Monthly Webinar Series May 2019 Todays Agenda Announcements & - - PowerPoint PPT Presentation

Monthly Webinar Series

May 2019

Today’s Agenda

Announcements & Trial Updates Sandi Cassard Recent Enrollments Christina Grabarits Rowing Competition & Top Enroller Christina Grabarits Protocol Refresher Scott Newsome and Ellen Mowry Q&A All

Announcements & Trial Updates

SANDI CASSARD

Study Updates – Enrollment

THANK YOU to activated sites for continuing to screen and enroll patients! We have 43 sites activated and 167 patients enrolled as of 4/30/19! Please try to find at least 1 new candidate each week so we can accelerate enrollment!!!

______________________________________________________________________________

Study Updates - Reminders

1) When consenting patients for the trial, please document the consent process, as detailed in the protocol and MOP, and upload signed consent form and completed DOC process form to VISION database under Source Docs tab, item # 10. 2) PLEASE ENTER VISIT DATA WITHIN 1 WEEK OF THE VISIT AND UPLOAD PDFs of SOURCE DATA SO WE CAN MONITOR THE DATA! We need all visit CRFs to verify the data. CRFs may be scanned as a single PDF, if preferred, and uploaded under Source Docs tab, item # 9.

Study Updates – Revised CRFs

3) Please see study website (http://treat-mstrial.org – Documents section) for most up-to-date case report forms (CRFs), including version 2.0 for baseline and month 6 visits. Month 12 visit CRFs are also posted.

• Month 6 Relapse Assessment CRF recently updated to capture data

from review of MRI performed after 6 months on DMT.

Study Updates – Revised CRFs

Study Updates – VISION Database - EDSS

4) Please ensure EDSS examiners use our study’s EDSS CRFs and NOT the neurostatus form.

• Recent updates in VISION database include fixing the order of entering the Ataxia

questions under cerebellar functional system. VISION database now matches CRFs.

Study Updates – Baseline MRIs

5) Please make sure to upload the baseline MRI used to risk stratify the patient. You may need to request CD from patient or ask patient to bring it in at next visit/mail it to you. See MRI manual – version 6.0 on the study website for instructions.

Announcements

Impact of Mt Everest Survey due! Email sent to sites with link to a brief 3-5 minute survey

• n 4/16.

Reminder email coming soon!

Recent Enrollments

CHRISTINA GRABARITS

The Rowing Competition

CHRISTINA GRABARITS

Rowing Competition Standings

1- Team E (44 points) 2- Team A (36 points) 2- Team F (36 points) 3- Team D (34 points) 4- Team H (26 points) 5- Team B (24 points) 6- Team C (22 points) 7- Team G (18 points)

Individual Site Competition

Site Points

• 1. Norton Neurology

124

• 2. UAB

109

• 3. UFL Gainesville

86

• 4. Christiana Care

71

• 5. Swedish

70

• 6. Advanced Neuro Spc

67

• 7. U Kansas Med Ctr

65

• 8. NYU

61

• 9. U Washington

54

• 10. Mayo Clinic

50

Rowing Competition Standings

Rowing Competition

https://treat.preludedynamics.com

Monthly Randomization Race

April’s Top Performers:

Site Randomizations

Geisinger Clinic 2 KU Medical Center Research Institute 2 Norton Neurology Services 2 University of Alabama at Birmingham 2 Johns Hopkins Hospital 6

April’s Top Enroller: Norton Neurology Services $50

TR TRaditional vs. Early Aggressive Therapy for Multiple Sclerosis (TREAT-MS) Trial

ELLEN M. MOWRY, M.D., M.C.R. ASSOCIAT ATE PROFESSOR OF NEUROLOGY AND EPIDEMIOLOGY JOHNS HOPKINS UNIVERSITY

SCOTT D. NEWSOME, D.O. ASSOCIATE PROFESSOR OF NEUROLOGY JOHNS HOPKINS UNIVERSITY

Overview/Reminder of Rationale for TREAT-MS MS

• There is

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• Whe

hether a more aggressive tr treatment str trategy early in in MS pr prevents lo longer- term dis isability is is not cle clear. .

• Th

Ther ere may be be sub subgroups of

• f pa

patie ients who ho wou

• uld

ld be benefit it mor

• re

e tha than ot

• the

hers

• Rece

cently pu published observ rvational stu tudies hi hint towards early aggressive th therapy min inimizing dis isability and conversion to secondary progressive MS vs. . tr traditional.

TREAT-MS: Objectives

• 1. To evaluate whether an “early aggressive” therapy approach, versus

starting wit ith a tr traditional th therapy, , in influences th the in intermediate-term ris isk of f dis disability pr progression.

=> => Will ill in investigate overall ll an and with ithin in str trata of

• f people at

t hig igher versu sus lo lower risk risk of

• f

lon longer-term dis isab abili ility

2.

• 2. To evaluate if

if, , among patients deemed at t lo lower ris isk for dis isability acc ccumulation who start on tr traditional, , fir first-line MS th therapies but experience br breakthrough dis disease, , th those who ho swit itch to a hig higher-efficacy th therapy versus a ne new fir first-line th therapy have dif ifferent in intermediate-term ris isk of f dis isability acc ccumulation.

TREAT-MS: Study Design

Overview: Pragmatic ic tria trial l enrolli lling 90 900 0 par articip ipants who meet 20 2017 17 cri criteria for rela lapsin ing- remittin ing MS Si Sites: ~5 ~50 0 si sites ac across ss th the Unit ited St States (ac (academic ic an and priv rivate neurology practices) In Interv rventions: Hig igher-efficacy versus tr traditional l th therapies Prim rimary ry Outcome: Di Disabili ility progression (E (EDSS-plu lus [r [rater-blin linded]) Par articipant Du Duration: Up to

• 54

54 months

EDSS=Expanded Disability Status Scale plus=Timed 25-foot walk and nine hole peg test

Eligibility Criteria

Inclusion Criteria Exclusion Criteria Age 18-60 Prior use of rituximab, ocrelizumab, alemtuzumab, mitoxantrone or cladribine Meets 2017 McDonald criteria for relapsing-remitting MS Use of any MS DMT for > 6 months^ or 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 antibody titer <0.9), OR negative for: Hepatitis B* and C*, TB** Prior treatment with experimental aggressive therapies,

• ther investigational immunomodulatory/suppressive

medication HIV negative Pregnant or breastfeeding If patient has prior history of chemotherapy*** or malignancy, documentation in chart explaining why potential risks of higher-efficacy therapy are justified Women of child-bearing age who are planning or strongly considering conception during the study time frame

*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

Risk Strata Determinants

Enrollment within 6 months of 1st attack: high risk if both Clinical or radiographic involvement of the spinal cord OR brainstem/cerebellum AND BRAIN MRI with >10 T2 lesions OR ≥4 Gadolinium-positive (Gad+) lesions, OR another attack in the first 6 months since the 1st attack, OR new lesions on MRI if a subsequent MRI is available already Enrollment > 6 months since 1st attack: high risk if any 2 of the 4 are true Clinical or radiographic involvement of the spinal cord OR brainstem/cerebellum BRAIN 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 that began > 6 months ago]) 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

Medication Classes

Traditional (First-line) Glatiramer acetate (Copaxone, Glatopa, other generics) Intramuscular interferon (Avonex) Subcutaneous interferon (Betaseron, Extavia, Rebif) Pegylated interferon (Plegridy) Teriflunomide (Aubagio) Dimethyl fumarate (Tecfidera) Fingolimod (Gilenya) Siponimod (Mayzent)* Early Aggressive Alemtuzumab (Lemtrada) Ocrelizumab (Ocrevus) Rituximab (Rituxan) Natalizumab (Tysabri) Cladribine (Mavenclad)*

*New; classification based on consensus-based approach by Study Advisory Committee (IRB approval pending)

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

• Gadolinium-enhancing lesions can be used as evidence of

breakthrough disease activity if the “month 6” first on treatment MRI is performed after 7 months* on 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

*Can use after new protocol revisions IRB approved

Visit Schedule & Activities

Visit Activity

Screening/ Baseline Month 6 +/- 3 months Month 12 +/- 3 months Month 18 +/- 3 months Month 24 +/- 3 months Month 30 +/- 3 months Month 36 +/- 3 months Month 42 +/- 3 months Month 48 +/- 3 months

Informed consent, screening/baseline evaluation X Medical history, relapse assessment and MRI review X X X X X X X X X Risk Stratification X Randomization X Medication review X X X X X X X X X Blinded EDSS exam X X X X X X X X X MS Functional Composite (MSFC)- 4 (with low-contrast visual acuity) X X** X X** X X** X X** X Symbol Digit Modalities Test X X X X Patient-Determined Disease Steps X X X X X Brain MRI* X* X X X X X OCT (if standard of care) X X X X X Safety/ Adverse event assessment X X X X X X X X

Please note:

*The baseline MRI will be done per local standard of care (some

sites may choose not to do it for patients who have recently had imaging; since the “month 6” MRI will be used for comparative baseline for both analyses and clinical decision-making. Repeat MRI at time of enrollment is up to discretion of treating physicians). ** At month 6, 18, 30, and 42 visits, only part of the MSFC-4 will be repeated: Timed 25-foot walk test and nine hole peg test.

Home-based patient-reported

• utcomes

Home-based ePRO

Baseline Month 3 +/- 3 months Month 9 +/- 3 months Month 21 +/- 3 months Month 33 +/- 3 months Month 45 +/- 3 months Month 48 +/- 3 months End of Trial

MSIS-29*

X X X X X X X

Patient-Determined Disease Steps

X X X X X X X X

Neuro-QoL**

X X X X X X X

Medication adherence survey

X X X X X X

Social status and lifestyle factors

X X X X

* MSIS-29: Multiple Sclerosis Impact Scale; ** Neuro-QoL: Quality of Life in Neurological Disorders

Primary Outcome: EDSS-plus

EDSS change (change at any 6 month time point of > 1.0 point if baseline EDSS is < 5.5 or of > 0.5 if baseline EDSS is > 6.0, that is sustained 6 months later) OR > 20% worsening on either the timed 25-foot walk test (T25FWT) or the nine hole peg test (9HPT) that is sustained 6 months later

Secondary Outcomes

• Patient-reported disability (Patient-Determined Disease Steps)
• Impact of MS (MSIS-29)
• Health-related quality of life (NeuroQOL)
• Relapse recovery
• Social status
• Clinical performance metrics (MS Functional Composite, Symbol Digit

Modalities Test, low-contrast letter acuity)

• Clinically significant adverse events (all SAEs and any AE that leads to dose

reduction or decision to stop medication])

Tertiary Outcomes

• Atrophy measures

 Brain magnetic resonance imaging and optical coherence tomography

• Inflammatory activity

 Relapses, T2 lesion burden, new/enlarging T2 lesions, and new T1 hypointensities

• Use of MS-related symptomatic medications and non-medication interventions

(including new prescriptions, increase in medication dosing/frequency, referrals)

Biobanking Substudy

• Overall goal is to identify biomarkers of long-term prognosis and treatment

response in MS

• Identification of prognostic biomarkers will allow: 1) for identifying patients

who may benefit the most in the future from a more aggressive treatment strategy up front; 2) for identifying biomarkers of treatment response that could help future discrimination of whether or not a treatment is working prior to the development of neurologic symptoms that may be irreversible and permanent

• The only eligibility criterion is that the participant previously was consented

in the TREAT-MS trial

• Time points for blood collection: baseline visit, month 6 visit, and possibly at

time of medication switch, and end of study

Other Important Reminders

• Treatment discontinuation for other reasons: 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.

• The factors that supported each individual treatment choice will be documented at

baseline and at any point a switch is made.

• Safety reporting: collating all the AEs experienced by participants for each MS-specific

disease-modifying therapies is out of the scope of this trial.

• If a participant is enrolled in error based on inclusion/exclusion criteria, the

participant will be deemed a screen failure and the randomization slot will be returned to the pool for reassignment (after version 1.9 of protocol IRB approved).

Lessons Learned- Referrals & Visits

• Know site level barriers; be adaptable with workflows (? Identify new referrals)
• Meet regularly with study team and colleagues (team and collaborator huddles)
• A little extra time goes a long way when discussing study (e.g. “add on” model,

end of clinic, short interval for follow-up)

• Emphasize that the study activities parallel those they would have anyways

(e.g. timing of visits, MRIs, etc)

• Great autonomy for the patient/clinician team will be maintained

Lessons Learned- Protocol

• Eligible candidates can be any relapsing remitting MS patient who is treatment-naïve or has

had limited exposure to one DMT per protocol (NO DISEASE DURATION CRITERION)

• If hepatitis B or C or Tb positive, can still be eligible for TREAT-MS if JCV antibody status is

compatible (negative or <0.9), or after appropriate treatment!

• Documenting HIV negative is required regardless of treatment chosen
• Screening/Baseline visits can be done over multiple visits
• The EDSS examiner can do all blinded assessments, just the EDSS, or EDSS and other blinded

assessments; they need to fill out own paperwork as close as possible to the clinic visit

• Baseline study-related assessments need to be done as close to signing consent as possible
• Treating clinician is not exclusive to PI

Screening for infections

Per prescribing guidelines, hepatitis B surface Antigen and anti-hepatitis C antibodies are used for screening

• Hepatitis B: surface antibody confirms presence (+) or absence (-) of immunity.

Someone who is surface antibody negative may indeed be infected with hepatitis B.

HIV: Preferable to screen with antibodies. PCR can also be substituted.

Lessons Learned- MRI

• Clearing up some MRI criteria “gray areas” (disability risk, new lesions over time):

1) >10 T2 lesions (brain) 2) lesion size and location (discussed size criteria but difficult to standardize based on literature and in a pragmatic trial; use your best judgment- if you think a lesion is demyelinating in nature-> it counts

• Early Exit Strategy: low threshold for switching treatment (allowed if ANY disease activity occurs

after 6 months on therapy) 1) Revision of timing and interpretation of month 6 MRI in assessing breakthrough disease activity; Gadolinium-enhancing lesions can be used as evidence of breakthrough disease activity if the “month 6” MRI is performed after 7 months on therapy (Consider doing MRI after 7 months on treatment) 2) Re-randomization at that point ONLY if the person was low-risk for disability at enrollment AND was initially on a first-line therapy (similar consideration as outside of a trial!)

MRI: Important

Please work with the MRI team, if you have not, to submit a baseline scan, or a dummy run (if allowed/approved at your site), WELL IN ADVANCE of your first month 6 MRI

• Poor-quality “month 6” MRI sets the stage for less useful imaging data for

the whole study

Even if a patient does NOT get a new MRI at baseline, you still must upload their most recent prior brain MRI into the Vision database!!!

• Easiest to remind patients to bring at the time of their clinic visit.

Lessons Learned- Other

• Since medications are all approved for MS, our PRA analysts said notification

to insurance company that patient is in trial NOT required (Recommend NOT stating trial involvement in notes)

• Consider referring to clinical study as opposed to clinical trial
• We have medication appeal letters and checklist of disease characteristics

with references that you can incorporate into clinic notes and/or insurance appeals (found on http://treat-mstrial.org [Documents tab])

• Try to limit time between discussion of study and signing of consent (applies

to those going home with consent)

Op Open en fo for Q r Que uest stio ions ns

Thank You for attending today’s webinar!

Encore tomorrow at 9 AM EDT!

June’s Monthly Webinar will be held on the 5th at 3 PM and 6th at 9 AM EDT