who presented with azotemia(7/14) were d/s with improved renal function • No complications of PE • Historical review revealed death in 3/11 patients not receiving PE Klemmer, Am J Kid Dis 2003

Induction for severe disease :MEPEX Trial Design

MEPEX –significant differences at 3 months • Surviving patients • • PE • MeP

dialysis independent 81 % 61%

on dialysis 19% 39%

p=0.012

• In the patient group as a whole • alive and dialysis –independent on dialysis or dead • PE 69% 31% p=0.023 • MeP 49% 51%

MEPEX - Renal recovery

What are the approaches to Achieve remission without CYC? • • • • • • • • •

Methotrexate –NORAM Rituximab – RITUXIVAS MMF Lefno TNF alpha inhibitors – WGET ATG IVIG Cyclosporin Deoxyspergaulin

INDUCTION THERAPY

Induction 3 - 6 mo.

Maintenance

NORAM: MTX vs CYC MEPEX: PE vs MP CYCLOPS: CYC iv vs oral WEGET: Etanercept vs placebo SOLUTION: ATG MYCYC: MMF Vs CYC RITUXIVAS NORAM: MTX vs CYC CYCAZAREM: AZA vs CYC IMPROVE: AZA vs MMF REMAIN: AZA, 24 mo vs 48 mo

Alternative agents MAINSTIRAN RAVE

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, 2 mg/kg/day or oral MTX, 20–25 mg/week for 12 months and then withdrew therapy. • both groups received same dose of steroid- 7.5 mg/d by 6 months and stop by 12 months • FU for 18 months • A third of these patients did have hematuria,may be ?an early renal trial in some of the patients, although none of them had biopsy-proven renal vasculitis de Groot,Rheumatology,2005

NORAM- Study Design Stop PRDN by 12 months

Mtx

Cyc

Remission @ 6 months

90

93

Months to remission

3

2

Relapse @ 18 months

70

Median cumulative Prdn dose

8.8 gm

Remarks P=0.78

No difference

46.5

P=0.02

significant

6.2 gm

P=0.001

significant

NORAM results

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 relapse than cyc

How to Maintain remission? • CYCAZAREM- early remission phase of generalized vasculitis- CYC vs AZA • WEGENT –AZA vs Mtx • WGET-role of Ethanercept

CYCAZAREM Trial • • -

Prospective RCT-open label trial by EUVAS New pts with WG or MPA 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

CYCAZAREM trial design n =144 AZA-73 , CYC-71 Mostly WG, creatinine- < 5.7 mg%

Jayne et al, NEJM, 349;1, 2003

CYCAZAREM - Results p=0.65

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)

WEGENT trial • To test that mtx is a/w less serious adverse events than aza • Primary outcome measure is not relapse rate but adverse event that causes drug discontinuation or death

WEGENT Trial design

AZA

MTX

55 pts

59 pts

RELAPSE @18

17.8

13.7

RELAPSE @ 36

50.1

46.7

RELAPSE FREE SURVIVAL @ 18

88.9

90.5

64.1

69

TOXICITY GRADE ¾@ 18

7.9

17.4

DRUG WITHDRAWL@36

11.1

17.4

RELAPSE FREE SURVIVAL @ 36

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 situation • A SETBACK TRIAL FOR MTX

2005

• 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 • 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

MMF • No RCTs till now Stassen et al Ann RD 2007

Langford et al

Koukoulaki et al

A&R 2004

Nephron clin prac 2007

High Refractory response rates but aavInd - a Rem.main induction trial maintenance 3 29 high relapse rate ,upto 50% 32 pts 14 wg pts 19-active disease rx Cr @ 2yrs25(78%) as well as100%adverse Pr 19 effects upto 70 6%(43%) relapse 61% 10 pt 14 Median Relapse free

16 mo

17.5 mo

14mo

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, then switch 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

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

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 • 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 cyclesdose: 0.5 mg/kg/day • Cycles stopped if WBC < 4000

Birck et al

Flossmann et al

JASN,2003

ARD ,2009

Refractory AAV

Relapsing or refractory AAV

Induction study

Induction Trial

20 pts

44 pts

CR

6

20(45%)

PR

8

22(50%)

Relapses

18(43%)

Median time to relapse

170(44-316 days)

Severe adverse effects

none

24(53%) Leucopenia related

15-DSG may be a safer alternative to CYC in remission induction ,but not yet approved for routine clinical use

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 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

Anti Thymocyte Globulin(ATG) • SOLUTION- Anti Thymocyte Globulin for • • • • • •

refractory vasculitis trial A single arm pilot study by EUVAS 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

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 severe • Lef- 6/26 –relapse;1-severe relapse • Total follow up- 21 months • High adverse rate of lef leading to stoppage in 4 pts

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• 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

Role of biologics in AAV • Ethanercept –WGET trial • Infliximab – ACTIVE trial • Rituximab

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) 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

RATTRAP • Infliximab Versus Rituximab In Systemic Necrotizing Vasculitis • Compares both in 200 pts with resistant AAV

ABAVAS • Abatacept in AAV • a pilot study by EUVAS

54 pts 35 wg+ 16 mpa,2 rv,1 mc 37 are refractory vasculitis(69%)

43 (81%)Remission

1 year f/u

28(85%) sustained remission

10 no Remission

6-bvas improved 1 -died 3 –remission induced with other agents

5(12%) relapses C mukt\htyar,r luqmani ,ARD 2005;64

Rituximab • • • • •

What is the place of Rituximab in AAV ? Induction Maintenance Relapses Refractory AAV

• • • • • •

Aim- efficacy & safety of rituximab Retrospectively - 65 pts with refractory AAV All pts achieved B cell depletion 2 REGIMENS LYMPHOMA regimen-375 mg/m2 weeklyx4 RA regimen-2 one gram iv 2 weeks apart

65 Refractory AAV pts

CR -49 (75%)

PR -15 (23%)

NO RESPONSE-1 (2%)

MEDIAN-11.5 mo

RELAPSE28(57%)

•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

Ra-30 Lym-26

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 Relapse in 5/11 as B cells returned(5-12 mo) However, all responded to retreatment Keogh ,A&R 2005

Rituximab In AAV remission induction • RITUXIVAS- Randomized open label trial comparing rituximab vs.cyc/aza in induction in refractory vasculitis • RAVE- RCT, double blind, placebo controlled-Oral cyc vs rituximab in remission induction in severe WG

Maintenance of remission using Rituximab in Systemic ANCA associated vasculitis • Inclusion-remission (first or after a second remission) • In the first 3 months after starting aza • Objectives• Decrease the relapse rate by 50% • Increase the tolerance of maintenance treatment

MAINRITSAN study design

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

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 • 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

Thank you