Monthly Webinar Series July 2019 Todays Agenda Announcements - - PowerPoint PPT Presentation

Monthly Webinar Series

July 2019

Today’s Agenda

Announcements & Trial Updates Madiha Qutab Recent Enrollments Amanda Bistran-Hall Rowing Competition & Top Enroller Amanda Bistran-Hall Retention Strategies Scott Newsome & Ellen Mowry Q&A All

Announcements & Trial Updates

MADIHA QUTAB

Study Updates – Enrollment

THANK YOU to activated sites for continuing to screen and enroll patients! We now have 46 sites activated and 236 patients enrolled as of 07/03/19, surpassing our 25% enrollment milestone! CONGRATULATIONS!!! We are in the process of onboarding up to 7 more sites to expand geographic coverage in the US. We enrolled 34 patients across all sites in June, but need to enroll >160 patients each month to reach our goal of 900 patients by the end of October,

• 2019. All sites need to do their part to make good on the commitment they

made to this trial! Please find at least 1 new candidate each week so we can accelerate enrollment!!!

Study Updates - Reminders

1) Starting last month, VISION began generating emails to study coordinators each Monday to address open queries. 2) Responding to queries in a timely manner helps your site and team in the rowboat challenge! 3) Please save and submit for review any page where you have entered data, made a change or responded to a query. Each page that appears “blue” must be submitted for review so the test tube turns “orange” in order for the page to be monitored. 4) All pages for a visit must be submitted for review to receive payment for the visit! THANK YOU for submitting data and uploading source documents promptly!

Study Updates – CRF changes

Please visit the study website: http://treat-mstrial.org to download recently updated case report forms (CRFs). The latest updates have V2.2 in the file name and impact the study-long AE, SAE, Concomitant Medications and Protocol Deviations forms as well as Interim Visit, Month 6 follow-up and Month 12 follow-up forms. PLEASE DISCARD OUTDATED CRFs and BEGIN USING THE LATEST CRFs found on the study website.

Study Updates – Coming soon

The central IRB has approved version 1.9 of the TREAT-MS trial protocol and version 1.3 of the master Informed Consent Form (ICF). Sites will receive an updated consent form shortly that incorporates recent changes to the protocol, including adding an EDSS exam, timed 25-foot walk test and nine-hole peg test to the months 18, 30 and 42 visits. Subcontract budgets will be amended this fall to include additional payment for these upcoming visits. Current contracting efforts are focused on the BIOBANKING SUBSTUDY funded by the National MS Society. A draft of this new subcontract is being sent to participating sites this summer and retroactive payments will be made for all samples drawn and processed/shipped since 2018 as soon as the subcontract is executed. THANK YOU for continuing to enroll and draw samples for the biobanking substudy!

Recent Enrollments

*AS OF MONDAY 07/08/19

DRAKE

The Rowing Competition

AMANDA BISTRAN-HALL

Rowing Competition Standings

1. Team E: 60 2. Team A: 55 3. Team F: 48 4. Team B: 46 5. Team H: 44 6. Team D: 41 7. Team C: 26 8. Team G: 20

Individual Site Competition

Site Points

Norton Neurology Services 157 University of Alabama at Birmingham 133 Swedish Health Services 112 Gainesville 112 Christiana Care 111 Advanced Neurology Specialists 105 University of Kansas Medical Center 88 Geisinger Clinic 83 University of Washington 81 University of California at Los Angeles 74

Rowing Competition Standings

Rowing Competition

https://treat.preludedynamics.com

Monthly Randomization Race

June’s Top Performers:

Site Randomizations

Norton Neurology Services 4 UCSD 4 Christiana Care 3 Swedish Health 3 Johns Hopkins University 6

June’s Top Enroller: Norton Neurology Services $50

July 2019 Webinar

ELLEN M. MOWRY, M.D., M.C.R. ASSOCIATE PROFESSOR OF NEUROLOGY AND EPIDEMIOLOGY JOHNS HOPKINS UNIVERSITY SCOTT D. NEWSOME, D.O. ASSOCIATE PROFESSOR OF NEUROLOGY JOHNS HOPKINS UNIVERSITY

Topics

• 1. Breakthrough disease, Modified Rio, re-randomization
• 2. Retention, adherence

TREAT-MS: Objectives

1. . To

• evalu

luate wheth ther 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

• f dis

isabil ilit ity progression. => => Will ill in inves estigate overall ll and with ithin str trata of

• f peo

eople at t high igher ver ersus lo lower risk risk of

• f lon

longer-term dis isabili lity

• 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 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

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, as defined by “TREAT-MS Maximum Tolerated Modified Rio Score”

TREAT-MS Modified Rio: Applies to Disease Activity that occurs AFTER 6 months on therapy!

Patient HAS NOT met modified Rio if:

• No relapse, none or only 1 new MRI lesion

Patient HAS MET modified Rio if:

• Any relapse, or ≥2 new MRI lesions at any single time point these outcomes assessed*
• Previously had one new MRI lesion, now acquires one additional MRI lesion*

 Should be assessed with “annual” MRIs (or earlier, if done earlier in window or at time

• f a relapse

*Remember that disease activity that occurred PRIOR TO 6 FULL MONTHS ON THERAPY is water over the dam! Our reference for treatment failure is anything that happens subsequently/while being treated when medications should be fully “kicked in”

Must the patient switch therapies if they meet maximum disease criteria

• No. We understand that switching therapy may NOT be indicated at the time!

But documentation that therapy switch was discussed is required. Why? Meeting these revised Modified Rio Score criteria= associated with worse intermediate-term disability

MRI logistics: timing of month 6 MRI: AS AGREED UPON BY SAC/SITE PIs

Perhaps the most critical MRI in terms of having it, and its timing. Why?

• Able to switch therapy for ANY NEW breakthrough 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-7 months: can serve as true reference MRI scan against which subsequent new lesions can be confirmed as

• ccurring “after 6 months on therapy”

>7 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.

• Consider ordering this MRI at >month 7 on DMT if you strongly believe in using those results to switch therapy

Has my patient met criteria for breakthrough disease?

Yes

• One or more relapses AFTER 6 months
• f therapy
• Follow-up MRI shows new lesion(s)

(where reference/comparison MRI was done AFTER at least 6 months on therapy)

• Follow-up MRI done AFTER 7 months
• n therapy shows gadolinium-

enhancing lesion(s) No

• One or more relapses BEFORE a full 6

months of therapy

• Follow-up MRI done BEFORE full 6

months of therapy shows new T2 lesion(s) (where comparison/reference MRI=baseline, or earlier within first 6 months)

• Follow-up MRI done WITHIN first 7

months on therapy that shows gadolinium-enhancing lesion(s)

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) 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)

*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) *New FDA-approved therapies will be added to medication lists after consensus-based approach by Study Advisory Committee

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.

Topics

• 1. Breakthrough disease, Modified Rio, re-randomization
• 2. Retention, adherence

Compliance or adherence

Trial is meaningless unless participants (and the study team!) adhere to interventions Think in very precise terms about meaning

• Term “drop out” often used but is ambiguous

Several aspects

• 1. Adherence to medications/interventions, breakthrough disease/switching rules
• 2. Adherence to visit schedules/reporting (missing main outcome)
• 3. Adherence to protocol (e.g. use eligibility criteria)

Lack of adherence leads to:

• Bias in either efficacy or safety
• Decreased power
• Uninterpretable results

Slides adapted from Deborah Grady, MD, PhD, UCSF

Attempt to have complete information for primary outcome

CRITICAL to get primary outcome from all those randomized

Techniques to assure complete follow up for primary outcome

• Have all participants come to final “close out” visit (even if missed other visits)
• Contact by telephone
• Use surrogate contact
• Use external data sources (National Death Index, Medicare, Kaiser, etc).

Missing data for primary endpoint…may be result of loss to follow up or due to… ?

Can lead to bias especially when long-term follow-up varies by treatment

• E.g. First-line drop out more than higher-efficacy
• Randomization no longer valid

Other forms of bias may exist in those lost

• Older, younger, sicker

Even random loss to follow up could have impact

• Loss of power
• Other forms of bias

Potential effect of incomplete visit follow-up on results in clinical trials

• Fracture Intervention Trial (alendronate vs. placebo)
• X-rays obtained at baseline, 2 years, 3 years
• Vertebral fractures defined from changes in radiographs
• FU radiographs on 97% of participants @ year 3

Time (yrs) Relative risk (CI)

BL to 2 0.34 (66% reduction) BL to 3 0.49 ( 51% reduction)

Effect of Incomplete Follow-up: Virtual Experiment

FIT I: Follow-up x-rays on 97% of surviving participants at year 3 What if follow-up less complete? Randomly “lose” 50% between year 2 and 3

Use of Survival Analysis for X-Rays in FIT I: Virtual Experiment

Time (yrs) Relative risk

2 0.34 3 0.49 3 (50% LTFU) 0.37 LTFU = Lost to follow-up

Effect of High Rate of Incomplete Follow-up

• n Results

If early results differ from later results, could create bias when comparing

• ne study to another

Even a “random” (therefore unbiased) loss to follow-up can affect results Clearly most losses to follow-up are not unbiased so more reasons for concern

• Loss of randomization
• Bias
• Less credibility of results

Potential impact of missing data for primary outcome

Hollis and Campbell, BMJ 2004

Effect of High Rate of Loss to Follow-up on Results

More generally, people lost to follow-up may be different than those who remain Could be differential in two treatment groups

• Due to treatment (e.g. estrogen)

Impact of loss to follow up

• Groups may no longer be comparable
• Loss advantage of randomization
• Could bias results

Adherence goals

Ideal in an explanatory trial: all participants continue to take medication (perfectly) throughout the trial and attend all follow-up visits until the very end Goal in a pragmatic trial: still prefer full adherence… or at least similar to “real world” Why might participants stop medication?

• Side effects (real or perceived) or worry about possible AEs
• Perceived lack of need
• Want to take a perceived “better” medication
• New info on old medication
• New competing medication
• Actual breakthrough disease (with or without re-randomization)
• Protocol-based switch

Effect of Stopping Medication: Classical interpretation

Examples: First-line medication users switch to higher-efficacy therapy==>become more like higher-efficacy patients Higher-efficacy switch to first-line==>become more like first-line

• Two groups become more similar
• Treatment effect is underestimated/conservative

Strategies to enhance adherence: Design

Pre-randomization

• 2 or more screening visits
• ►►►►Exclude those who will move or non-adherent ◄◄ ◄◄

Intervention: standard of care dosing (remind participants!) Study visits

• Close enough to maintain contact/not too close

Study measurements

• Painless, interesting, useful
• Give patients results (when possible)
• Remember these are largely STANDARD OF CARE and patients paid for their extra time

needed to complete the few study-specific outcomes!

Strategies to enhance adherence: implementation

***Educate participants***

• Importance of science and their on-going participation
• Expectations for participation in study

***Warm and fuzzy stuff***

• Participants to feel appreciated
• Staff in clinic spend enough time
• Sensitive to scheduling needs

Ease of logistics/transportation to clinics

• Compensation to offset travel-related costs/extra time

Strategies to enhance compliance

Information, Newsletters, other Emphasize early follow-up

• Most drop outs occur in early study period
• FIT (4 years total); 2/3 of drop outs occurred in first year, most of

those in first 6 months

• JHU coordinator and PIs work hard to encourage ongoing

participation (call, email)… extra TLC goes a long way

Adherence to Follow-up visits

Goal: visits all on time (within window)

• TREAT-MS window intentionally broad in alignment with pragmatic study… but

should not be used to justify a lot of missing visits or measurements

• Keep in mind that collecting EDSS, timed 25-foot walk, and 9-hole peg test are

THE MOST IMPORTANT parts of the study Set appointments flexibly Reminders prior to appointments Listen to concerns/problems

Study Management Methods to Enhance Adherence

Monitor adherence during study Important to assess as go along

• Spot systematic or individual problems (and make corrections)

We are doing so through the VISION website Response to queries in timely fashion

• We are intentionally NOT monitoring as heavily as industry-sponsored trial
• We ask YOU to recognize the importance of quality study data by giving your best

Adherence to medication is not the same as adherence to visit schedule

“Drop out” is very vague term Can have perfect visit adherence (come to all visits on time) but--

• Not take a single study med pill
• Take only 60% of pills

If miss visits or stop coming to visits, then generally don’t take study medication

• Exceptions do occur..could take study medications but not attend

follow-up visits

Follow-up visits for those who have stopped study medications?

Practice varies dramatically across studies Option 1: Stop follow-up as soon as drug stops Option 2: Continue to collect follow-up info Advantages of each

• For TREAT-MS we want to continue to follow participants, ideally

getting them back on the therapy class to which they were assigned….

Follow-up visits for those who have stopped study medications?

Practice varies dramatically across studies Option 1: Stop follow-up as soon as drug stops Option 2: Continue to collect follow-up info (highly recommended)

Can do formal intention to treat analysis Can do all sorts of subsets and per protocol analyses Increase costs Saves money Won’t see long term negative effects

CONSORT Guidelines for Reporting Results of Trials

http://www.consort-statement.org/ “The CONSORT statement is an important research tool that takes an evidence- based approach to improve the quality of reports of randomized trials. The statement is available in several languages and has been endorsed by prominent medical journals such as The Lancet, Annals of Internal Medicine, and the Journal

• f the American Medical Association”

Includes guidelines for reporting trials and the “Consort Flowchart”

CONSORT checklist

The Consort E-Flowchart Aug. 2005

Follow-up and Adherence: summary

Best trial:

• All participants remain on medication
• All participants are followed for primary outcome until end of study
• Pre-planned analysis and handling of deviations from protocol

Design and implementation of study can help move toward that goal Important to report details about adherence and how it could affect results

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

Thank You for attending today’s webinar!

The August Monthly Webinar will be held on the 7th at 3 PM and 8th at 9 AM EDT