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HOW TO BUILD A PROSPECTIVE THERAPEUTIC TRIAL
Loïc Guillevin Hôpital Cochin, Université de
Paris EFIM Research course 11 May 2007
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MAINTENANCE TREATMENT IN WEGENERGRANULOMATOSIS Ri
tuximab vs azathioprine
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TREATMENT OF SYSTEMIC VASCULITIS
Oral cyclophosphamide

• In Wegener s granulomatosis the  gold
  standard  ?
• Effective, but
• 50 relapses and major side effects
• Bladder cancer x 33
• Lymphoma x 11
• Solid tumors x 2.4

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WEGENER S GRANULOMATOSIS
Recommendations for pulse cyclophosphamide

• 0.6 to 0.7gr/sq.m (or 15 mg/kg) D0, D15, D30
• then every 3 weeks until remission
• 0.5 gr/sq.m in case of renal insufficiency or in
  patients gt 65 yr.old

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TREATMENT OF SYSTEMIC VASCULITIS
Pulse cyclophosphamide

• In PAN and MPA (Gayraud, Br J Rheumatol 1997
  36 1290)
• Comparable efficacy
• Half-less side effects
• No more relapses

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CYCLOPS - Study design
CYC 2mg/kg/d po ? 1.5 mg/d
AZA Prd
Prednisolone (mg/d)
7.5
60
25
12.5
Month
0
3 (-6)
12
18
6 (-9)
9
Induction
Consolidation
Maintenance
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CYCLOPS - Epidemiology

• pulse CYC d.o. CYC
• n 78 76
• median age years 61 62 (18-79) (22-79)
• female/male 35 / 42 28 / 48
• RLV / MPA / WG 12 / 36 / 26 9 / 28 / 26
• Creat. at entry µmol/l 173.5 211 (67 -
  681) (74 - 440)
• GFR at entry ml/min 32 30 (5-134) (3-114)
• median BVAS at entry 20 21 (11 - 37) (10 - 41)

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Outcomes

• pulse CYC d.o. CYC
• evaluable/treated 73/77 65/71
• remissions 67 (92) 56 (86)
• relapses 13 (19) 6 (11)
• GFR 18 mo 50.25 66.75 ml/min (9.5 -
  134) (20 -122)
• ESRD (n) 5 3
• SAE (n) 3 6

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Disease free survival
daily oral
pulse
p0.95
daily oral censored
pulse censored
months
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RELAPSES OF SYSTEMIC VASCULITIS
From prospective trials of the French Vasculitis
Group
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TREATMENT OF SYSTEMIC VASCULITIS
NEW STRATEGIES FOR MAINTENANCE TREATMENT
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ANCA VASCULITIDES
CYCAZAREM,

• Comparison of 3 to 6 mo. oral CYC CS then
  azathioprine or oral CYC for 12 mo. 10 mg/d
  CS. After 12 mo all the patients were treated
  with azathioprine
• 150 patients followed for 18 mo.

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Randomized trial of cyclophosphamide versus
azathioprine as remission maintenance therapy for
ANCA-associated vasculitis D Jayne for the EUVAS
group. New Engl J Med July 2003
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Randomized trial of cyclophosphamide versus
azathioprine as remission maintenance therapy for
ANCA-associated vasculitis D Jayne for the EUVAS
group. New Engl J Med July 2003
15
Randomized trial of cyclophosphamide versus
azathioprine as remission maintenance therapy for
ANCA-associated vasculitis D Jayne for the EUVAS
group. New Engl J Med July 2003
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ANCA VASCULITIDES
NORAM,

• Comparison of CYC vs MTX for induction of
  remission in non-renal ANCA vasculitis
• 100 patients
• At 6 mo the remission rates were 89.8 (MTX) and
  93.5 (CYC)

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Relapse MTX 69.5 and CYC 45
NORAM . K de Groot for the EUVAS, Arthritis
Rheum, 2005
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ANCA VASCULITIDES
WEGENT

• Pulse CYC for induction of remission (6 to 9
  pulses)
• MTX or AZA to maintain remission
• 120 patients

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WEGENT
Systemic Wegeners granulomatosis 2 organs
involved or kidney involvement or 1 organ
involved general symptoms (fever, weight loss)
Microscopic polyangiitis with FFS 1
IV CYC 0.6 g/m2 (d1, d15, d30)
0.7 g/m2/3 wk
Azathioprine 2 mg/kg/d or Methotrexate 25 mg/wk
Cotrimoxazole 1600 mg/d
2 yr
12 mo
6-12 mo
INDUCTION
MAINTENANCE
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WEGENT
126 randomized
12 Received gtgt 12 mo of maintenance
114 analyzed
59 MTX
55 AZA
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WEGENT
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WEGENT
Relapse-free survival curves
MTX n 59
AZA n 55
p 0.36
Relapse-free survival at 18 mo AZA 77.9
66.989.0 MTX 82.4 72.492.3
Relapse-free survival at 24 mo AZA 67.5
53.981.0 MTX 72.6 60.085.2
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WEGENT
Event-free survival curves
AZA n 55
MTX n 59
p 0.73
Event-free survival at 18 mo AZA 70.6
58.582.8 MTX 67.2 55.179.4
Event-free survival at 24 mo AZA 61.9
47.776.1 MTX 57.9 44.371.4
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WEGENT
MPA
Wegener
25
CD 20

• Le CD 20 nest pas exprimé par les cellules
  souches lymphoïdes B ni par lymphocytes B
  sécrétant les immunoglobulines.
• Le CD20 ne sinternalise pas, ne circule pas sous
  forme libre

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Monoclonal anti-CD20 (rituximab)

• WG CR at 11 mo, disappearance of ANCA
  (Specks, 2001)
• Refractory ANCA Vasculitides (n 11) ? 100
  CR
• (Keogh, 2005)
• RAVE Rituximab in ANCA-Associated Vasculitis
• oral CYC vs AntiCD20 for 3-6 mo

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BIOLOGICS IN SYSTEMIC VASCULITIS
Rituximab in Wegeners

• Open, pilot study, Keogh, 2005, Arthritis Rheum,
  52 268
• 10 patients, refractory to major drugs
• Clinical response in all patients
• Circulating B cells became indetectable
• ANCA titer decreased

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RAVE
1 to 3 pulses MPS
RTX 375 X 4 CS placebo CYC
CSCYC oral, 3 to 6 months
AZA 12-15 months
Placebo AZA
CROSS OVER IF NEEDED
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ANTI-CD20 Ab
Which role ?

• Induction treatment
• Maintenance treatment
• Treatment of relapses

Side effects ?

• Leukoencephalitis (JC), role of previous
  immunosuppression
• Other infections ?

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TREATMENT OF SYSTEMIC VASCULITIS
A NEW TREATMENT FOR MAINTENANCE ?
31

• MAINRITSAN
• MAINtenance of remission using
• RITuximab in Systemic ANCA associated
  vasculitides
• Systemic WG or MPA with FFS ? 1
• Newly diagnosed or after a relapse treated with
  CS-CYC

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MAINRITSAN
What are the issues ?

• Decrease the number of relapses
• Improve the tolerance of maintenance treatment

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MAINRITSAN
Inclusion criteria

• ANCA vasculitides
• Remission (first or after a second remission)
• In the 3 first months after starting azathioprine

34
MAINRITSAN
Non inclusion criteria

• Other vasculitides
• Active vasculitis
• Cancer, pregnancy, infection etc.

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Induction
Maintenance
MP pulses D1 - 3
CS
10 mg/d
5 mo
/- Plasmapheresis
RITUXIMAB 1 g at D1
( if ANCA or CD19/20 / 6 mo )
6-10
IV CYC D1-15-30 then /3 wk
Azathioprine 2 mg/kg/j
18 mo
3-6 mo
21-24 mo
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MAINRITSAN
Hypothesis

• Decrease the relapse rate by 50
• presently, relapse rate at 18 months is 22, and
  40 at 28 months.
• Number of patients 140 patients

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Hôpital Cochin, Paris
www.vascularites.org