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Randomized Controlled Trials of Methotrexate & Mycophen Randomized Controlled Trials of Methotrexate & Mycophen

Randomized Controlled Trials of Methotrexate & Mycophen - PowerPoint Presentation

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Randomized Controlled Trials of Methotrexate & Mycophen - PPT Presentation

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

mtx prednisone mmf methotrexate prednisone mtx methotrexate mmf line mycophenolate placebo 2008 trial 2016 mofetil patients study qmg sanders

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Slide1

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?