Content Visual Function Endpoints in Clinical Trials - - PDF document

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Content Visual Function Endpoints in Clinical Trials - - PDF document

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Content Visual Function Endpoints in Clinical Trials

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SLIDE 1

Visual Function Endpoints in Clinical Trials Clinical View Eberhart Zrenner Center for Ophthalmology Institute for Ophthalmic Research University of Tübingen Germany

Content

Basics: Structure and Function Function Testing: Psychophysics in Ophthalmology Function Testing Electrophysiology in Ophthalmology Retinal Imaging Assessing Activities of Daily Living Patient Reported Outcomes (PRO) of Visual Function Examples from Ongoing Studies Financial Disclosure The author performs or performed advisory tasks during the 5 most recent years for Acucela, Allergan, Bayer, Boehringer Ingelheim, Merck, Neurotech, Pfizer, Retina Implant AG, Servier and QLT; he is shareholder of Retina Implant AG and inventor on patents concerning electronic subretinal implants.

Retina Choroid Sclera Fovea,Macula RPE Lens

Iris

Cornea

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SLIDE 2
  • High sensitivity

Low spatial resolution No colour discrimination Low sensitivity High spatial resolution Colour discrimination

Retinal Structure and Function

  • The Phototransduction process: many things can go wrong

Rhodopsin

The Short, Middle and Long Wavelengths Sensitive Cones

Cone Mosaic in the Fovea

cone

rods

Courtesy of T. Sharpe Courtesy of H. Waessle From: J. Dowling: The Retina. 1987

( courtesy of Paul R. Martin, 1998 )

„Brighness Channel“ „Darkness Channel“

Information Processing in the Retina

~ 120 million photoreceptors „The natural computer“ ~ 1 million ganglion cell fibres sending pulses to the brain

⇓ ⇓ ⇓ ⇓ ⇓ ⇓ ⇓ ⇓

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SLIDE 3

Cones ERG

multifocal ERG

Colour vision Reading speed, Pupil, Eye movement, intraocular pressure Visual Acuity, Refraction, Anterior segment Examination

  • Fundi oculi

Visual fields

  • Functional Diagnostics

Best Corrected Visual Acuity (BCVA)

Snellen chart

Functional Diagnostics

Best Corrected Visual Acuity (BCVA)

Snellen chart ETDRS chart (Standard)

Functional Diagnostics

Best Corrected Visual Acuity (BCVA)

Snellen chart ETDRS chart (Standard Freiburg Visual acuity Test (FRACT) with Landolt CBring (ComputerBScreen test )

  • K. SchulzeBBonsel, et al., Visual Acuities “Hand Motion”

and “Counting Fingers” Can Be Quantified with the Freiburg Visual Acuity Test.

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SLIDE 4

Functional diagnostics

Colour vision testing

Lanthony Panel DB 15 Test Roth 28Bhue Test FarnsworthBMunsell 28 or 100 Test

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WEB based evaluation tool: http://www.torok.info/colorvision/dir_for_use.htm (Dr. Bela Török)

FunctionalDiagnostics

Contrast Vision

PelliBRobson Chart Mesoptometer

With and without glare

Hamilton Veale Test

Functional diagnostics

Visual Field testing

Visual field testing

Static perimetry 30° Kinetic perimetry 90°

Functional diagnostics

Visual Field testing

Visual field testing

Static perimetry 30° Kinetic perimetry 90°

Microperimetry

Central Vision Eye Movement Compensated

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SLIDE 5

Functional diagnostics:

Dark Adaptation

Adaptometer (Roland Consult)

cone branch rod branch

Functional Diagnostics

Pupillography

Relative Afferent Pupillary Defect (RAPD) Pupillography

AMTECH Pupillograph Infrared Image

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  • Surrogate Endpoints

A , according to the FDA is a biomarker that is “reasonably likely, based

  • n

epidemiologic, therapeutic, pathophysiologic, or other evidence to predict clinical benefit.” The best surrogate endpoint is a biomarker that changes along with clinical endpoints.

Csaky et al, IOVS 2009

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SLIDE 6

Clinical Electrophysiology of the Visual System

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  • Categorization of function tests:

Electroretinogram: sites of action

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Outer Retina: Origin of the ERGBresponses

Ganglion cells Bruch's membrane Choriod capillaries Retinal pigment epithelium Photoreceptors Horizontal cells Amacrine cells Bipolar cells Müller glia cells

ERG a-wave ERG b-wave OP´s

DTLBFibre Electrode Jet Electrode

87 9

ISCEV Standard Ganzfeld ERG

For further Information see www.iscev.org

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  • 1. Isolated rod responses
  • 2. Rod and cone Max. Responses
  • 3. Inner Retina OPs
  • 4. Isolated Cone Responses
  • 5. Cone flicker Responses
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SLIDE 7

Investigating effects on temporal fidelity

  • f retinal cells

Example: Effects of Zatebradine, an Ih channel blocker, 2.5 mg/kg,

  • n flicker ERG

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Open circles: control, Filled circles: Zatebradine, Triangles: 5 hrs after application

Gargini et al, Vision Research 39,1767-1774,1999

Retinal Pigment Epithelial Cell (RPE)

  • Assessing the RPE / Photoreceptor complex:

InterBphotoreceptor Matrix (IPM)

  • Photoreceptor

Outer Segment (OS)

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//,,, is photoisomerized to , and reisomerized to //, 'A is almost completely dependent on a normal visual cycle function.

Assessing the RPE / Photoreceptor complex:

ERG amplitude recovery after bleaching If retinoid cycle is affected, „time to reach threshold“ during dark adaptation may be useful , after a bleach of 400 cd/m2 ( 30 s)

min after bleach min after bleach Messias A, Zrenner E, Tzekov R, McGee D, Peters T, Wilhelm B, Baryluk A, Kubota R, Gekeler F. ,,B, 7 7 0 Doc Ophthalmol. 120(2):165B74, 2010 bBwave amplitude[MV] !" , # $%"#, &'"'"'( )*+,-+*..+

The ElectroBoculogram:

assessing the integrity of the photoreceptor / RPE complex

Marmor MF et al. ISCEV Standard for Clinical ElectroBoculography. Doc Ophthalmol (2011) 122:1–7 see also www.iscev.org

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SLIDE 8

Multifocal ERG (mfERG) allows to electrically map retinal sensitivity

500 nV 128 mSec 1 2 3 4 5 6 7 8 9 10 nV/deg^ 2 0 deg 25 25 1 2 3 4 5 6 7 8 nV/deg^2 0 deg 25 25 200 nV 128 mSec 1 2 3 4 5 6 7 8 9 10 nV/deg^2 0 deg 25 25 200 nV 128 mSec

normal Retinitis pigmentosa M. Stargardt Stimulus field 64 independently Flickering Hexagons 64 local ERGs

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Visually evoked cortical Potentials (VEP)

Visual pathway

FlashBVEP PatternBVEP Pattern Reversal Transient

Retinal imaging

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SLIDE 9

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Patient Reported Outcomes (PRO)

A PRO is a measurement of any aspect

  • f a patient`s

health status that is reported and or scored directly by the patient, free

  • f interpretation

by a physician, researcher or other person. It is an account of how the patient functions or feels relative to a health condition or therapy. Good measurements should have unidimensionality, hierarchical order, and equal interval spacing

Varma et al., IOVS 2010

Patient Reported Outcomes (PRO)

A PRO would measure any of the following: Symptoms Symptom impact and functioning Disability or handicap Adverse events Treatment tolerability Treatment satisfaction HealthBrelated quality of life

Varma et al., IOVS 2010

PRO: Available instruments

  • Activities of Daily Living Scale (ADVS)

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  • Daily Living Tasks Dependent on Vision

(DLTV)

  • Impact of Vision Impairment (IVI)
  • Macular Disease Quality of Life

Questionnaire

  • B$,1'C*D(most common, wellBequipped)
  • Visual Function Index (VFB14)
  • LowBLuminance Questionnaire

(LLQ)

  • Miedziak's instrument
  • VisionBspecific sickness impact

profile (SIPV)

  • Turano's instrument
  • VisionBRelated Quality of Life

Questionnaire

  • RetinopathyBDependent QOL

Varma et al., IOVS 2010

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SLIDE 10

Ongoing Clinical trials in legally blind patients Upcoming Clinical trials in legally blind patients

Courtesy of Dr. Christian Hamel

Relevant studies

Subretinal electronic implants

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Primary Outcome Measures:

  • Activities of daily living and mobility significantly improve with implantBON shown via

activities of daily living tasks, recognition tasks, mobility, or a combination thereof

Secondary Outcome Measures:

  • Visual acuity/lightBperception and/or objectBrecognition measured with

FrACT/BaLM/BaGA/VFQB25

  • Patient long term safety and stability of implant function

Zrenner et al, Proc. R Soc. B 278: 1489ff, 2011

Functional diagnostics in subretinal electronic Implants

BaLM (basic light and movement test) BaGA (recognition of stripe patterns)

Zrenner et al, Proc. R Soc. B 278: 1489B1497 (2011)

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SLIDE 11

Functional diagnostics in subretinal electronic Implants

Tasks of daily living (more naturalistic scenes)

Zrenner et al, Proc. R Soc. B 278: 1489B1497 (2011)

Gene therapy dramatically improves rod light sensitivity

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Summary

Monitoring of visual function for safety and efficacy in very low and ultraBlow vision patients is difficult The tools are there, but have to be selected depending

  • n the cellular target structure

Psychophysics Electrophysiology as surrogate marker Retinal Imaging as surrogate marker Assessment of Activities of Daily Living (ADL) Patient Reported Outcomes (PRO) of visual function

Some of the ongoing studies have developed novel tests in order to monitor ultraBlow vision changes which, however , are not yet validated

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