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Trial registered on ANZCTR


Registration number
ACTRN12614000497606
Ethics application status
Approved
Date submitted
3/04/2014
Date registered
12/05/2014
Date last updated
11/04/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
The RAAMP study. Ranibizumab versus aflibercept for age-related macular degeneration, using multifocal objective pupil perimetry.
Scientific title
A randomised trial evaluating the ability of multifocal objective pupil perimetry to track macular function in treatment-naive eyes with wet Age-Related Macular Degeneration (AMD), treated with either aflibercept or ranibizumab.
Secondary ID [1] 284359 0
nil
Universal Trial Number (UTN)
Trial acronym
The RAAMP study.
Linked study record

Health condition
Health condition(s) or problem(s) studied:
wet age related macular degeneration (AMD) 291518 0
Condition category
Condition code
Eye 291889 291889 0 0
Diseases / disorders of the eye

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intravitreal Aflibercept 2mg. This will be given monthly for three months, then patients will be reviewed monthly for a further 22 months, and injections will be given using a pre-defined pro-re-nata (prn) protocol based on clinical activity (on OCT and fundoscopy), with no pre-mandated injections. The visit schedule will be organised for each patient on enrollment, and adherence to the protocol will be closely monitored with scheduled reminders prior to each visit and recall within 1 week if visits are missed.
At each monthly visit multifocal objective pupil perimetry (mfPOP) will be performed. This 10 minute non-invasive test uses subtle pupil responses to visual stimuli as an objective measure of the sensitivity of visual function in that region of the visual field.
Intervention code [1] 289088 0
Treatment: Drugs
Comparator / control treatment
An identical schedule of visits, and clinical decision making protocol, except using intravitreal injections of ranibizumab 0.5mg.
Control group
Active

Outcomes
Primary outcome [1] 291810 0
Multifocal objective pupil perimetry measures of macular function.

The temporal pattern of the outcome measure, and it's correlation with clinical measures of disease activity will be evaluated. 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.
Timepoint [1] 291810 0
Ongoing assessment (see above)
Secondary outcome [1] 307595 0
Best corrected visual acuity. letter score, as measured using logMAR style charts.
Timepoint [1] 307595 0
3 months, 12 months and 2 years from start of treatment.
Secondary outcome [2] 307596 0
Total number of injections required during the 100 week study period.
Timepoint [2] 307596 0
At completion of the study, at the 104 week visit. If an injection is required at the 104 week visit this is not included in the total.

Eligibility
Key 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 >=20 letters (6/120)
Minimum age
50 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.

Glaucomatous optic neuropathy or any other optic neuropathy in the study eye

Diabetes mellitus or any other disease known to affect retinal function.

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
* myopic macular degeneration, retinal vein occlusion).
* 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.
* 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.

Study design
Purpose of the study
Diagnosis
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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. Treatment allocation will be done using sequentially numbered opaque envelopes, with the randomisation sequence described below.

If the patient is not found to be eligible for the study they will be referred back to their ophthalmologist for prompt treatment.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The method of randomisation will be block randomisation, with variable block size. 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

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 pro-re-nata (prn) protocol with monthly review. These reviews will occur at the usual study visits.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / 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 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 to 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 N-deviation 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 random effects. In this way the maximum power can be obtained to investigate subject-wise 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.

Our previous study, which did not use the new CV mfPOP method, was well enough powered with 20 subjects to detect improvement on anti-VEGF treatment at the p < 0.005 level for both response amplitude and delay. Assuming a comparable change in macular sensitivity with disease onset, this improved SNR provides a power of 0.99 for a p-value of 0.01 and a sample size of 20 persons who convert (0.97 for p<0.001). With N = 30/arm the power is higher allowing smaller effects to be estimated.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
5/02/2015
Actual
29/01/2015
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
60
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,SA
Recruitment hospital [1] 2276 0
The Canberra Hospital - Garran
Recruitment hospital [2] 2977 0
Flinders Medical Centre - Bedford Park
Recruitment postcode(s) [1] 7951 0
2605 - Garran
Recruitment postcode(s) [2] 8688 0
5042 - Bedford Park

Funding & Sponsors
Funding source category [1] 288998 0
Government body
Name [1] 288998 0
NHMRC
Country [1] 288998 0
Australia
Primary sponsor type
University
Name
Australian National University (ANU)
Address
The John Curtin School of Medical Research
The Australian National University
GPO Box 334
Canberra City ACT 2600
Country
Australia
Secondary sponsor category [1] 287678 0
Hospital
Name [1] 287678 0
Canberra Hospital
Address [1] 287678 0
Canberra Hospital
Yamba Dve
Garran ACT 2605
Country [1] 287678 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290808 0
ACT health Human Research Ethics Committee
Ethics committee address [1] 290808 0
Ethics committee country [1] 290808 0
Australia
Date submitted for ethics approval [1] 290808 0
Approval date [1] 290808 0
15/01/2014
Ethics approval number [1] 290808 0
ETH.11.13.319

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 17 17 0 0
/AnzctrAttachments/366072-12.20 - eth.11.13.319 - Essex - oos approval-1.pdf

Contacts
Principal investigator
Name 47346 0
Prof Ted Maddess
Address 47346 0
Eccles institute of Neuroscience
John Curtin School of Medical Research
Australian National University
Canberra ACT 0200
Country 47346 0
Australia
Phone 47346 0
+61 2 6244 3769
Fax 47346 0
Email 47346 0
[email protected]
Contact person for public queries
Name 47347 0
Rohan Essex
Address 47347 0
Canberra Hospital
Yamba Dve
Garran ACT 2605
Country 47347 0
Australia
Phone 47347 0
+61 2 6244 3769
Fax 47347 0
Email 47347 0
[email protected]
Contact person for scientific queries
Name 47348 0
Rohan Essex
Address 47348 0
Canberra Hospital
Yamba Dve
Garran ACT 2605
Country 47348 0
Australia
Phone 47348 0
+61 2 6244 3769
Fax 47348 0
Email 47348 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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