Download Study Manual

Draft 1. January 10, 2014
A randomised clinical trial of intravitreal ranibizumab (Lucentis) vs.
intravitreal aflibercept (Eylea) for the treatment of age-related macular
degeneration (AMD).
Study Manual
COORDINATING CENTRE
Academic unit of Ophthalmology
Australian National University
Canberra Hospital
Yamba Dve.
Garran ACT 2505
Australia
CHIEF INVESTIGATOR
Professor Ted Maddess
Tel +61 2 6125 4099
[email protected]
INVESTIGATORS
Dr Rohan Essex; (m) 0417 504 965
Dr Randev Mendis
Prof JM Provis
Dr CF Carle (PhD)
Dr F Sabeti (PhD)
ASSOCIATE INVESTIAGTORS
Prof Robyn Guymer
Prof Tien Wong
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1. Research Plan
1.1 Background
Age-related Macular Degeneration (AMD) is a very common problem in the elderly.
“Wet” AMD is the aggressive form of the disease characterised by choroidal
neovascularisation, sub macular fibrosis, and rapid progression to blindness when left
untreated. On average there are approximately 3 new patients with wet AMD
diagnosed per week in the ACT. Additionally, the fellow eyes of patients with known
unilateral wet macular degeneration are at high risk of developing wet macular
degeneration (43% at 5 years).1
The mainstay of treatment for Macular degeneration is intraocular injections with either
Lucentis or Eylea, both very similar drugs, with clinically proven equivalent efficacy. 2
Initial studies demonstrated the efficacy of monthly treatment, however it has been
shown that equivalent results can be achieved with less than monthly dosing. 2,3,4 Less
than monthly dosing is often given on a pro re nata (PRN) basis, with monthly review,
and treatment only when there is clinical evidence of disease activity.
There is presently debate as to which of the two agents is the better treatment for
Macular degeneration. One study suggests that the frequency of Eylea therapy can be
reduced to second monthly with similar results to monthly Lucentis, however postmarketing clinical experience does not support a duration of action twice that of
Lucentis.2 Additionally the study design was such that less than monthly Lucentis was
not evaluated.
Multifocal pupillographic perimetry (mfPOP) is a novel objective measure of visual
function developed by the Chief investigator and co-investigator 1. With Coinvestigators 2 and 3, it has been shown to be a sensitive measure of retinal function in
AMD, and also to measure improvement in macular function with treatment.
References
1. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial
of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related
macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001
Oct;119(10):1417-36.
2. Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related
macular degeneration. Ophthalmology 2012;119:2537-2548.
3. CATT_Research_Group. Ranibizumab and bevacizumab for neovascular age-related macular
degeneration. New England J Med 2011;364:1897-1908.
4. Chakravarthy U, Harding SP, Rogers CA, Downes SM, Lotery AJ, Culliford LA, Reeves BC; IVAN
study investigators. Alternative treatments to inhibit VEGF in age-related choroidal
neovascularisation: 2-year findings of the IVAN randomised controlled trial. Lancet. 2013 Oct
12;382(9900):1258-67.
5. Sabeti F, Maddess T, Essex RW, James AC. Multifocal pupillography identifies ranibizumab
induced changes in retinal function for exudative age-related macular degeneration. Invest
Ophthalmol Vis Sci 2012;53:253-260.
1.2 Objective
The investigators plan to randomise 60 patients with new onset wet AMD to either
Lucentis or Eylea therapy and to manage them according to standard, accepted clinical
practice. They will be followed using both the standard testing and also mfPOP to see if
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Draft 1. January 10, 2014
mfPOP is an effective tool at monitoring disease progress on therapy, and also to see if
mfPOP can detect any subtle differences between the two medications.
The specific aims of the study are to test the following hypotheses:
 Aim 1: To determine whether the clinical changes in disease activity, particularly
early disease recurrence while on treatment, can be detected using mfPOP.

Aim 2: To determine the temporal relationship between the clinical changes in
disease activity and mfPOP results (i.e. to determine if mfPOP results precede
clinical changes, change in parallel, or lag behind clinical changes).

Aim 3: To observe whether mfPOP can detect any differences between the two
agents.

Aim 4: To observe whether there are any differences between the two agents
using conventional clinical endpoints (visual acuity, frequency of injections,
macular thickness as measured by OCT)
Safety outcomes will be:
 Incidence and severity of ocular adverse events including severe (>15 letter)
loss of vision and increase in geographic atrophy (on fundus autofluorescence).
 Incidence and severity of non ocular adverse events.
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2. Design
Outline
The study will be a double blind, randomised controlled trial, comparing ranibizumab
and aflibercept for the treatment of new onset wet AMD. Following confirmation of
eligibility, patients will be randomised to one of the treatment groups. The treatment
regimen used will be a “prn” (pro re nata) regimen, with the first three injections
mandated. The patient and the clinicians assessing the patient will be masked to
treatment allocation. A separate, un-masked clinician will perform the injections when
required. The study will run for 2 years.
2.1 Eligibility and consent
Patients who are thought to be eligible for the study will be referred to the study centre
at ANU (by an ophthalmologist) where they will be seen within 2 weeks. Baseline
assessments will be performed, and fluorescein angiography will be performed at this
visit (or a copy of the angiogram will be reviewed if it has been performed elsewhere).
Study inclusion/exclusion criteria will be checked. If the patient is found to be eligible
for the study then the study will be explained, and an information sheet will be provided
to the patient. Provided the patient understands the study and has no questions,
informed consent will be obtained. Randomisation then occurs, and injection 1 will be
scheduled within 1 week of this visit (max 2 weeks), and the study visit schedule will be
mapped.
If the patient is not found to be eligible for the study they will be referred back to their
ophthalmologist for prompt treatment.
2.1.1 Inclusion Criteria
 Age >= 50 years
 New diagnosis of unilateral wet AMD requiring treatment with anti-VEGF agents
in the opinion of the investigator.
 Best corrected visual acuity of >=15 letters (6/120)
2.1.2 Exclusion Criteria
 Previous treatment with anti-VEGF agents in the study eye (previous laser
greater than 6 months ago is acceptable, but not within 6 months)
 Haemorrhage greater than 50% of the lesion area.
 Wet AMD in the fellow eye requiring anti-VEGF therapy, or other disease in the
fellow eye requiring, or likely to require anti-vegf therapy within 2 years. (end
stage wet amd in the fellow eye is acceptable, as are drusen of any extent)
 Presence of disease known to affect pupil movement in response to efferent
stimuli, eg posterior synechiae, third nerve lesion, etc.
 Known allergy to ranibizumab or bevacizumab.
 Maculopathy due to other causes (e.g. diabetic macular oedema, myopic
macular degeneration, retinal vein occlusion).
 Myopic refraction <=-6 diopters (spherical equivalent), or >=+6 diopters. In
patients who have had refractive procedures (cataract surgery or refractive
surgery), the refraction prior to the procedure is used. If not available, then the
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Draft 1. January 10, 2014







presence of fundus features consistent with high myopia (significant periparillary
atrophy, posterior staphyloma) will be used as exclusion criteria.
Choroidal neovascularisation due to causes other than AMD (eg pathologic
myopia, multifocal choroiditis, angioid streaks, sorsby’s macular dystrophy,
previous macular laser, Central serous retinopathy )
An ocular condition that would prevent visual acuity improvement despite
resolution of oedema (such as foveal atrophy, sub-foveal fibrosis or optic
atrophy)
Treatment with anti-VEGF agents within the previous six months (ocular, to the
study eye, or systemic).
Cataract surgery within the last 6 months.
Cataract that is likely to require surgery within 2 years
Intercurrent severe disease such as septicemia, or any other condition which
would affect follow-up or photographic documentation (e.g. geographical,
psycho-social)
Patient has a condition or is in a situation that in the investigator’s opinion may
put the patient at significant risk, may confound the study results, or may
interfere significantly with the patient’s participation in the study
2.2 Randomisation
The method of randomisation will be block randomisation, with variable block size (2 to
4). There will be no stratification unless a second study site is enrolled, in which case
there will be stratification by site. Randomisation allocations will be placed in
sequentially numbered opaque envelopes, and the number on the envelope will be the
study number allocated to the patient.
If both eyes of a patient are eligible for the study at baseline then the right eye will be
randomised, the left will receive the opposite medication, and both will be allocated the
same study number, annotated L or R. If the fellow eye subsequently becomes eligible
for the study then it will receive the full baseline assessment, be allocated to the
opposite treatment to the first eye, and receive the same study number (annotated L or
R). A separate study consent form will be obtained.
2.3 Masking
The investigator and the patient will be masked to the randomisation allocation. Any
inadvertent or deliberate unmasking of investigator, patient, or both will be documented
and reported.
The clinician performing the injections will not be masked to treatment allocation, nor
will the clinician who writes the script for the anti-VEGF medication. This will probably
(but not necessarily) be the same person. Each patient will have two charts made up
for the purposes of the study – one with the clinical assessments in it and a second,
sealed chart containing the randomisation allocation and the injection details. Prior to
any injections the injecting clinician will double check the sealed chart against the open
chart to ensure the correct medication will be given. Again, any deviation from the
treatment protocol will be documented.
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2.4 Visit schedule and Testing
Regardless of the specific anti-VEGF the patient is randomised to, the injection
schedule and indications for treatment will be the same.
Patients will be reviewed monthly. Monthly will be defined as every 4 weeks. On
enrolment the visit schedule will be planned for the two years of the study. A visit may
be brought forward or delayed by no more than 2 weeks, however subsequent visits will
still occur at the originally planned time. If a visit cannot be performed within this timeperiod due to unavoidable circumstances is will be regarded as missed, and the next
scheduled visit will be attended. Re-mapping the visit schedule will be permitted during
the study if necessary, but there will still be 28 study visits (enrolment, baseline, plus 13
per year).
The visit schedule is presented in appendix 1.
The enrolment/screening visit will occur one week prior to the first injection.
Randomisation will occur at this screening visit. On the day of the first injection the
vision and fundus will be checked again. If there is a significant change in acuity (>5
letters) the mfPOP will be repeated, and the new acuity and mfPOP result will be used
as the baseline. If there is a significant new haemorrhage present (>50% of the lesion
area) the eye will be withdrawn from the study. This will be reported, but the eye will not
contribute to the results.
Injections will be given at baseline, visit 1 and visit 2. At all subsequent visits injections
will be given as required, based on lesion activity. The lesion activity and the indication
for injection must be documented on the visit form.
If necessary for patient care, appointments may be made for any patient to be seen
between scheduled visits. Such visits do not require documentation unless a
complication is detected or treatment is performed.
Patients will be asked at every visit whether they have had a stroke or a heart attack
since the last visit. Any patient missing an appointment will be contacted within 1 week
to establish their status and another appointment will be made. All admissions to
hospital for any reason will be treated as severe adverse events and reported.
The study datasheets appear in appendix 2
2.4.1 Visual acutity testing and refraction
Refraction and visual acuity measurements will be performed for all patients by a
trained vision examiner. A second examiner will also be trained to serve as a back-up
should the primary examiner be absent. The name of the vision examiner should be
documented in the patient’s source document at each visit.
Subjective refraction will be conducted prior to visual acuity testing to obtain bestcorrected vision at screening visit, week 24 and week 52. Refraction equipment
required includes:
1. logMAR (ETDRS style) distance visual acuity chart
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2. Phoroptor with minus cylinder lenses
3. Jackson cross-cylinders of 0.25, 0.5
Best corrected visual acuity will be measured on a retroilluminated LOGMAR chart
mounted on a stand. The lens correction from the subjective refraction will be placed in
the trial frame worn by the patient. The patients non-tested eye will be occluded. The
patient should begin by reading the top line of the chart and continue reading every
letter on each smaller line, from left to right on each line. The examiner records the
total letters read (0 if no letters are correct) on the data collection form. Patient should
continue until the last letter it is possible for them to read. When a patient cannot read
at least 20 letters on the chart at 4.0 metres, the patient is moved closer to 1.0 meter
from the chart. The spherical correction in the trial frame should be changed by adding
+0.75 diopters to correct for the closer test distance. The patient may fixate
eccentrically or turn or shake his/her head to improve visual acuity. If the patient’s
visual acuity is so poor that he/she cannot read any chart letters when tested at one
meter then the patient’s ability to count fingers, detect hand motion, or have light
perception should be evaluated.
The visual acuity and refraction datasheet is presented in appendix 5.
2.4.2 OCT assessment
OCT can be performed through an undilated pupil, however if quality is poor the scan
will be performed post dilation. The Heidelberg Spectralis OCT will be used for all
scans.
2.4.3 mfPOP assessment
Two mfPOP stimulus variants that test the central 30° (macular) and 60° (wide-field) of
the visual fields of both eyes will be utilised. They will use the new clustered volleys
mfPOP presentation method and use yellow stimuli presented on a 10 cd/m 2
background.
2.4.4 Fundus autofluorescence
Fundus autofluorescence images will be acquired using the Heidelberg Spectralis
device.
2.4.5 Fundus photography
Colour fundus photography will be performed using the Canon CR-2 digital nonmydriatic camera. Mydriasis is permissible if image quality is poor. A single photo,
centred on the fovea will be used.
2.4.6 Intraocular Pressure assessment
Intraocular pressure (IOP) will be assessed using Goldman applanation tonometry.
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2.5 Activity assessment, and indications for treatment
Indications for treatment at visits 3 thru 27
At each visit from visit 3 thru visit 27, treatment is indicated if the lesion is active.
Treatment is withheld if the lesion is inactive or borderline.
If an injection (either mandatory or as required) is contraindicated on the day of
assessment (eg due to concurrent conjunctivitis), it must be performed within 2 weeks
of this visit. If this cannot be done it will be given at the next study visit.
Definitions of lesion activity
Inactive
A lesion will be defined as inactive if there is no intra- or sub- retinal fluid attributable to
leak from choroidal neovascularisation*, and no new macular haemorrhage.
*The following examples are not regarded as fluid due to leak from choroidal
neovascularisation
 small, stable pockets of intra-retinal fluid over areas of geographic atrophy,
 outer retinal tubulation
 subretinal fluid due to retinal deformation at the margins of tall drusen or tall
PED.
 Serous pigment epithelial detachment (PED)
Active
 Intra- or sub- retinal fluid attributable to leak from choroidal neovascularisation,
 New macular haemorrhage
Borderline
If it is unsure whether some changes on an OCT represent fluid due to leak from CNV,
but the clinician is not prepared to grade the lesion as inactive, then the lesion may be
graded as borderline, provided the visual acuity is not more than 5 letters worse than
the previous visit, and the patient does not report any subjective loss of vision. This
would also be the case if it is unclear whether a fleck of haemorrhage is present.
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2.6. Intravitreal injection
Treatment with intravitreal ranibizumab or aflibercept will be performed in a minor
procedures area in the clinic under sterile conditions.

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


The injection eye will be prepared with several drops of G. amethocaine 1%
The eye is flushed with 5% providone-iodine (or aqueous chorhexidine if the
patient has a known allergy or sensitivity to betadine)
A small amount of 2% lignocaine may be then administered subconjunctivally
with a 30G needle to the site of the injection, if it is necessary for adequate
anaesthesia.
After inserting an eyelid speculum, sterilized callipers are used to measure the
injection site
0.05 ml of the study drug will be injected into the vitreous with a 30G needle.
No antibiotics are necessary post injection.
2.7 Cataract Surgery
Ideally cataract surgery would be deferred until the end of the study (104 weeks).
If there is progression of cataract to the extent that withholding surgery would be
unethical, then surgery is permissible. If surgery is to take place, the study medicine
will be given at the time of surgery (or within 1 week), regardless of disease activity.
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3 Adverse events
The medical staff are experienced in managing all adverse events associated with
intravitreal therapy.
The incidence of adverse events will be recorded throughout the two years of the study.
Adverse events to be reported are the following:
Ocular
Infectious Endophthalmitis
Retinal Detachment and Vitreous Haemorrhage
Damage to the Crystalline Lens
Cataract Progression to surgery
Loss of vision >=15 letters
Change in area of geographic atrophy as assessed with fundus
autofluorescence.
Systemic
Admission to hospital
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4 Statistical analysis
Data will be analysed on the basis of intention to treat.
The primary clinical endpoint will be change in BCVA from baseline at 12 months.
Other clinical endpoints will be
 Change in BCVA from baseline at 3, and 24 months
 Proportion with >0 letter change. At 3, 12 and 24 months
 Number of injections in the two year study period.
Clinical Endpoints to be compared at each timepoint will be
 OCT central macular thickness
 Change in BCVA from baseline
Safety endpoints will be those discussed in section 3, compared at 24 months.
mfPOP output will be compared at 3, 12 and 24 months, looking for any differences in
response between the two medications.
Temporal responsiveness of mfPOP to clinical activity will be assessed by presenting
plots of mfPOP results, synchronised with observed changes in clinical activity. For
each patient, their disease course will be divided into a number of segments as follows:
1. active to inactive: First injection (or first injection after a period of disease inactivity)
to first visit when the eye is graded as inactive and no injection is required.
2. inactive to active: First visit when the eye is graded as inactive to first visit when the
eye is graded as active, and requires an injection.
The results for all like segments (active to inactive or inactive to active) for all patients
will be pooled and the mfPOP results will be analysed to see if the mfPOP results
correlate with the changes in clinical activity, and if indeed they may predict changes in
disease activity.
The mfPOP results for aflibercept and ranibizumab eyes, as analysed above, will be
compared.
The mfPOP device generates visual field indices for sensitivity and response delay at
44 locations per visual field, the two eyes being measured concurrently, and by
responses measured from the two pupils. Thus, a given mfPOP test generates 176 (=2
pupils, x 2 eyes x 44 locations per visual field) data points. This creates problems of
multiple comparisons. This issue will be dealt with in two ways depending on
requirements.
The first is to generate a single number per eye, such as the mean of the worst Ndeviation from normal within the visual field measured by the pupil providing the best
signal to noise ratio. This provides full Bonferroni correction. These summary statistics
will be used for methods such as receiver operator characteristic (ROC) plot analysis,
and Kaplan-Meier survival (KMS) analysis, and cross-correlation anlaysis. ROC
analysis will look at the sensitivity and specificity for 1) predicting progression during prn
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management or 2) based on the baseline mfPOP predicting which patients are
responders after the first three injections. The KMS analysis would look at issue like
which patients had outcomes worse that some criterion after N-months of prn
management. The cross-correlation analysis will look at the time lag between changes
in mfPOP measures and disease becoming active under prn management. These
summary measures will also be combined with summary measures from other
instruments, such as the OCT or acuity. This would involve created combined scores
using method such as Fisher’s linear discriminant analysis.
The second method to deal with multiple comparisons will to use linear mixed models
where the variables with possible repeated (correlated) measures are entered as
random effects. In this way the maximum power can be obtained to investigate subjectwise effects like the differences between treatment with ranibizumab or aflibercept. We
will also use these models to attempt a components of variance analysis looking at the
proportions variance accounted for by eye, subject, visit and disease stage, and the
correlations between each, and their significance.
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5. Quality assurance
Standardized protocols have been developed for mfPOP, assessment of lesion activity,
intraocular injection, measurement of best-corrected visual acuity, OCT and intraocular
pressure.
The major quality assurance features of the study are:
 Standardised eligibility and exclusion criteria
 Prospective, random treatment allocation
 Adherence to treatment protocol and follow-up program
 Intention to treat statistical analysis
 Double-blind study design.
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Appendix 1.
Schedule of Visits – Year 1 (schedule is identical regardless of treatment allocation)
Screen
Wk -1
Study Consent
Concomitant Meds & Concurrent
Procedures
LogMAR BCVA
Week
0
Wk
4
Wk
8
Wk
12
Wk
16
Wk
20
Wk
24
Wk
28
Wk
32
Wk
36
Wk
40
Wk
44
Wk
48
Wk
52
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
LogMAR VA using previous refraction
Low contrast VA
X
IOP
Matrix 10-2
X
X
Dilated fundal examination
X
Cataract grading
OCT
Fundus autofluorescence
mfPOP
X
X
X
X
Fundus Colour Photography
X
Fluorescein angiography
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Treatment with Study medication
Y
Y
Y
prn
prn
prn
prn
prn
prn
prn
prn
prn
prn
prn
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Page No. 14 of 16
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Appendix 1. (cont)
Schedule of visits - Year 2 (schedule is identical regardless of treatment allocation)
Concomitant Meds &
Concurrent Procedures
Wk
56
Wk
60
Wk
64
Wk
68
Wk
72
Wk
76
Wk
80
X
X
X
X
X
X
X
Wk
84
X
Wk
88
Wk
92
Wk
96
Wk
100
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cataract grading
OCT
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Not
counted.
X
Fundus Colour Photography
Treatment with Study
medication
Adverse Events
X
X
Fundus autofluorescence
mfPOP
X
X
Matrix 10-2
Dilated fundal examination
X
X
Low contrast VA
IOP
X
X
LogMAR BCVA
LogMAR VA using previous
refraction
Wk 104
prn
prn
prn
prn
prn
prn
prn
prn
prn
prn
prn
prn
X
X
X
X
X
X
X
X
X
X
X
X
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