Mo Mont nthly Webi binar nar Series Series May, 2018 Todays - - PowerPoint PPT Presentation
Traditional vs. Early Aggressive Therapy for Multiple Sclerosis TREATMS Mo Mont nthly Webi binar nar Series Series May, 2018 Todays Agenda Announcements Amanda Bistran Hall Protocol Training Scott Newsome IRB Processes
Traditional vs. Early Aggressive Therapy for Multiple Sclerosis TREATMS
May, 2018
Amanda Bistran‐Hall
Scott Newsome
Cindy MacInnis
Steve Mayo
Christina Grabarits
Team
are available through your Site Managers
JHU
JHU open
to re recruitment as as of
mid‐Apri April 2018. 2018.
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BREAKING KING NEW NEWS: Fir First subj subject ect en enrolled lled ye yeste sterday at at Johns Johns Hopki Hopkins! s!
PI: Scott Newsome
ELL ELLEN M.
MOWR WRY, M. M.D., M. M.C. C.R. R. ASSOCIA ASSOCIATE PR PROFESSO SOR OF OF NEUR NEUROLOG OGY AND AND EPID EPIDEMIO IOLOGY JO JOHNS HOPKIN HOPKINS UNIVER UNIVERSITY SITY
SC SCOTT D.
NEWSOME, E, D. D.O. O. ASSO ASSOCIA CIATE PR PROFESSOR OF OF NEUR UROL OLOG OGY JO JOHNS HOPKIN HOPKINS UNIVER UNIVERSITY SITY
Ther
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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
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
e: Disab Disability lity pr progr
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
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 antibody titer <0.9), OR negative for: Hepatitis B* and C*, TB** Prior treatment with experimental aggressive therapies,
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
Enrollment within 6 months of 1st 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 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 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
1:1 randomization 1:1 randomization
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) Early Aggressive Alemtuzumab (Lemtrada) Ocrelizumab (Ocrevus) Rituximab (Rituxan) Natalizumab (Tysabri)
*Should not utilize dosages that exceed the maximally approved dosage for MS (or, in the case of rituximab, than the maximally approved dosage for rheumatoid arthritis) *New FDA‐approved therapies will be added to medication lists after consensus‐based approach by Study Advisory Committee
High risk disability indicators Low risk disability indicators
allowable a discussion about change in therapy
therapy if excessive breakthrough has occurred
Original: >4 new T2 lesions (MRI)=1 point; 1 relapse=1 point; 2 relapses=2 points
Later re‐classified for those who scored 1 point (based on activity from months 12‐18) into:
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
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 MS Functional Composite (MSFC)‐ 4 (with low‐contrast visual acuity) 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
*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 visit, only part of the MSFC‐4 will be repeated: Timed 25‐foot walk test and nine hole peg test.
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 (including employment status) and lifestyle factors (diet and exercise) X X X X * MSIS‐29: Multiple Sclerosis Impact Scale; ** Neuro‐QoL: Quality of Life in Neurological Disorders
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
Modalities Test, low‐contrast letter acuity)
reduction or decision to stop medication])
Brain magnetic resonance imaging and optical coherence tomography
Relapses, T2 lesion burden, new/enlarging T2 lesions, and new T1 hypointensities
(including new prescriptions, increase in medication dosing/frequency, referrals)
response in MS
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
in the TREAT‐MS trial
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.
baseline and at any point a switch is made.
specific disease‐modifying therapies is out of the scope of this trial.
treatment strategies in the relapsing‐remitting phase of MS can prevent, delay,
trial will be guided by a Study Advisory Committee and safety oversight by a Data Safety Monitoring Board
Who pays for MRIs?
Will the sponsor be providing source documents? When do you think they will be distributed to the sites?
will be available by May 15 on the TREAT‐MS website http://treat‐mstrial.org
Who are the blinded raters? How many do we need? Which do which tests? What should their qualifications/backgrounds be? What training will they need?
contrast vision test and SDMT.
combination of assessments (e.g., EDSS and timed 25 foot walk only).
assistant or nurse practitioner with experience doing a neurologic exam.
research/study coordinator or technician.
these assessments (they are not blinded).
Who are the blinded raters? How many do we need? Which do which tests? What should their qualifications/backgrounds be? What training will they need?
certificate (level A, B or C) from a prior trial or prior experience completing the Kurtze EDSS exam for an investigator‐initiated trial.
training and certification through neurostatus.net.
members (review of these slides and on‐line post‐test completion).
Who are the blinded raters? How many do we need? Which do which tests? What should their qualifications/backgrounds be? What training will they need?
coordinator or medical assistant on the IRB study team who has reviewed the training videos and completed the on‐line post‐tests.
practice administering tests to their co‐workers prior to administering tests to study patients.
cover for absences and vacations.
Important Reminder!!!
SDMT examiners) MUST remain blinded to the patient’s risk stratum, randomized class of MS medications and specific MS therapy.
refrain from asking the patient these questions and remind the patients to limit conversation and avoid talking about their MS therapy or how it is administered.
What kind of recruitment materials will we receive? Will recruiting be done through the National MS Society?
referring provider flyer to send to community neurologists, and a pocket‐sized deck card for use in the clinic (quick reference including inclusion/exclusion criteria).
are stakeholders in our study and will also highlight the study
What data are collected from the clinic note? Do you have a suggested template?
and follow‐up visits that may be used for the trial which will be available when the CRFs are provided (by May 15). If our site sees patients more often than every 6 months, how do we document those visits?
discretion if there is information to report. AE and concomitant medication forms are not visit specific and can be updated as new information is learned.
Is there anything special that we need to know to work with pharmacy?
care medications per usual practice. There is no “study drug” provided in this study so no need to work with a research pharmacy.
specific patients if insurance denies approval of prescribed medication.
Will there be an MRI Manual? And OCT manual? Can you share tips or best practices for working with radiology and ophthalmology?
the CMSC expert guidelines and will be ordered as standard of care
radiology centers close to your site where your patients usually go for their MRIs. Start‐up funds are provided to cover the cost of acquiring the first dummy run MRI. The cost of additional dummy run MRIs will be reimbursed on an as needed basis.
We will not have a separate manual, but will accept uploads of printed
report form.
Cindy MacInnis
Cindy MacInnis, MBA, CCRP Research Services Navigator Trial Innovation Network
sIRB team [Operations & Compliance Staff]. If warranted, site additions may be sent to the convened IRB for review [site-specific factors impact the criteria for approval]
and distributed to site
Step 3: Addition of Sites Via Change In Research
distributed to sites with a local context questionnaire (LCQ) + site-specific consent template
forms - communicate site- specific concerns, locally required language for the consent, etc.) and return.
Step 2: Relying Site performs Local Context Review
Review of main study documents: protocol, template consent, other (as needed)
IREx – done by IRB liaison
Step 1: Agreements & Initial IRB Submission
1.
Protocol
2.
Consent discussion document
3.
Local Context Questionnaire
4.
Master Informed Consent + Study Site Information Pages
language is added to this section
– i.e. Amendments to the site information pages would not change the approval date of the master consent
5/3/2018 39
study this informed consent form includes two parts. The first part of this document includes information that applies to all study sites. The second part of the consent form includes information specific to the study site where you are being asked to enroll.”
Sections referencing the Study Site Information Pages (in blue)
cIRB stamp of approval added after site is approved Two approval dates:
Template for Required Local Consent Language
JHU IRB finalizes your site’s information pages and adds signature line/s and header information during the site approval process.
JHU IRB combines your site information pages with the master consent pages to form your final, approved stamped consent form to use for consenting patients The IRB approved consent form will be sent to sites along with IRB approval notification of the site’s participation
Steve Mayo
Don’t: Share your password with anyone Write it down where it could be found Let anyone view your screen Do: Logout before leaving your computer Protect the security of printouts
Patients List Sites List
System Navigator
Christina Grabarits
1) Recognize and reward site adherence to a timed start‐up plan 2) Assist sponsors, coordinating center managers and monitors with tracking the start‐up process
enjoyable!
team makes it through each “Base Camp,” or Month of the 90‐day Start‐ Up
climb past the “Valley of Silence” (Month 1 IRB & Contracts)
2 Regulatory [Essential] Documents)
Training)
(Activation!) Activation!
The Summit
End of Month 3
Lhotse Wall
End of Month 2
Icy Lhotse Wall
End of Month 1
Valley of Silence
Receipt of Protocol and Contract
Base Camp
Your Mount E ve r e st Navigator s
navigate you through your 90‐day start up process
Carolyn: carolynhkoenig@gmail.com Sarah: slenington@optonline.net
Sarah Lenington Carolyn Koenig
higher importance, as determined by the risk assessment, receive higher task value
points for time‐ sensitive tasks
deducted for late submissions
*1 Pt for Webinar Attendance
ELEVATION
Mount Everest Standings ccc cc
*Not fit to scale
76.2
72.6
70.8
Columbia Presbyterian 63.0 58.6 66.6 83.4 68.4
51.4
Month1
https://etm.preludedynamics.com
ve r e st R
For ____________________
Encore Performance: Tomorrow 9am June’s Monthly Webinar: Live Database Training will be held on the 6th at 3pm and 7th at 9am Eastern