身 RRNME EARN FAST RICK S RI Randomized controlled trials of ww.rrnmfcom Methotrexate mycophenolate in MG Richard」. Baron,MD Gary Gronseth, MD Chair, Department of Neurology Vice Chair, Department of Neurology Gertrude and dewey Ziegler Professor of University of Kansas Medical Center Neurology Kansas city, ks University distinguished Professor Vice Chancellor for research University of Kansas Medical Center Kansas city, Ks
Randomized Controlled Trials of Methotrexate & Mycophenolate in MG 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 Kansas City, KS Gary Gronseth, MD Vice Chair, Department of Neurology University of Kansas Medical Center Kansas City, KS www.rrnmf.com
Mycophenolate Mofetil (CellCept) Mechanism: select/rev cytostatic eff on t&B cells Early Studies · Ciafaloni2001 8/12(67%)improved in 2 mos Chaudhry 2001 50%of 20 Mg pts improved in 6-12 mos ·CoS2000 59%of 29 MG pts improved in 6-12 mos Meriggioli et al 2003 °85pts-73%imp Meriggioli et al 2003 Blinded RCT-14 pts/5 months Rx MM-QMG imp 2.5 Plac-QMG imp 0.24(p=0.30)
Mechanism: select/rev cytostatic eff on T&B cells Early Studies • Ciafaloni 2001 • 8/12 (67%) improved in 2 mos • Chaudhry 2001 • 50% of 20 MG pts improved in 6-12 mos • Cos 2000 • 59% of 29 MG pts improved in 6-12 mos • Meriggioli et al 2003 • 85 pts-73% imp • Meriggioli et al 2003 • Blinded RCT-14 pts/5 months Rx • MM-QMG imp 2.5 • Plac-QMG imp 0.24 (p=0.30) Mycophenolate Mofetil (CellCept)
Mycophenolate Mofetil Rand/ Control Trials in Mg Sanders colleagues (MSG Aspreva sponsored-138 Neurology 2008; 71: 394 subjects(Sanders et al Neurol Investigator initiated funded 2008;71400) by FDA-ODG Can already be on prednisone Must be achr-Ab pos ·9 month tria No prior Is Rx 2.5 gm MM Vs plac All placed on pred 20 10-QMG3 mos .20-MMT. MG-ADL AChR-Ab, SFEMG °80 subjects
Mycophenolate Mofetil Rand/Control Trials in MG • Sanders & colleagues (MSG Neurology 2008;71:394) • Investigator initiated funded by FDA-ODG • Must be AChR-Ab pos • No prior IS Rx • 2.5 gm MM vs. plac • All placed on pred 20 • 1 o – QMG 3 mos • 2 o – MMT, MG-ADL • AChR-Ab, SFEMG • 80 subjects • Aspreva sponsored-138 subjects (Sanders et al Neurol 2008;71:400) • Can already be on prednisone • 9 month trial
Mycophenolate Mofetil Rand/Control Trials in MG Sanders colleagues(MSG Neurology quantitative 2008;71394) myasthenia gravis score over ti y treatment group Week Vertical bars indicate one SEM Aspreva sponsored-138 subjects(Sanders Figure 2 ntotal Quantitative Myasthenia Gravis score(QMO S)in the et al Neuro/ 2008; 71: 400) RESULTS FOR BOTH NO SIGNIFICANT DIFFERENCE The and point includes the weak 36 and early termination viait Early termination nalysen aton carnied forward method tor the week 30vs
Mycophenolate Mofetil Rand/Control Trials in MG Sanders & colleagues (MSG Neurology 2008;71:394) Aspreva sponsored-138 subjects (Sanders et al Neurol 2008;71:400) RESULTS FOR BOTH: NO SIGNIFICANT DIFFERENCE!
Mycophenolate Mofetil Rand/ Control Trials Why Negative? Drug does not work Prednisone improved all pts and masked MM effect Studies were not long enough Endpoints were not good enough Non-homogenous populations enrolled
Mycophenolate Mofetil Rand/Control Trials Why Negative? •Drug does not work • Prednisone improved all pts and masked MM effect • Studies were not long enough • Endpoints were not good enough •Non-homogenous populations enrolled
Phase ll trial of methotrexate in mg Barohn and Muscle Study group FDA OPD R01 FD003538IND#101, 306 A randomized double-blind placebo-controlled study 50 patients 25 receiving MTX; 20mg/week 25 receiving placebo/12 mo study Hypothesis- 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. lowa. 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 J 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
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 study • 50 patients ̶ 25 receiving MTX; 20mg/week ̶ 25 receiving placebo/12 mo study • Hypothesis – 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
A randomized controlled trial of methotrexate for patients with generalized Neurology.2016Jul587(1):57-64. myasthenIa gravis PM|D:27306628 PMCID: PMC4932232 Objective To determine the steroidl-sowring effect of methotrexate OTX) n pa erts with rmp Taf M Bn, MD merwht4 to 12. secondary outeome Carlene lackan. Reshui rolled MTX did rot reduce the morth 4-1 Jane F. on adverse eont was r no storoid-ooaing benefit of MTX in MG over 12 moths of treat Micael Benatar, MD faed for a better undrstanding af outeome masure variahairy for futre cinical trials rs wotm genaral Ericka Simpe MD MG MTX does not significatly reduce the prednisone AUDTC over 12 months of therapy Rachid L Bahn. M M纪C nificant morbidity. Symptoms indude difficulties 式二二 ine and coape Azathioprine's steroid-sparing benefi 92016
Neurology. 2016 Jul 5;87(1):57-64. PMID: 27306628 PMCID: PMC4932232
MG MTXtrial: Primary outcome Prednisone area under the curve Intent-to-treat analysis using multiple imputation method Mean prednisone dose in Methotrexate group 3340.54±2404.61 Placebo 3811.62±1971.4 ·Pva|ue:0.14 Average daily prednisone dose · Methotrexate group 13.26±9.54 Placebo group 15.13±7.82
MG MTX trial: Primary outcome Prednisone area under the curve Intent-to-treat analysis using multiple imputation method Mean Prednisone dose in : • Methotrexate group: 3340.54 ± 2404.61 • Placebo : 3811.62 ± 1971.4 • P-value : 0.14 Average daily prednisone dose • Methotrexate group: 13.26 ± 9.54 • Placebo group: 15.13 ± 7.82
MG MTX Trial: Secondary outcome Measures Methotrexate Placebo mean Difference betweenPvalue Mean change change Placebo and mtx QMG 1.6±3.5 28±4.5 1.88 0.08 MGMMT 5.6±4.6 -3.7±77 1.9 0.14 MGQOL 4.3±92 -4.8±11.4 0.5 0.38 MGADL -1.4±23-0.26±29 1.14 0.059 G Composite 4.8±4.4 2.5±5.4 2 0.052 *Intent-to-treat analysis using multiple imputation
MG MTX Trial: Secondary Outcome Measures Methotrexate Mean change Placebo mean change Difference between Placebo and MTX P value QMG -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 2.3 0.052 *Intent-to-treat analysis using multiple imputation
MG MTX Trial: Is it Negative"? Why? MTX/MMF do not work Prednisone probably works too well Difficult to do studies with patients on prednisone Underdose methotrexate High number of Pbo drop outs Not enough patients(underpowered Statistical handling of dropouts
MG MTX Trial: Is it “Negative”? Why? • MTX/MMF do not work • Prednisone probably works too well • Difficult to do studies with patients on prednisone • Underdose methotrexate • High number of PBO drop outs • Not enough patients (underpowered) • Statistical handling of dropouts