Traditional vs. Early Aggressive Therapy for Multiple Sclerosis TREATMS Mo Mont nthly Webi binar nar Series Series May, 2018
Today’s Agenda • Announcements Amanda Bistran ‐ Hall • Protocol Training Scott Newsome • IRB Processes Presentation Cindy MacInnis • Trial Master File Steve Mayo • Mt. Everest Christina Grabarits • Q & A Team
Announcements • For all webinars, both a PDF copy of the slide presentation and a video recording are available through your Site Managers • Monthly Webinars are held on the 1 st Wednesday at 3pm and 1 st Thursday at 9am of every month • In order to attend, you must register • Contact your Site Managers with any questions! • Carolyn: carolynhkoenig@gmail.com • Sarah: slenington@optonline.net
Study Study Upda Updates tes JHU JHU open open to to re recruitment as as of of mi mid ‐ Apri April 2018. 2018. Scr Screening ing charts charts has has id identified 7 poten potential ca candi ndida dates tes and and scr screening ing visits visits ha have ta taken pl place ace fo for 1 week eek ‐ Thr Three pa patie tients ts curr curren ently tly re review ewing co consent ent fo form ‐ One One ineligib eligible le due due to to pl planni anning ng pr pregnancy nancy ‐ One One consid iderin ing options options fo for th ther erapy ve versus us clin clinic ical tria trial ‐ Tw Two wi will be be see seen th this is we week BRE BREAKING KING NEW NEWS: Fir First subj subject ect en enrolled lled ye yeste sterday at at Johns Johns Hopki Hopkins! s!
Protocol Training PI: Scott Newsome
TRaditional TRaditional vs vs. Ea Early Ag Aggr gressiv essive Ther Therap apy fo for Multiple ltiple Scler Sclerosis sis (TRE (TREAT ‐ MS MS) Tr Trial ELL ELLEN M. M. MO MOWR WRY, M. M.D., M. M.C. C.R. R. SCOTT D. SC D. NEW NEWSOME, E, D. D.O. O. ASSOCIATE PR ASSOCIA PROFESSO SOR OF OF ASSOCIA ASSO CIATE PR PROFESSOR OF OF NEUR NEUROLOG OGY AND AND EPID EPIDEMIO IOLOGY NEUR UROL OLOG OGY JOHNS HOPKIN JO HOPKINS UNIVER UNIVERSITY SITY JO JOHNS HOPKIN HOPKINS UNIVER UNIVERSITY SITY
Ra Rationale onale fo for TRE TREAT ‐ MS MS Ther There ar are multiple ltiple eff effective FD FDA ‐ appr approv oved ed ther therapies apies fo for relap lapsin ing ‐ re remitt tting MS MS; how however, the they ha have mi mini nima mal im impact once once the the pr progr ogressiv ssive phase phase has has ensued ensued These These ha have di differ eren ent le levels ls of of effic ficacy; acy; som some ar are tr trad aditio itional nal (i (i.e., .e., fir first ‐ lin line), while ile other others ar are hi higher gher ‐ eff effica cacy but but ca carry gr grea eater ris risks of of seriou serious adv adverse eve events ts Pi Pivotal clin clinic ical trials trials fo for appr approved ed MS MS ther therap apies ies ha have sho shown no no to to mo modes dest di differ erences ences in in di disabili sability ty accrual accrual dur during the the [sho [short] rt] trial trial per periods ods Wh Whet ether a mo more aggr aggressiv sive tr trea eatm tmen ent st strate tegy early early in in MS MS pr prevents events lo longer ‐ te term disab disability lity is is not not clear clear In In par particular icular, whet whether her ther there ar are subgr subgroup ups of of MS MS pa patien tients ts who who wo would bene benefit fit mo more than than other others is is unkno unknown wn
TRE TREAT ‐ MS MS: Obj Object ctives es 1. 1. To To ev evaluate te whet whether her an an “e “early ag aggr gressiv essive” ther therapy appr approach, ch, ve versus sta starting ng wi with a tr tradition aditional ther therapy, influences uences the the in interm rmedia iate ‐ ter term risk risk of of di disabi sabili lity ty pr progr ogression. ssion. => => Will ill in investig igate over overall and and wi within st strata rata of of people people at at hi higher gher ve versus lo lower risk risk of of lo longer ‐ te term disability disability 2. 2. To ev evaluate te if if, am among pa pati tien ents ts deem deemed ed at at lo lower risk risk fo for disab disability lity accum accumula lation tion who who sta start on on tr trad aditio itional, l, fir first ‐ lin line MS MS ther therapies ies but but ex experience br break eakthr hrough ough di disease, sease, those those who who swi switch ch to to a hi higher gher ‐ eff effica cacy ther therapy ve versus a ne new fir first ‐ lin line ther therapy ha have di differ eren ent inte termediate te ‐ ter term risk risk of of di disabili sability ty accum accumula lation. tion.
TRE TREAT ‐ MS MS: Study Study Desi Design gn Over Overvi view: ew: Pr Pragmat matic trial trial enr enrollin lling 900 900 particip participan ants ts who who me meet et 2017 2017 crit criteria ia fo for rela lapsin ing ‐ re remitt tting MS MS Sit Sites: s: ~45 ~45 si sites acr across ss the the Uni United ed St States (a (academic and and pr private neur neurology ology pr practices) actices) In Interventions: s: Hi Higher gher ‐ eff effica cacy ver versus us tr traditio aditional nal ther therap apies ies Pr Primary Out Outcom ome: e: Disab Disability lity pr progr ogression ssion (EDSS EDSS ‐ plus plus [r [rater ‐ blind linded]) d]) Particip rticipan ant Dur Duration: tion: Up Up to to 54 54 mon months ths EDSS=Expanded Disability Status Scale plus=Timed 25 ‐ foot walk and nine hole peg test
Eligibility Cri Eligibility Criteri eria Inclusion Criteria Exclusion Criteria Age 18 ‐ 60 Prior use of rituximab, ocrelizumab, alemtuzumab, mitoxantrone or cladribine; use of any MS DMT for > 6 months^ Meets 2017 McDonald criteria for relapsing ‐ remitting MS Use of any MS DMT within past 6 months; treatment with teriflunomide within past 2 years unless rapid wash out done Must be EITHER JC virus Ab negative or low positive (index Prior treatment with experimental aggressive therapies, antibody titer <0.9), OR negative for: Hepatitis B* and C*, other investigational immunomodulatory/suppressive TB** medication HIV negative Pregnant or breastfeeding Women of child ‐ bearing age who are planning or strongly If patient has prior history of chemotherapy*** or considering conception during the study time frame malignancy, documentation in chart explaining why potential risks of higher ‐ efficacy therapy are justified *Patients who demonstrate satisfactory use of antivirals for Hepatitis B or who successfully completed treatment for Hepatitis C may be enrolled, if approved by a gastroenterologist; **Patients with past history of appropriately ‐ treated TB (latent or active) are eligible; **None in past year; ^ If on DMT for ≤ 6 months, reason for discontinuation must not have been breakthrough disease
Ri Risk sk Str Strata Determi Determinan ants Enrollment within 6 months of 1 st attack: high risk if both Clinical or radiographic involvement of the spinal cord OR brainstem/cerebellum AND MRI with >10 T2 lesions OR ≥ 4 Gadolinium ‐ positive (Gad+) lesions, OR another attack in the first 6 months since the 1 st attack, OR new lesions on MRI if a subsequent MRI is available already Enrollment > 6 months since 1 st attack: high risk if any 2 of the 4 are true Clinical or radiographic involvement of the spinal cord OR brainstem/cerebellum MRI with >10 T2 lesions OR ≥ 4 Gad+ lesions Residual damage (incomplete recovery based on exam [Functional System Score ≥ 2 , with the deficit(s) on exam corresponding to the region of prior relapse]) Ongoing activity in the past year: 2 or more relapses OR ≥ 3 new MRI lesions in past year OR ≥ 2 Gad+ lesions
Orig igin inal Randomi Randomization tion 1:1 randomization 1:1 randomization
Me Medicat cation on Classes Classes Traditional (First ‐ line) Early Aggressive Glatiramer acetate (Copaxone, Glatopa, other generics) Alemtuzumab (Lemtrada) Intramuscular interferon (Avonex) Ocrelizumab (Ocrevus) Subcutaneous interferon (Betaseron, Extavia, Rebif) Rituximab (Rituxan) Natalizumab (Tysabri) Pegylated interferon (Plegridy) Teriflunomide (Aubagio) *Should not utilize dosages that exceed the maximally approved Dimethyl fumarate (Tecfidera) dosage for MS (or, in the case of rituximab, than the maximally approved dosage for rheumatoid arthritis) Fingolimod (Gilenya) *New FDA ‐ approved therapies will be added to medication lists after consensus ‐ based approach by Study Advisory Committee
Swi Switch in in Ther Therap apy fo for Br Breakthr eakthrough? ough? High risk disability indicators Low risk disability indicators
De Defi fining ning Br Breakthr eakthrough ough Di Disease sease • ANY breakthrough disease after 6 months on therapy will make allowable a discussion about change in therapy • Treating clinicians required to document discussion of switching therapy if excessive breakthrough has occurred • Modified Rio score will be used to define excessive breakthrough: Original: >4 new T2 lesions (MRI)=1 point; 1 relapse=1 point; 2 relapses=2 points ◦ Scores of 2 to 3= treatment non ‐ response with respect to progression risk at 4 years. Later re ‐ classified for those who scored 1 point (based on activity from months 12 ‐ 18) into: ◦ Medium ‐ low risk (no relapses, <2 new MRI lesions) same as score of zero ◦ Medium ‐ high risk ( ≥ 1 relapse or ≥ 2 new MRI lesions) same as score 2 or 3
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