Clinical Trial Details
— Status: Withdrawn
Administrative data
| NCT number |
NCT02309502 |
| Other study ID # |
R03019 |
| Secondary ID |
|
| Status |
Withdrawn |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
October 2012 |
| Est. completion date |
December 2015 |
Study information
| Verified date |
March 2020 |
| Source |
Manchester University NHS Foundation Trust |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Diabetic retinopathy (DR) is a leading cause of new cases of blindness in people aged 20 to
65 years worldwide.
Patients with DR may go on to develop a more severe form of the disease called Proliferative
Diabetic Retinopathy (PDR), a condition in which abnormal new blood vessels may rupture and
bleed inside the eye. When this advanced stage of retinopathy occurs, pan-retinal
photocoagulation (laser treatment) is usually recommended.
The purpose of the investigators study is to find if treating patients using a single session
of lower intensity laser (Pascal® Pan Retinal Photo-Stimulation, P-RPhS) at an earlier stage
in Diabetic Retinopathy (during the severe non-proliferative diabetic retinopathy stage) when
the abnormal new vessels are not developed, will prevent diabetic patients to develop PDR.
Patients included in the study will be randomized in three arms (randomization). In one arm
patients will be treated with the normal parameters used in Pascal® laser, the second arm
patients will be treated with a lower intensity than normal, using the Endpoint management
system (a new software from the Pascal® laser which allow us to decrees the intensity of the
burns (invisible burns) showing some landmarks with normal intensity so the area which has
been treated can be viewed. And in the third arm the patients will be observed.
Description:
The published evidence from clinical trials in the literature has demonstrated that
conventional PRP using 2000-2500 burns may be used safely and effectively in PDR patients
over 2 or 3 sessions. A recent audit of 313 Pascal laser treatments performed at Manchester
Royal Eye Hospital (2007-2008) has demonstrated that 1952 burns may be used safely and
effectively in routine ophthalmic practice for PDR.
A recent study (PETER PAN study) which has been presented at the Association for Research in
Vision and Ophthalmology (ARVO) 2011 Annual Meeting and also submitted for publication (Am J
Ophthalmol) has shown that performing primary 20ms Pascal targeted retinal photocoagulation
(TRP) and reduced fluence/minimally-traumatic panretinal photocoagulation (MT-PRP) in a
single session using 2,500 burns can be safe and effective in treating PDR, without negative
effect on visual fields. Therefore, it seems reasonable to think that a single session of
3000 burns 20ms with Endpoint Management set at 70% fluence will be safe and effective to
treat patients with severe NPDR as similar or less total energy would be delivered to the
retina-RPE complex.
Topcon's Endpoint Management (EM) software is based on a computational model of retinal
heating and an Arrhenius damage model to determine optimal pulse duration and laser power for
various levels of pulse energy. The algorithm varies the power and duration concurrently to
maximize the margins between visible and sub-visible photocoagulation endpoints, providing a
linear control over an inherently nonlinear process of coagulation.
When utilising EM, the user first titrates to a comfortable visible endpoint. Establishing a
titration endpoint is important as it gives a consistent baseline, ensuring repeatable
results between patients. With the Endpoint Management option activated, the laser output in
a pattern is a percentage of this titration energy. Power and duration are both modulated to
make this energy adjustment, allowing for a fine gradation of laser dosage and control over
treatment endpoints. The visible titration endpoint can be references throughout the course
of treatment by enabling the Landmark feature, which crates reference lesions at the
titration dose at the corners of the pattern. This provides visible feedback on dosage and
positioning of treated areas.
Importantly, the EM approach to laser therapy allows the physician to consistently operate in
the realm of therapeutic relevance for sub-visible treatments. When no burns are visible, the
biggest risk becomes lack of therapeutic effect. The Arrhenius integral-based algorithms in
Endpoint Management adjust power and duration to provide the best "path" between endpoints,
moving smoothly from the ophthalmoscopically-visible titration point to
angiographically-only, OCT-only, and sub-visible/ therapeutic regimes. The Landmark feature
allows the user to determine the local effect of the titration dose, and make adjustments as
uptake varies across the treated area. The result is more predictable sub-visible laser
delivery with the widest window of safe, effective treatment.
The Pascal® system with EM utilizes 577nm laser wavelength compared to the 532nm laser
wavelength which was utilized in previous Pascal® laser studies. However, previous studies
have not been able to demonstrate that clinical effectiveness was dependent on the laser
wavelength.
In order to reduce the risk of complications after PRP whilst maintaining clinical efficacy,
the optimal regime may be to utilize a technique of a lower intensity burn with reduced power
while applying a larger number of treatment burns to cover the retinal area. It may also be
important to "target" the laser treatment to the retinal area of "penumbra" or critically
hypoxic retina based on angiographic tests.
"Ischaemic penumbra" is the critically hypoxic tissue characterised by Hypoxia-inducible
factor-1 (HIF-1) upregulation and secretion of angiogenic proteins such as Vascular
endothelial growth factor (VEGF). In ischemic diabetic retinopathy, there are 3
theoretical/postulated locations of such critically hypoxic inner retina:
1. Along the interface between the inner retinal area still oxygenated via retinal
capillaries and the (more peripheral) area of capillary non-perfusion,
2. Alongside the medium-sized retinal arteries and hyperoxaemic retinal veins forming
arterio-venous anastomoses while traversing non-perfused inner retina ("Krogh secondary
tissue cylinders"), and
3. Mid-peripheral non-perfused inner retina obtaining a degree of oxygenation from the
choroid via O2 penetration of the "metabolic O2 barrier" formed by the rod inner
segments.
Fundus autofluorescence and Fourier-domain OCT imaging data suggested that a lower burn
intensity and reduced fluence burn could achieve effective uptake within the outer retina..
confirmed effective laser uptake using the Pascal® multi-spot technique at 10-20ms pulse
durations (Laser energy delivered to the tissue can be reduced by either reducing the
intensity of the laser or the duration of the burn). Furthermore, the analysis of
barely-visible laser titration burns showed effective thermal destruction of the inner
segments of the photoreceptors which, because of their highly energetic metabolism, are the
principal tissue target for laser photocoagulation.
In the treatment of PDR, the severity of visual field loss may correlate with burn density,
longer pulse duration, and higher fluence. The ETDRS recommended 1 burn-widths spot-spacing,
however the investigators aimed to maximize retinal laser coverage in a single sitting, and
also to allow potential re-treatments to be safely placed between previous arrays of burns
thus preventing overlapping laser burns and nerve fiber layer defects.
Visual acuity, visual field (VF) testing, and optical coherence tomography (OCT) are
important tools for quantifying the degree of visual dysfunction. Central (24 degree) visual
field measures in diabetic patients have been shown to correlate well with the stage of
retinopathy according to the ETDRS scale. Pan-retinal photocoagulation has been shown to have
a marked effect upon the central visual field measured with both global indices (Mean
Deviation and Pattern Standard Deviation) and point-by-point measures. OCT is a sensitive
instrument to diagnose and monitor DMO, and central retinal thickness (CRT) measures are used
in clinical practice.
In addition, a multispectral camera has been used effectively in a recent study (Manchester
Targeted Retinal Photocoagulation Study, MTRAP), with promising results produced that may
help explain the clinical effects of the study laser treatment.
ETDRS data did not show that initiating scatter photocoagulation prior to the development of
high-risk proliferative diabetic retinopathy in patients with type I diabetes will reduce the
risk of severe visual loss. However, ETDRS analyses did indicate that for patients with type
II diabetes, it is especially important to consider scatter photocoagulation at the time of
the development of severe nonproliferative or early proliferative retinopathy.
Ferris also showed that patients with type II diabetes, or older patients with diabetes, are
more likely to benefit from early scatter photocoagulation than patients with type I
diabetes.
The recommendation of the Royal College of Ophthalmologists is to consider PRP only once the
retinopathy reaches the proliferative stage.
The reasons why scatter laser PRP is not generally recommended for severe NPDR in the UK (and
to prevent progression to PRD thereby) include: (i) uncertainty over desirable clinical
end-points of treatment (eg. whether moderate NPDR or mild NPDR), and (ii) the likelihood of
complications of PRP (such as DMO and visual field loss) that outweigh the potential benefits
of early treatment. However, all recommendation up to date are based on the experience and
results using argon laser as per EDTRS guidelines.
It is important to assess the benefit of Pascal single-session subthreshold scatter
panretinal photocoagulation. As previously mentioned, all previous attempts of early PRP
involved the use of argon laser systems and different treatment strategies: full retinal
thickness burns, less number of burns and multiple treatment sessions. Laser treatment using
these parameters is currently considered to be tissue ablative. It was also not possible, at
the time, neither to image with as much clarity as the investigators can today the area of
retinal ischaemic penumbra nor to treat the peripheral retina as far anteriorly as it can be
done today. The investigators have shown that using Pascal20ms light burns allows for a
tissue healing response as shown by Optical Coherence Tomography (OCT) and Fundus
Autofluorescence (AF) retinal imaging.
The use of minimally-traumatic high-burn dosimetry (3000 burns) Pascal Pan Retinal
Photo-Stimulation in Pre-Proliferative Diabetic Retinopathy may have implications in terms of
NHS diabetic eye care. Single session treatment with Pascal retinal laser may have a
significant cost saving effect for NHS departments, as the treatment time is significantly
reduced as well as the number of required sessions and outpatient clinic appointments.
The Pascal system would allow larger number of patients to be safely treated per clinic
session. Reducing the number of patients at risk of conversion to proliferative disease could
not only have a significant cost saving effect for the NHS by reducing the frequency of
hospital visits and cost of treatment but, most importantly would offer a significant overall
benefit to the patient.
Currently, the Diabetic National Service Framework and English National Screening Programme
for Diabetic Retinopathy have outlined targets for treating PDR at within two weeks of
diagnosis in the eye clinic and from diabetic screening services. In current practice, this
target may be only achievable in around 75% of patients. If clinical hypothesis is achieved,
then a higher percentage would perhaps be achievable as the number of patients with
proliferative retinal diabetic disease that require treatment would go down.
Novel P-RPhS Pascal treatment strategies may improve the comfort and safety of the patient's
laser journey, and increase the compliance with laser treatment and follow-up.
