Download Study Manual

Final revision . September 25, 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
[email protected]
Dr Randev Mendis
Prof JM Provis
Dr CF Carle (PhD)
Dr F Sabeti (PhD)
ASSOCIATE INVESTIAGTORS
Prof Robyn Guymer
Prof Tien Wong
Page No. 1 of 17
Final revision . September 25, 2014
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 (prn with monthly review, following a 3 month induction period). They will be
Page No. 2 of 17
Final revision . September 25, 2014
followed using both the standard testing and also mfPOP to see if 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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Final revision . September 25, 2014
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
(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 wet AMD requiring treatment with anti-VEGF agents in the opinion
of the investigator. Bilateral new disease is acceptable, as is unilateral new disease
and end-stage disease in the fellow eye.
 Best corrected visual acuity of >=20 letters (6/120)
2.1.2 Exclusion Criteria
 Wet AMD in the fellow eye already receiving anti-VEGF therapy, or other disease in
the fellow eye requiring anti-vegf therapy. (end stage wet amd in the fellow eye is
acceptable, as are drusen of any extent)
 Anti-VEGF therapy in the fellow eye within the last 6 months, or systemically within
6 months.
 Previous treatment with anti-VEGF agents in the study eye ever. (previous laser
greater than 6 months ago is acceptable, but not within 6 months)
 Haemorrhage greater than 50% of the lesion area.
 Glaumomatous optic neuropathy in the study eye
 Presence of disease known to affect pupil movement in response to efferent stimuli,
eg posterior synechiae, third nerve lesion, etc.
 Cataract surgery within the last 6 months. Cataract that is likely to require surgery
within 2 years
 Maculopathy due to other causes
Page No. 4 of 17
Final revision . September 25, 2014




o diabetic macular oedema, myopic macular degeneration, retinal vein
occlusion).
o Myopic refraction <=-6 diopters (spherical equivalent). 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 presence
of fundus features consistent with high myopia (significant periparillary
atrophy, posterior staphyloma) will be used as exclusion criteria.
o 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)
Any 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.
Known allergy to ranibizumab or aflibercept.
2.2 Randomisation
The method of randomisation will be block randomisation, with variable block size (2 to
4). There will be stratification by study site if more than one is participating.
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.
Randomisation will occur at visit #-1 (see study schedule).
2.2.1 Second eye involvement
Patients (not eyes) will be randomised. Only one eye of a patient will be included in the
study. If both eyes of a patient are eligible for the study at baseline then the right eye
will be included.
If the fellow eye subsequently develops wet AMD requiring anti-VEGF therapy then it
will receive the same medication as the study eye.
Fellow eyes requiring anti-VEGF therapy during the study will be managed using a prn
protocol with monthly review. These reviews will occur at the usual study visits, and
treatment will be given by the un-masked “injecting” investigator.
2.3 Masking
The investigators will be masked to the randomisation allocation. This includes all
investigators involved in patient assessment, including those performing acuity
assessments, and the doctors(s) who determine disease activity. They must not
perform nor witness the injections, nor be involved in generating the prescriptions for
the patient. No record of the study medication will be made in the clinical chart other
than in the “sealed section” (see below).
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Final revision . September 25, 2014
The patient will be masked to treatment allocation. They cannot handle their
medication at any stage (e.g. pick it up from the pharmacy). The un-masked injecting
investigator (and their assistant if present) will not mention the name of the study
medication within earshot of the patient.
Each study site must have at least one un-masked investigator. The clinician(s)
performing the injections (the “injecting investigator”) and the clinician who writes the
prescription for the anti-VEGF medication will not be masked. This will probably (but
not necessarily) be the same person. The clinical chart of each study participant will
have a sealed section containing the randomisation allocation and the injection details.
Prior to any injections the un-masked injecting clinician will double check the sealed
chart against the open chart to ensure the correct medication will be given.
Any inadvertent or deliberate unmasking of investigator or patient, will be documented
and reported.
Page No. 6 of 17
Final revision . September 25, 2014
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 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 time-period 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.
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
investigators will ensure that a significant new haemorrhage has not occurred since the
previous enrolment visit. 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 been hospitalised, or suffered 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.
2.4.1 Visual acuity testing and refraction
Refraction and visual acuity measurements will be performed for all patients by a
trained vision examiner.
Subjective refraction will be conducted prior to visual acuity testing to obtain bestcorrected vision at screening visit, week 12, week 52 and week 104. Refraction
equipment required includes:
1. Snellen projection distance visual acuity chart or retroilluminated LOGMAR chart.
2. Phoroptor with minus cylinder lenses, or trial lens set.
3. Jackson cross-cylinders of 0.25 and/or 0.5.
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Final revision . September 25, 2014
Best corrected visual acuity will be measured on a retro-illuminated logMAR chart
mounted on a stand, starting with the chart at 4m. The lens correction from the
subjective refraction will be placed in the trial frame worn by the patient. The patient’s
non-tested eye will be occluded. The patient may fixate eccentrically or turn or shake
his/her head to improve visual acuity.
With the chart at 4m, the examiner records the total letters read. If a patient can read
all the letters on a line it is acceptable to assume they can read all larger letters.
Provided the patient can read all the letters on the top line at 4m, the letter score will be
thirty plus the number of letters read
If the patient cannot read all of the top line on the chart at 4.0 metres, the total number
of letters read at 4.0m is recorded. The patient is then moved 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 number of letters read at 1.0 m on
the top 6 lines of the chart only is then recorded. In this setting the letter score is the
number of letters read at 1m, plus the number read at 4m. NOTE – visual acuity must
be 20 letters or more at baseline for study eligibility.
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.
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, using the “Dense” Spectral-Domain OCT protocol.
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 or equivalent. Mydriasis is permissible if image quality is poor. A
single photo, centred on the fovea will be used.
Page No. 8 of 17
Final revision . September 25, 2014
2.5 Activity assessment, and indications for treatment
Indications for treatment at visits 3 thru 26
At each visit from visit 3 thru visit 26, 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, and the reason
for delay will be documented and reported.
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*, no new macular haemorrhage, and no increase
in volume of pigment epithelial detachment.
*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.
 Stable serous pigment epithelial detachment (PED). See below for definition of
stable.
Active
 Intra- or sub- retinal fluid attributable to leak from choroidal neovascularisation,
 New macular haemorrhage
 Serous of fibrovascular pigment epithelial detachment which is not stable. This
could be
o increasing in size since last review, or
o decreasing in size in response to previous injection at last review. In this
setting injections will be indicated monthly until the volume of the PED
stabilises.
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 active (or 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. Treatment is withheld in this setting.
Page No. 9 of 17
Final revision . September 25, 2014
2.6. Intravitreal injection
Treatment with intravitreal ranibizumab or aflibercept will be performed in a minor
procedures area in the clinic under sterile conditions.






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 mark the
injection site (3mm from the limbus if pseudophakic, 4mm if phakic.
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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Final revision . September 25, 2014
3 Adverse events
At each study visit the following adverse events to be reported are to be documented
(since the previous visit):
Ocular
Infectious Endophthalmitis
Retinal Detachment
Vitreous Haemorrhage
Damage to the Crystalline Lens
Cataract Progression to surgery
Systemic
Admission to hospital
Cerebrovascular events (transient ischaemic attack and stroke)
Cardiac ischaemic events (unstable angina, new onset angina, acute myocardial
infarction)
Page No. 11 of 17
Final revision . September 25, 2014
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.
 Change in autofluorescence, specifically area of georgraphic atrophy, at 24
months.
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.
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
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
Page No. 12 of 17
Final revision . September 25, 2014
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
correltions between each, and their significance.
Page No. 13 of 17
Final revision . September 25, 2014
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.
Page No. 14 of 17
Final revision . September 25, 2014
Appendix 1.
Schedule of Visits – Year 1 (schedule is identical regardless of treatment allocation)
Screen
Wk -1
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
Visit#
-1
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Study Consent
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant Meds & Concurrent
Procedures
LogMAR BCVA
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
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. 15 of 17
Final revision . September 25, 2014
Appendix 1. (cont)
Schedule of visits - Year 2 (schedule is identical regardless of treatment allocation)
Visit #
Concomitant Meds &
Concurrent Procedures
Wk
56
14
Wk
60
15
Wk
64
16
Wk
68
17
Wk
72
18
Wk
76
19
Wk
80
20
X
X
X
X
X
X
X
Wk
84
21
X
Wk
88
22
Wk
92
23
Wk
96
24
Wk
100
25
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
Matrix 10-2
Dilated fundal examination
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
Not
counted.
X
Fundus Colour Photography
Treatment with Study
medication
Adverse Events
X
X
Fundus autofluorescence
mfPOP
X
X
Cataract grading
OCT
X
X
Low contrast VA
IOP
26
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
Page No. 16 of 17
Final revision . September 25, 2014
Page No. 17 of 17