CHM Therapy Outcome Measure Notes Following is DRAFT rev 11-23-2015
Opening notes:
  • Loss of visual field and sensitivity corresponds with loss of structure in CHM, - preserve structure = stop or slow sight loss: OCT (4+plane), volumetric OCT topography, fundus photography, autofluorescence, OCT angiography, AOSLO
  • Visual field: Goldmann, Humphrey, Octopus next generation microperimetry
  • Light sensitivity: next generation Microperimetry, full field scotopic/photopic sensitivity
  • Color sensitivity: Farnsworth Munsell 100 or 15 hue color sensitivity test (manual and computerized versions)
  • Functional tests for paper reading and or ambulation at variable light and light to dark and dark to light adaptation time
  • Visual acuity as primarily a safety measure


Relevant endpoints (additional references available):


Ellipsoid Zone (EZ) Area publications regarding correlation of retinal structure to visual field:
Dr. Birch - Ellipsoid Zone OCT aka EZ Area validation being sought from FDA
__A Comparison of Methods for Tracking Progression in X-Linked Retinitis Pigmentosa Using Frequency Domain OCT.__ Ramachandran R, Zhou L, Locke KG, Birch DG, Hood DC. Transl Vis Sci Technol. 2013 Nov;2(7):5. Epub 2013 Nov 11. PMID:24349883
__Spectral-domain optical coherence tomography measures of outer segment layer progression in patients with X-linked retinitis pigmentosa.__ Birch DG, Locke KG, Wen Y, Locke KI, Hoffman DR, Hood DC.JAMA Ophthalmol. 2013 Sep;131(9):1143-50. doi: 10.1001/jamaophthalmol.2013.4160. PMID:23828615.
__Transition zones between healthy and diseased retina in choroideremia (CHM) and Stargardt disease (STGD) as compared to retinitis pigmentosa (RP).__ Lazow MA, Hood DC, Ramachandran R, Burke TR, Wang YZ, Greenstein VC, Birch DG. Invest Ophthalmol Vis Sci. 2011 Dec 20;52(13):9581-90. doi: 0.1167/iovs.11-8554. PMID:22076985
__Method for deriving visual field boundaries from OCT scans of patients with retinitis pigmentosa.__ Hood DC, Ramachandran R, Holopigian K, Lazow M, Birch DG, Greenstein VC. Biomed Opt Express. 2011 Apr 5;2(5):1106-14. doi: 10.1364/BOE.2.001106. PMID: 21559123


Possible additional endpoints:


Standard diagnostics and measures:
  • ETDRS VA (Reported in Lancet)
  • OCT changes in retinal structure (Reported in Lancet)
  • Microperimetry (Reported in Lancet)
  • Dark adapted retinal sensitivity (Reported in Lancet)
  • Fundus photography (Reported in Lancet)
  • Autofluorescence (Reported in Lancet)
  • Contrast sensitivity
  • Full field scotopic/photopic threshold
  • Goldmann VF
  • Humphrey VF
  • Esterman VF
  • Octopus VF?
  • ERG


Other notes:
  • Adaptive optics not widely available: __http://www.ncbi.nlm.nih.gov/pubmed/25190651__
  • Mobility course is primary outcome measure for the Phase III LCA2/RPE65 gene therapy trial in the US based on the clinicaltrials.gov listing. It will be challenging to use such an obstacle course for CHM due to the fact that sight loss precedes cell loss in LCA2 and sight loss is closely correlated to cell loss in CHM. Dramatic improvements in field of vision are not expected in CHM gene therapy trials as have been seen in the LCA2 trials, particularly in younger patients.
  • No published data for CHM:
    • Functional MRI - visual cortex (LCA2)
    • Pupillary light reflex (LCA2)


Additional considerations and options:
  • Patient selection - symmetrical and rapid disease progression
  • Biomarkers - non-molecular for now until in vivo protein activity detection possible
  • Reading ability/speed - reduction in or loss of the ability to read is the most common reason for disability - __http://www.ncbi.nlm.nih.gov/pubmed/16395143__
  • Possible variation on reading test:
Reading test incorporating variable light levels and printed text:
  1. Placement of a printed page with standardized font in black on standardized brightness level white page at standardized distance for reading - IreST standard text
  2. Dark or light adapt?
  3. Add controlled light with variable intensity
  4. Record reading speed in 1? minute incremental blocks while increasing light level by 1 lux steps each 1? minute starting at zero and increasing until reading speed plateaus
  5. Add reverse high to low light intensity test?
Relevant Trials:RW 6-10-2015


NightstaRx, Inc. (__www.nightstarx.com__) in the United Kingdom is sponsoring gene therapy clinical trials


Phase I/II clinical trial for CHM Oct 2011: __http://www.clinicaltrials.gov/ct2/show/NCT01461213__
12 patients non-randomized - 6 low dose 1x10(10), 6 high dose 1x10(11)
6 month followup for primary outcome measures
24 month followup for secondary outcome measures
Publication of initial results: __http://www.ncbi.nlm.nih.gov/pubmed/24439297__
Primary Outcome Measures:
  • Visual acuity [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  • Best corrected visual acuity, following cataract surgery if indicated
Secondary Outcome Measures:
  • Microperimetry, OCT and fundus autofluorescence [Time Frame: 24 months ] [ Designated as safety issue: No]
  • Structure function correlations at the margins of the retinal degeneration


Phase II clinical trial for CHM Mar 2015: __https://clinicaltrials.gov/ct2/show/NCT02407678__
30 patients non-randomized
Primary outcome measures
  • Change from baseline in best corrected visual acuity in treated eye, compared to untreated control eye [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
Secondary outcome measures
  • Change from baseline in autofluorescence evaluation in treated eye, compared to untreated control eye [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Change from baseline in central visual field using microperimetry readings in treated eye, compared to untreated control eye [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Spark Therapeutics (__www.sparktx.com__) is sponsoring a Phase 1-2 study of AAV2-hCHM gene therapy for REP1/CHM: __https://clinicaltrials.gov/ct2/show/NCT02341807__
10 patients - 5 low dose 5x10(10), 5 high dose 1x10(11)
  • Primary Outcome Measures:

    -Safety and tolerability (assessed by physical exam, vital signs, laboratory changes over time, and adverse events) [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

    -Safety and tolerability of a single dose of AAV2-hCHM will be assessed by physical exam, vital signs, laboratory changes over time, and adverse events.

Ian MacDonald - University of Alberta is sponsoring a Phase I safety study utilizing the NightstaRx AAV2/CHM vector: __http://clinicaltrials.gov/ct2/show/NCT02077361__
6 subjects non-randomized - 1x10(11)
Primary Outcome Measures:
  • Number of patients with ocular and systemic adverse events [ Time Frame: 2 years ] [ Designated as safety issue: Yes ] This is assessed by standard ocular examinations and vector dissemination and inflammation assays.
Secondary Outcome Measures:
  • Changes in visual field [ Time Frame: Baseline and up to 2 years following vector delivery ] [ Designated as safety issue: Yes ] - This is assessed by Goldmann perimetry and microperimetry; measurements before and after vector delivery are compared.
  • Changes in visual function [ Time Frame: Baseline and 2 years following vector delivery ] [ Designated as safety issue: Yes ] - This is assessed by multifocal electrophysiology, full field scotopic threshold, spectral domain optical coherence tomography, fundus photography and fundus autofluorescence; measurements before and after vector delivery are compared.

Byron Lam - University of Miami BPEI is sponsoring a Phase I safety study utilizing the NightstaRx AAV2-REP1 (10e11 vg) vector: __https://clinicaltrials.gov/ct2/show/NCT02553135__
6 subjects non-randomized


Primary Outcome Measures:
  • Change in best corrected visual acuity from baseline [Time Frame: 24 Months] [Designated as safety issue: No] ETDRS visual acuity chart


Secondary Outcome Measures:
  • Change in retinal macular autofluorescence from baseline [Time Frame: 24 months ] [ Designated as safety issue: No ] Macular autofluorescence
  • Changes in microperimetry from baseline [ Time Frame: 24 months ] [ Designated as safety issue: No ] Macular microperimetry
  • Number of participants who experience an adverse event [ Time Frame: 24 months ] [ Designated as safety issue: Yes ] Adverse events during treatment and follow-up period

Notes:
  • Expecting similar six patient NightstaRx vector study at Tubingen Germany to start ~late 2015
  • The investigator sponsored phase I studies are starting at high dose 1x10(11)

Spark Therapeutics (__www.sparktx.com__) is sponsoring a Phase III study of AAV2-hRPE65v2 gene therapy for RPE65/LCA2: __http://clinicaltrials.gov/ct2/show/NCT00999609__
24 patients - 16 in treatment group and 8 in control group
Primary Outcome Measures:
  • Mobility testing [ Time Frame: One year ] [ Designated as safety issue: No ]
Secondary Outcome Measures:
  • Additional visual/retinal function tests [ Time Frame: One year ] [ Designated as safety issue: No ]
  • Ophthalmic exams, physical exams, immunology studies, clinical labs, & adverse event recording [Time Frame: Two years] [Designated as safety issue: Yes]

Applied Genetic Technologies Corp. is sponsoring a Phase I/II study of rAAV2-CB-hRPE65 gene therapy for RPE65/LCA2: __http://clinicaltrials.gov/ct2/show/NCT00749957__
12 patients non-randomized
12 month followup for primary outcome measures
12 month followup for secondary outcome measures

Sanofi is sponsoring a Phase I/II study of EAIV/ABCA4 gene therapy for Stargardt’s disease:
__http://clinicaltrials.gov/ct2/show/NCT01367444__
28 patients non-randomized
48 weeks followup for primary outcome measures
48 weeks followup for secondary outcome measures
Sanofi additional clinicaltrials.gov listing for long term followup:__http://clinicaltrials.gov/ct2/show/NCT01736592__

The Foundation Fighting Blindness Clinical Research Institute (__http://www.nnri.info/__) is sponsoring a Phase II efficacy study of Valproic Acid (FDA approved for other indications) for autosomal dominant Retinitis Pigmentosa: __http://clinicaltrials.gov/ct2/show/NCT01233609__
90 patients randomized
52 week followup for primary outcome measures
15 month followup maximum for secondary outcome measures
Microperimetry Devices
__http://www.optos.com/en-US/Products/Retinal-imaging-products/OCT-imaging/Microperimetry/__
  • Field 29.8 Max 20dB


__http://www.centervue.com/product.php?id=639__
  • Field 36 Max 36dB


__http://www.nidektechnologies.it/ProductsMP1All.htm__
  • Field 22.58 Max 20dB
  • Note: Nidek plans to introduce the MP-3 with 34dB capability in mid 2015 in EU and mid 2016 in US but it will not have scotopic capability



Publications:
Assessment of Central Retinal Sensitivity Employing Two Types of Microperimetry Devices - Liu etal TVST - 2014: __http://tvstjournal.org/doi/pdf/10.1167/tvst.3.5.3__
Main testing parameters of the OCT/SLO and the MP-1
Parameter OCT/SLO / MP-1
Field of review 298 / 22.58
Background illumination/color 10 cd/m2/white / 1.27 cd/m2/white
Maximum differential Luminance 125 cd/m2 / 127 cd/m2
Stimulus size/color Goldmann II/white / Goldmann III/white
Stimulus duration/intervals 200/1500 ms / 200/1500 ms
Attenuation scale 0–20 dB / 0–20 dB
Fixation target Red cross/28 diameter / Red cross/28 diameter
Test grid Polar-3 (28 points) / Polar-3 (28 points)
Threshold strategy 4-2 / 4-2