Non-Damaging Photothermal Therapy of Non-exudative Age Related Macular Degeneration
Phase: NA
Conditions: Macular Degeneration, Retinal Drusen
Sponsor: Stanford University

 
 
 
 
Non-Damaging Photothermal Therapy of Non-exudative Age 
Related Macular Degeneration 
Study Protocol and Statistical Analysis Plan 
NCT02569892 
 August 15, 2018 

1 
 
Title:  
Non-Damaging Photothermal Therapy of Non-exudative Age Related Macular 
Degeneration 
 
Introduction 
 
Age Related Macular Degeneration (AMD) is the leading cause of blindness 
and visual disability among patients exceeding 60 years of age in the western 
hemisphere. The clinical presentation of AMD ranges from soft drusen in 
patients with normal visual acuity to geographic atrophy or subfoveal 
choroidal neovascularization (CNVs), disciform scarring and eventually legal 
blindness.1  
 
Approximately 10 to 15% of patients with AMD develop severe visual 
loss due to geographic atrophy characterized by the atrophy of retinal pigment 
epithelium, choriocapillaris and outer retina or due to exudative AMD. 
Nonexudative AMD is responsible for about 25% of the severe visual loss and 
the remaining is caused by neovascular AMD2. Fortunately, with the 
introduction of pharmacological anti-VEGF treatments to neovascular AMD, 
exudative AMD can be effectively treated, thereby maintaining good visual 
acuity for extended period of time. However, there is still no treatment for 
nonexudative AMD other than vitamin supplementation, and patients 
inevitably progress to advanced disease and associated visual loss.3 
 
The cumulative incidence of new exudative or atrophic lesions in 
eyes initially free of advanced AMD has been estimated as 8.6% at one year, 
16.4% at two years and 23.5% at three years.4 The five-year risk of CNV 
occurrence in the fellow eye of patients who have already experienced CNV in 
the first eye, varies from 7% to 87% depending on the coexistence of four 
main risk factors (presence of five or more drusen, focal hyperpigmentation, 
one or more large drusen and systemic hypertension). 
Owing to the risk of vision loss associated with the presence of large 
volume of drusen, retinal laser treatment was proposed to prevent 
progression to advanced AMD. Several clinical trials have been conducted to 
test the effect of laser photocoagulation on reabsorption of drusen in the 
macula.5-12 Laser burns were applied to the retina, either directly to the drusen 
or following predefined patterns. Argon, krypton, dye or diode lasers have 
been used with varying levels of energy (ranging from sub-visible to faint or 
intense whitish retinal lesions).  The assumption was that phagocytic cells or 
macrophages clearing the laser-induced debris in the retina, RPE and choroid 
could also reduce or eliminate the drusen. It was also speculated that laser 
could trigger release of cytokines and growth factors from the RPE, which 
may act on drusen regression.  
A systematic review of all clinical trials using laser treatment of drusen 
demonstrated that there was a significant reduction of drusen over time. 
However there was also found a slight increase in the incidence of CNV and 
geographic atrophy, albeit not statistically significant 3. This increase could be 
related to the fact that conventional photocoagulation used in most of these 
trials damaged the Bruch’s membrane, consequently inducing CNV. 
Therefore, a non-damaging laser treatment strategy might be able to induce 
drusen regression without the known side effects of photocoagulation. This 
hypothesis is supported by the fact that “subthreshold” laser treatments of the 
drusen resulted in their reduction with much fewer side effects than with 

2 
 
conventional visible burns: 6 out of 63 eyes treated with visible burns 
developed CNV within 3 months of treatment, while no such CNV was 
reported for subthreshold treatment. Despite the drusen reduction, the 
treatment did not slow the progression to geographic atrophy or to CNV, 
compared to observation in this trial. This might be due to very small number 
(a few tens) of laser spots applied to the macula. Our approach might rectify 
this deficiency by applying higher density of the treatment: 500 non-damaging 
spots. 11-12 
Micropulse laser photocoagulation avoids the excessive heating which 
causes visible burns, tissue necrosis, and related collateral effects13, while 
providing similar clinical benefits as conventional laser coagulation.14 -19 
However, the lack of a reliable titration for every patient and absence of visible 
endpoint makes it difficult for the physician to (a) know which retinal areas 
have been treated and (b) to ensure the adequate amount of laser energy in 
the treatment. In addition, the dense coverage of the retina with the sub-
visible laser exposures typically requires more than 500 spots in the macula, 
which is difficult to accomplish without pattern scanning laser. These issues 
prevented acceptance of this technology in clinical practice. 
We have developed the titration protocol for PASCAL laser, which 
ensures that pulse energy is within the range of clinical efficacy, but does not 
exceed the tissue damage threshold 21 in every patient. This protocol, called 
EndPoint Management, has been recently tested in a clinical trial, which 
demonstrated its safety and efficacy in treatment of Central Serous 
Retinopathy22 using 30% energy settings. The trial demonstrated lack of 
tissue damage and excellent tissue response to the treatment, even after 
multiple retreatments. The average retreatment period in this trial was found 
to be 6 months.   
We propose to use the same laser parameters for treatment of the 
macula in patients with early AMD to prevent drusen growth and 
advancement of the disease into geographic atrophy or neovascularization. 
 
AIMS OF THE STUDY 
 
1. To determine whether photothermal therapy (PTT) of the macula with 
EpM® reduces the volume of drusen in the macula.  
2. To determine whether PTT decreases the incidence of advanced AMD 
(neovascular AMD or geographic atrophy).  
 
The primary efficacy outcome measure will be the reduction in drusen 
volume in the central 3mm circle over 12, 18, 24 months in subjects treated 
with PTT, compared to observation alone.    
The secondary efficacy outcomes after the month 12, 18, 24 of follow up will 
be: 
• Functional outcome:  
▪ Mean change in visual acuity in both groups. 
• Anatomical outcome:  
• Reduction of drusen growth; 
• Prevention of neovascular AMD; 
• Prevention of geographic atrophy based on OCT and 
FAF.   

3 
 
• Safety Assessments. Safety of the treatment will be assessed for 
ocular adverse event incidence (AEs) and serious AEs (SAEs), 
based on the reports of the patients and examination during or 
between visits until the month 24 of follow up.  After 24 months, 
subjects will then be followed for an additional 3 years for 
observation 
• Serious adverse events (SAEs) will be monitored continuously.  
 
 
STUDY METHODS 
 
Design: 
 
• Prospective, Randomized Clinical Trial (RCT). 
• 24 months with an additional 3 year observation follow up period. 
Subjects will be seen once a year and undergo non-invasive testing.  
• Total patient recruitment 56 patients.   
• Number of arms: 2 arms. 
• Number of patients:  28 patients in each arm. 
 
Patient Recruitment 
 
1. Initial Assessment   
 
The study will enroll 56 eyes in total. Patients will be initially assessed 
as part of their standard management and, if fulfilling all the inclusion criteria, 
will be referred to a Study Investigator.  
At the initial assessment, the investigator will confirm that the patient 
has satisfied the eligibility criteria stated in the Study Protocol (SPR) and the 
study will be discussed in full with the study participant (SP). If interested in 
participating, the SP will be given a written informed consent to take home for 
further consideration. The patient will have a minimum of 24 hours to decide 
whether or not to take part in the study.   All study procedures, will be 
explained to the SP by the investigator or staff member. The nature of the 
study will be also explained to the SP together with hazards of the study 
procedures, including any possible adverse events. The SP will be informed 
that he or she is free to terminate participation in the study for any reason.   
Any patient unwilling to participate at this stage will be managed as 
part of the appropriate routine eye care pathway. 
The study patient will undergo the Examination Procedures at the 
Baseline visit. The data from these tests will be used for study data analysis. 
 
2. Examination Procedures at Baseline and Follow-up visits 
 
(1)  ETDRS best corrected visual acuity.   
(2) Slit lamp biomicroscopy: dilated fundus examination with 78D Volk lens, 
intraocular pressure by Goldmann applanation tonometry. 
(3) Spectral domain OCT (Cirrus SD-OCT): Macular/macular cube/Volume 
scan & average central retina thickness and Drusen volume.  
(4) Fundus photography and autofluorescence. 
 

4 
 
The treatment will be randomised at this stage, and the SP will be 
allocated to arm A (treat) or arm B (observe). The 56 eyes will be randomly 
allocated to each of the two study arms, 28 in each arm. The SP will be given 
a trial number, and the treatment record will be coded. For patients where 
both eyes meet eligibility criteria both eyes will be enrolled with the Right Eye 
randomly assigned to active treatment arm or sham arm, with the Left Eye 
assigned to the opposite arm.  
 
3. Treatment Visit: 
 
The SP will undergo treatment within 14 days after the examinations are 
performed. 
 
Patient-eligibility 
 
Inclusion criteria: 
 
1. Older than 60 years of age. 
2. Male or female patients with nonexudative AMD with a drusen volume of of 
at least 0.03mm3 on OCT within the central 3mm circle centered on the fovea.  
3. Adequate pupil dilatation and clear media to perform color, red-free 
imaging, fundus autofluorescence imaging, and OCT imaging. 
4. Able to give an informed consent.  
 
Exclusion criteria: 
 
1. Presence of signs of advanced AMD, such as CNV, haemorrhages or 
macular atrophy based on OCT and FAF.  
2. Previous macular laser treatment.  
3. Any previous ocular condition that may be associated with a risk of 
developing macular oedema. 
4. Vitreomacular traction determined clinically and /or by OCT, which in the 
opinion of the investigator contributes to the macular oedema (associated 
or causing a detachment of the fovea). 
5. Presence of other macular disease such as epiretinal membrane, macular 
telangiectasia.  
6. Ocular or periocular infections. 
7. Planned intra-ocular surgery within one year. 
8. Patient is unavailable for follow-up visits. 
 
Study Examination Procedure 
 
Baseline: 
 
1. Full patient history including age, gender, ethnic group, diabetes 
history, medical history, medication history, ocular history, driving 
history, smoking status. 
 
 
Baseline and Follow-up visits (see table): 
 

5 
 
1. ETDRS BCVA 
2. Slitlamp biomicroscopy:   
Dilated fundus examination with 78D Volk lens 
Intraocular pressure by Goldmann applanation tonometry 
3. Spectral domain OCT 
4. Optical coherence tomography angiography if available on site. 
5. Fundus photography and autofluorescence. 
 
 
Study Treatments Schedules: 
 
Laser: 
• Pupillary dilatation:  Will be achieved using Tropicamide 1% and 
Phenylephrine 2.5%.  One drop instilled every five minutes repeated 
three times. 
• Anaesthesia: Topical anaesthetic will be applied to the cornea, prior to 
the commencement of treatment. 
• Lens: Area centralis contact lens will be coupled to the cornea with 1% 
methylcellulose or equivalent. 
• Laser system: Pascal® laser with 532 nm (green) or 577 nm (yellow) 
wavelength, with EndPoint Management Software (EpM) at 30%, 200 
m spot diameter and 0.25 spot-width spacing. A grid-pattern 
treatment will be applied to the area of retinal thickening as per OCT. 
The total number of spots should exceed 500, including the full macula 
grid + plus patterns of 2x2 inside the grid and patterns of 3x3 or 4x4 
outside the grid.  
 
Arm A:   
Patients will be treated initially (Day 0) and every 6 months during the follow 
up, if meet retreatment criteria.  
• Number of laser spots: 
>500. Customized grid pattern to cover area 
of drusen. 
• Spot size: 
 
200m 
• Duration for titration: 15 or 20 ms 
• Exposure:                     Laser power will be titrated to produce a barely 
visible burn, considered a 100% at EpM®. For the treatment, energy is set 
at 30% to achieve non-damaging exposures. 
• Titration power range: 
100 to 200 mW 
• Spot spacing:  
 0.25 spot-width-apart. 
• Retreatment criteria:  
o Meet initial inclusion/exclusion criteria 
o Does not exhibit significant reduction in drusen volume 6 months 
after previous treatment. Significant is a 50% reduction in the cube 
root volume of drusen. 
 
Arm B:   
Patients will be treated with a sham laser (zero therapeutic power, only the 
aiming beam) and observed.  
 
PATIENT FOLLOW-UP: 

6 
 
All participants will receive treatment at the initial treatment day and will have 
follow-up visits at 1 month (optional), 3, 6, 9, 12, 18, 24 months. 
 
At the end of the 24 month period there will be an additional 3 year follow up. 
During the 3 year follow up, there would be no active component, the subjects 
will be seen once per year and undergo visual acuity testing and non-invasive 
retinal imaging to monitor for long term effects of treatment. This should not 
place a significant burden on the subjects since they are typically seen every 
6 to 12 months for routine follow-up. 
 
Best-corrected visual acuity (BCVA) using ETDRS charts at a distance of 4 
meters, digital fundus photography, fundus autofluorescence, ocular 
coherence tomography (OCT), ocular coherence tomography angiography 
(OCTA when available on the site) will be carried out at baseline and at each 
follow-up visit. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*OCTA will be done if available on site 
 
STUDY RANDOMIZATION PROCEDURE 
 
The subjects will be allocated to each arm of the study with simple 
randomization method using a computer-generated randomization list and 
sequentially number, sealed, opaque envelopes (SNSOE). 
After a subject has signed informed consent, their name will be written 
on the selected envelope by the Clinical Trials Coordinator. The 56 eyes will 
TEST, treatment 
Baseline 
0 
1 
optional 
3 
6 12 
18 
24 
Laser treatment 
 
x 
 
 
x 
x 
x 
x 
ETDRS visual 
acuity (BCVA) 
x 
x 
x 
x 
x 
x 
x 
x 
Slitlamp 
x 
x 
x 
x 
x 
x 
x 
x 
OCT  
X 
X 
X 
X X 
X 
X 
X 
OCTA* 
X 
X 
X 
X X 
X 
X 
X 
Digital Fundus 
Photography 
X 
X 
X 
X X 
X 
X 
X 
Fundus 
autofluorescence 
X 
X 
X 
X X 
X 
X 
X 

7 
 
be randomly allocated to one of the two arms. The computer randomization 
will be done by the Clinical Trials Coordinator. The randomization table will be 
given to an independent person, who will sequentially label 56 envelopes, and 
enclose the written treatment type within the envelope. The study arm will be 
coded numerically for each subject. 
 
METHOD OF STATISTICAL ANALYSIS 
 
The data will be analysed using analysis of covariance, adjusting for 
baseline and disease severity. Results will be presented as differences 
between the treatment arms with their associated 95% confidence intervals, 
and non- significant effects interpreted in the context of these and the limited 
power of the study. 
 
SAMPLE SIZE: 
 
We estimated our sample size based on previous comparable 
publications that included approximately 50 eyes on average.11-12 
 
EFFICACY MEASURES:  
 
Primary Outcome: 
• Reduction in drusen volume in arm A compared to arm B. 
 
Secondary Outcomes: 
• Mean change in visual acuity (ETDRS letters) 
• Mean change in average central retinal thickness (ACRT) after 
12, 18, 24 months of follow up. 
• The proportion of patients with ACRT < 300 µm on Spectral 
domain OCT after 12, 18, 24 months of follow up  
• Conversion into GA or CNV 
 
SAFETY MEASURES: 
 
• Monitoring of adverse events (AEs) and serious adverse effects 
(SAEs) (the incidence of ocular AEs and SAEs). 
• Assessment of the retinal autofluorescence to identify any laser 
burn. 
• Signs of any laser burn identified at RPE-photoreceptors layers 
on DRI-OCT. 
 
ADVERSE EFFECTS: 
 
• Any medical incidence in patients who received laser that could be 
associated with the treatment delivered in the research study. 
• Any temporal or transitory adverse effect that has relationship to the 
study therapy. 
REPORTING ADVERSE EVENTS (AE)  AND SERIOUS ADVERSE EVENTS 
 

8 
 
• With any AE, we will treat the SP as appropriate to prevent further 
complications and to potentially resolve the event. 
• SAEs and AE will be reported immediately (when the subject is in the 
office, if possible or within 24 hours of learning of the event) to the 
principal investigator, study coordinator and sponsor. The SP subject 
will be referred for further medical treatment if required. 
• Follow-up reports on AEs should indicate whether the AE is presumed 
to be device-related, or a result of other factors, and should be 
recorded on the Adverse Events Report. The Adverse Events Report 
should be completed each time the subject is seen during the 
management of the incident and at resolution of the incident. 
• All AEs occurring from the time of written informed consent throughout 
the course of the study (end of study is defined as the end of the scan 
acquisition) will be recorded at the study site.    
• The AE should be made to describe it in terms of a diagnosis.  If a 
clear diagnosis has been made, individual signs and symptoms will not 
be recorded unless they represent atypical or extreme manifestations 
of the diagnosis, in which case they should be reported as separate 
events.  If a clear diagnosis cannot be established, each sign and 
symptom must be recorded individually. 
 
All the adverse events shall be recorded in detail as specified below: 
Name (Type) 
The common name of the adverse event that appeared shall 
be written down.  
Date of onset 
The first date that the physician in charge found the adverse 
event shall be written down. 
Causal 
relation 
Write down probable causes, and classify the causal relation 
with the test device depending on the presence or absence of 
the causal relationship as defined below. The adverse events 
that are judged to have no relation with the test devises are 
classified as complications; all the others are classified as 
adverse device effects. 
Probably not 
related 
The adverse event is definitely related to other 
than the test device. (Complication) 
Possibly 
related 
The adverse event is possibly related to the 
test device; the causal relationship with the 
test devices is fully undeniable. (Adverse 
device effect) 
Probably 
related 
The cause of the adverse event cannot be 
located. However, the adverse event is 
probably related to the test device. (Adverse 
device effect) 
Definitely 
related 
The adverse event is definitely related to the 
test device. (Adverse device effect). 
Severity 
The severity shall be classified into mild, moderate and severe 
based on the criteria: 
Mild 
The symptom is mild and expected to heal 
soon. 

9 
 
Moderate 
The symptom is described as neither mild nor 
severe. 
Severe 
The finding is serious and expected to 
interfere with the subject’s daily life depending 
on the subject’s physical predisposition or the 
circumstances under which the adverse event 
appeared.  
Symptom, 
progress and 
treatment 
Necessity for treatment and progress from the detection of the 
adverse event and the determination of outcome shall be 
written down. 
Outcome 
The classification into “healed”, “unchanged”, “aggravated”, or 
“death” and the outcome date shall be written down. If the 
subject died, statement of death shall be made. 
Views on the 
adverse 
event 
Views on the adverse event by the physician in charge shall 
be written down. Omission is allowed if there are no special 
comments.  
  
POTENTIAL RISKS:  
 
• Complications of conventional laser therapy including marked vision 
loss, paracentral scotomas or accidental application of laser in the 
fovea. There is limited data regarding potential risks of photothermal 
therapy, however, due to its non-damaging nature, it is expected to be 
safer than conventional photocoagulation.  
 
STUDY PATIENT DISPOSITION 
 
Completed SP: A completed SP is one who has not been discontinued from 
the study and has completed all study related procedures. 
 
Discontinued SP:  SP may be discontinued prior to their completion of the 
study due to: 
• subject request 
• adverse events 
• protocol violations 
• administrative reasons (e.g., inability to continue, lost 
to follow up) 
• termination of the study 
Note: In addition, any SP may be discontinued for any sound medical reason. 
Notification of a SP discontinuation and the reason for discontinuation will be 
clearly documented. 
 
STUDY TERMINATION 
 
The study may be stopped at any time by the investigator, the sponsor, and/or 
study monitor with appropriate notification. 
 
STUDY COMPLIANCE 

10 
 
An investigator should not deviate from the clinical protocol. Should a 
deviation occur the date of and reason for deviations will be documented by 
the monitor via the monitoring report and further detail may be requested from 
the investigator. Deviations will be reported to the sponsor immediately.   
 
MONITORING AND QUALITY ASSURANCE  
 
Study Monitoring 
The designated study monitor will review the protocol, regulatory 
obligations, and other material or equipment relevant to the conduct of the 
study prior to the start of the study with the principal investigator/co-
investigator(s) and pertinent study staff. Monitoring visits will occur as 
necessary during the course of the investigation to verify: 
• The rights and well-being of subjects are protected. 
• The conduct of the investigation is in compliance with the currently approved 
protocol. 
• The integrity of the data. 
• Device accountability adequate study documentation. 
 
CONFIDENTIALITY 
Recording of Data   
SP data recorded during the study will be documented in the patient’s 
clinical file. In the data analysis the SP will only be identified by the subject 
number, and by their initials if also required. If, as an exception, it is 
necessary for safety or regulatory reasons to identify the SP, the sponsor or 
its representative, and the investigator are bound to keep this information 
confidential. 
All personal SP data collected and processed for the purposes of this 
study will be maintained by the investigator and his staff with adequate 
precautions as to ensure that the confidentiality of the data in accordance with 
local laws and regulations. 
 
PUBLICATION POLICY 
 
Authorship and manuscript composition will reflect cooperation among 
all parties involved in the study.  Authorship will be established before writing 
the manuscript.  
   
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