Richard J Barohn MD Chair Department of Neurology Gertrude and Dewey Ziegler Professor of Neurology University Distinguished Professor Vice Chancellor for Research University of Kansas Medical Center ID: 603765
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Randomized Controlled Trials of Methotrexate & Mycophenolate in MG
Richard J. Barohn, MD
Chair, Department of NeurologyGertrude and Dewey Ziegler Professor of NeurologyUniversity Distinguished ProfessorVice Chancellor for ResearchUniversity of Kansas Medical CenterKansas City, KSGary Gronseth, MDVice Chair, Department of NeurologyUniversity of Kansas Medical CenterKansas City, KS
www.rrnmf.comSlide2
Mechanism: select/rev cytostatic eff on T&B cells
Early Studies
Ciafaloni 20018/12 (67%) improved in 2 mosChaudhry 200150% of 20 MG pts improved in 6-12 mosCos 200059% of 29 MG pts improved in 6-12
mos Meriggioli et al 2003
85 pts-73% imp Meriggioli et al 2003Blinded RCT-14 pts/5 months Rx
MM-QMG imp 2.5Plac-QMG imp 0.24 (p=0.30)
Mycophenolate
Mofetil
(
CellCept
)Slide3
Mycophenolate
Mofetil Rand/Control Trials in MG
Sanders & colleagues (MSG Neurology 2008;71:394)Investigator initiated funded by FDA-ODGMust be AChR-Ab posNo prior IS Rx2.5 gm MM vs. plac
All placed on pred 20
1o – QMG 3 mos2o – MMT, MG-ADL
AChR-Ab, SFEMG80 subjects
Aspreva
sponsored-138 subjects
(Sanders et al
Neurol
2008;71:400)
Can already be on prednisone
9 month trialSlide4
Mycophenolate
Mofetil Rand/ControlTrials
in MGSanders & colleagues (MSG Neurology 2008;71:394)
Aspreva
sponsored-138 subjects (Sanders et al Neurol
2008;71:400)
RESULTS FOR BOTH:
NO SIGNIFICANT DIFFERENCE!Slide5
Mycophenolate
Mofetil Rand/Control Trials
Why Negative?Drug does not workPrednisone improved all pts and masked MM effectStudies were not long enoughEndpoints were not good enoughNon-homogenous populations enrolledSlide6
Phase II Trial of Methotrexate in MG
Barohn and Muscle Study Group FDA OPD R01 FD003538/IND #101,306
A randomized, double-blind, placebo-controlled study50 patients25 receiving MTX; 20mg/week25 receiving placebo/12 mo
studyHypothesis – adding MTX therapy will improve the MG manifestations so that prednisone dose can be reduced and clinical measures of MG severity will improve
The primary measure of efficacy will be the 9-month prednisone area under the curve (AUC)Secondary: QMG, MG ADL, MG Comp, MG QOL15 20 sites – KUMC, UTSW, UTSCSA, UC-Irvine, OSU, U. North Carolina, U. Virginia, UCSF – Fresno, U. Miami, U. Indiana, MGH, CPMC, U. Iowa, Toronto, Phoenix, Methodist, NM Center Houston, Penn State, U. Florida, U. Toronto
Conclusion: NEGATIVE STUDY
Pasnoor M, He J, Herbelin L, Burns TM, Nations S, Bril V, Wang AK, Elsheikh BH, Kissel JT, Saperstein D, Shaibani JA, Jackson C, Swenson A, Howard JF, Goyal N, David W,
Wichkund
M, Pulley M, Becker M, Mozaffar T, Benatar M,
Pazcuzzi
R, Simpson E, Rosenfeld J, Dimachkie MM, Statland JM, Barohn RJ, The Methotrexate in MG Investigators of the Muscle Study Group. A Randomized controlled trial of methotrexate for patients with generalized myasthenia gravis. Neurology. 2016; 87:57-64. PMCID:PMC4932232.Slide7
Neurology
. 2016 Jul 5;87(1):57-64.
PMID: 27306628PMCID: PMC4932232Slide8
MG MTX trial: Primary outcome
Prednisone area under the curve
Intent-to-treat analysis using multiple imputation methodMean Prednisone dose in :Methotrexate group: 3340.54 ± 2404.61Placebo : 3811.62 ± 1971.4P-value : 0.14Average daily prednisone doseMethotrexate group: 13.26 ± 9.54Placebo group: 15.13 ± 7.82Slide9
MG MTX
Trial: Secondary Outcome
MeasuresMethotrexate Mean changePlacebo mean change
Difference between Placebo and MTX
P valueQMG
-1.6 ±3.5
.28 ± 4.5
1.88
0.08
MGMMT
-5.6 ± 4.6
-3.7 ± 7.7
1.9
0.14
MGQOL
-4.3 ±9.2
-4.8 ± 11.4
0.5
0.38
MGADL
-1.4± 2.3
-0.26± 2.9
1.14
0.059
MG Composite
-4.8 ±4.4
-2.5± 5.4
2.30.052
*Intent-to-treat analysis using multiple imputationSlide10
MG MTX Trial: Is it “Negative”?
Why?
MTX/MMF do not workPrednisone probably works too wellDifficult to do studies with patients on prednisoneUnderdose methotrexateHigh number of PBO drop outsNot enough patients (underpowered)Statistical handling of dropoutsSlide11
MG MTX Trial: Is it “Negative”?
Why?
Prednisone probably works too wellMaybe hard to do MG studies with patients on prednisoneMethotrexate does not workUnderdose methotrexateHigh number of PBO drop outsNot enough patients (underpowered)Statistical handling of dropoutsSlide12
Myasthenia Gravis
My Rx Recommendations - prior to 2007
1st Line: Tensilon Mestinon Prednisone Thymectomy
2nd Line: Azathioprine
Mycophenolate Mofetil Cyclosporine 3rd Line:
IVIg Plasmapheresis
My Rx Recommendations – 2016
1st Line:
Enlon
Pyridostigmine
Prednisone
Thymectomy
!
2nd Line: Azathioprine
Cyclosporine
IVIg
3rd Line:
Plasmapheresis
Mycophenolate
Mofetil
Methotrexate4th Line: Rituximab? 5th Line: ? Cyclophosphamide ? Tacrolimus Slide13
Poor Internal Validity?
Study Risk of Bias
Meriggioli
2003 MMF Class II
MSG 2008 MMF
Class I
Sanders 2008 MMF Class I
Pasnoor 2016 MTX Class ISlide14
Imprecision
?
Sanders 2008 MMFPasnoor 2016 MTXDifference in Daily Prednisone Use
Favors MMF or MTX
Favors Placebo
Meta-analysis MMF
Pasnoor 2016 MTX
Difference in Change in QMG
Favors MMF or MTX
Favors PlaceboSlide15
Poor External Validity?