OCT as an Outcome Measure in Clinical Trials

Robert Bermel, MD Staff Neurologist and Medical Director

Mellen Center for Multiple Sclerosis

Disclosures

•  Research support from Biogen and Genentech •  Personal compensation for consulting: Biogen,

Genentech, Genzyme, Novartis

Why OCT as an outcome measure?

•  A pathologically specific measure of: •  Unmyelinated axons, in pRNFL •  First-order sensory neurons, at the macula

•  Directly related to: •  Low contrast letter acuity •  Visual QOL

•  Optic neuritis as a model system •  Reproducibility •  Ease of patient participation •  Changes over time •  Sensitivity to treatment effect???

Typical scan protocol Cirrus

•  Optic Disc cube 200x200

• Macular Cube 512x128

Quality Control Standards for scan completeness, signal strength, motion, scan obstruction/blink.

Spectralis •  Glaucoma RNFL

-  768x496 with an ART of 100

•  Axonal RNFL-N -  1536x496 with an ART

of 100

•  Posterior Pole -  61 scan lines spaced

12µm apart, -  768 A-scans with an

ART of 25

Opt

ic N

erve

Hea

d M

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Trial design: Acute Optic Neuritis

placebo

Baseline Month 6 OCT OCT

active

Month 2 OCT

Month 4 OCT

Study drug (active or placebo)

Safety follow-up

Key Issues: •  Timing of enrollment after optic neuritis •  Controlling for swelling in the peripapillary RNFL

Sample size: n=35 per arm, measured at 6 months, if 50% treatment effect

Henderson et al Brain 2010; 133; 2592–2602

RNFL loss after AON

Henderson et al Brain 2010; 133; 2592–2602

Use fellow eye as control or GCIP thickness

Trial design overview: SPMS

placebo

Baseline Month 18 OCT OCT

active

Month 6 OCT

Month 12 OCT

Month 24 OCT

Key Issues: •  Rate of change over time •  Occurrence of ON during trial •  Enrichment possible based on disease activity? Sample size: n=400-600 per arm to show 6.6uM difference between arms

Talman et al. Ann Neurol 2010

Efficacy Trials Incorporating OCT

Agent DesignAuthor/PI Phase OCTrole OCTresult Technology #Sites

erythropoe(nAON SühsKW 2 primary posi(ve TD 3

phenytoin AON Ra<opoulosR 2 primary posi(ve SD 2

opicinumab AON CadavidD 2 secondary NS SD 33

MSC MS ConnickP 2a secondary NS TD 1

MSC MS CohenJ 1-2 secondary NS SD 1

clemas(ne AON GreenA 2 secondary inprogress SD 1

ibudilast MS FoxR 2 secondary inprogress SD 28

others!

Phenytoin in acute optic neuritis

Raftopoulos R et al. Lancet Neurol. 2016; 15:259-69.

Opicinumab: RENEW trial

Cadavid D et al. Lancet Neurol 2017 Mar

Lessons: Timing of intervention Severity of ON

Logistics of OCT in Trials

•  May be unfamiliar to traditional neurology sites •  Potential operator variability •  Multiple, evolving technologies

Roles of an OCT Reading Center

•  Protocol development input •  Instrument-specific manuals of operations •  Site/technologist training, certification •  Handling, storage, archiving of source images •  Quantitative data management •  On-study scan review and grading •  Quality assurance with feedback to sites •  Study closeout, query resolution, OCT database

lock

OCT Reading Center Data Flow

Site Digital OCT

Reading Center

Manual review/ grading

Quality feedback

Incidental findings

Master Study

Database

Resources

Neurology 2016;86:2303–2309

PLoSOne 2014

MS International May 2015

Takeaways:

•  OCT is well-suited as an outcome measure in clinical trials targeting neuroprotection

•  Trial designs include acute optic neuritis and SPMS

•  Unique complexities apply to each trial design •  OCT reading center can facilitate issues of

standardization, quality control, grading, and data management

•  IMS VISUAL is paving the way for OCT to play a key role in demonstrating neuroprotection