Monthly Webinar Series January, 2019
Today’s Agenda Announcements/Trial Updates Christina Grabarits This Month’s Top Enroller & Prize Winner! Christina Grabarits Breakthrough Diseases & Re-Randomizations Ellen Mowry & Scott Newsome Commitment Pledge Responses Ellen Mowry & Scott Newsome Mt. Everest & Rowing Competition Christina Grabarits Q & A Team
Announcements/Trial Updates CHRISTINA GRABARITS
TREAT-MS Trial Study Updates We now have 29 sites activated and 64 patients enrolled!!! We need each activated site to screen at least 6 patients each month and enroll 3-4 each month so we can reach our goal of 900 enrolled by June 30, 2019! Thank you for your dedication to the trial and please reach out with questions! The Johns Hopkins Coordinating Center is here to support you!!!
Next in-person Study Advisory Committee (SAC) meeting will be held in Dallas, TX on Save the Date!!! February 27, 2019 from 1:30 – 5 pm, preceding the ACTRIMS meeting.
Activated Sites *AS OF FRIDAY, 12/28/18
Recent Enrollments *AS OF FRIDAY, 12/28/18
Monthly Randomization Race December Enrollments: Site Randomizations University of Washington 1 Norton Neurology Specialists 2 Christiana Care 1 University of Kansas Medical Center 2 University of Alabama at Birmingham 3 Johns Hopkins 3 Total this month 12
December’s Top Enroller: University of Alabama at Birmingham $50
Breakthrough Disease and Re-randomization ELLEN M. MOWRY, M.D., M.C.R. SCOTT D. NEWSOME, D.O. ASSOCIATE PROFESSOR OF ASSOCIATE PROFESSOR OF NEUROLOGY AND EPIDEMIOLOGY NEUROLOGY JOHNS HOPKINS UNIVERSITY JOHNS HOPKINS UNIVERSITY
TREAT-MS: Objectives 1 . To evaluate whether an “early aggressive” therapy approach, versus starting with a traditional th ther erapy, in influ fluen ences th the e in inter ermediate-term risk risk of of dis isabil ilit ity progression. => => Will ill in inves estigate overall ll and with ithin str trata of of peo eople at t high igher ver ersus lo lower risk risk of of lon longer-term dis isabili lity 2. 2. To evaluate if if, , among patients deemed at t lo lower ris risk for dis isability ac accumulatio ion who start on tr traditional, , fir first-line MS th therapies but experience breakthrough dis isease, , th those who switch to a a hig igher-efficacy th therapy ver ersus a new fir first-line th therapy have different in intermediate-term ris risk of f dis isability accumulation.
Risk Strata Determinants 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
Original Randomization 1:1 randomization 1:1 randomization
Switch in Therapy for Breakthrough? High risk disability indicators Low risk disability indicators
Defining Breakthrough Disease • 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
TREAT-MS Maximum-Tolerated Modified Rio Score End of Year 1: a Modified Rio Score of 2- 3, or in “medium - high” risk subgroup End of Year 2: a) if prior Modified Rio Score was medium-low risk (at year 1); anything more than 1 additional T2 hyperintensity at year 2 MRI (or earlier in year 2 if a relapse occurs prior to the year-end visit) b) if Year 1 Modified Rio Score was 0, a Modified Rio Score of “medium - high” risk or greater Subsequent years will be treated in the same fashion. For example, at the end of year 3: a) if prior Modified Rio Score was medium-low (at year 2): anything more than 1 additional T2 hyperintensity by end of year 3 (or earlier in year 3 if a relapse occurs prior to the year-end visit) b) if Year 2 Modified Rio Score (at year 2) was 0, a Modified Rio Score of “medium - high” risk or greater
MRI logistics: timing of month 6 MRI Perhaps the most critical MRI in terms of having it, and its timing. Why? Able to switch therapy for ANY NEWbreakthrough disease occurring AFTER 6 months on therapy Doing the month 6 MRI at the wrong time can reduce the ability to use it to support claim for breakthrough disease: If “month 6” MRI is completed (relative to start date of first therapy) : ≤ 6 months: for the subsequent MRI scan, we will only be able to confirm a new lesion occurred “after 6 months on therapy” if the new lesion is enhancing >6 months-8 months: can serve as true reference MRI scan against which subsequent new lesions can be confirmed as occurring “after 6 months on therapy” >8 months: if a new lesion is present AND enhancing, we can assume it developed “after 6 months on therapy;” if not enhancing, the MRI will simply be a reference MRI scan against which subsequent new lesions can be confirmed Advice: unless you are controlling the scheduling of the “month 6 MRI,” don’t order it until AFTER they have been on the therapy for 6 months. ◦ If you prefer to have MRI in hand at the visit, since clinic visit windows are wide, perhaps schedule MRI plus clinic visit for a bit >6 months AFTER start date of DMT
Who Gets Re-randomized for Breakthrough? High risk disability indicators Low risk disability indicators
Switch in Therapy for Breakthrough? High risk disability indicators Low risk disability indicators • The other patients do not have a re-randomization for first breakthrough if they are changing therapy • If patients in the re-randomized group have a second breakthrough after 6 months on THAT therapy, there is no more randomization
Medications by Treatment Class 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) (Cladribine, if it becomes FDA-approved) Teriflunomide (Aubagio) Dimethyl fumarate (Tecfidera) *Should not utilize dosages that exceed the maximally approved dosage for MS (or, in the case of rituximab, than the maximally approved dosage for RA) Fingolimod (Gilenya) *New FDA-approved therapies will be added to medication lists after consensus-based approach by Study Advisory Committee
Re-randomization Demo in Vision
Documenting Treatment Switches • Treatment discontinuation for reasons other than breakthrough: Participants who discontinue therapies for reasons other than breakthrough disease (e.g. intolerance, adverse effect, desire to conceive) will be encouraged (except in the instance of trying to conceive or pregnancy itself, or when such treatment is otherwise contraindicated) to choose another therapy within the efficacy class to which the discontinued therapy belongs. • Regardless of reason for switch, the factors that supported each individual treatment choice will be documented at baseline and at any point a switch is made.
Commitment Pledge ELLEN M. MOWRY, M.D., M.C.R. SCOTT D. NEWSOME, D.O. ASSOCIATE PROFESSOR OF ASSOCIATE PROFESSOR OF NEUROLOGY AND EPIDEMIOLOGY NEUROLOGY JOHNS HOPKINS UNIVERSITY JOHNS HOPKINS UNIVERSITY
Your Commitment is KEY! Activated sites as of 12/11/18 have received this commitment letter from the trial PIs at Johns Hopkins along with this commitment pledge Sign and send back your commitment pledge ASAP
Sites Returned Commitment Pledge Date Signed Date Letter Letter Site Sent to Site Received from Site Advanced Neurology Specialists 12-Dec-18 13-Dec-18 University of Maryland 12-Dec-18 13-Dec-18 New York University School of Medicine 12-Dec-18 14-Dec-18 University of Kansas Medical Center 12-Dec-18 17-Dec-18 University of South Florida Health 12-Dec-18 20-Dec-18 Columbia Presbyterian 11-Dec-18 21-Dec-18 University of Miami 12-Dec-18 21-Dec-18 Central Texas Neurology 12-Dec-18 14-Dec-18 University of Washington 11-Dec-18 14-Dec-18
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