Clinical trial NCT03113006: The Individually-Marked Panretinal Laser phoTocoagulation for Proliferative Diabetic Retinopathy Study (TREAT)
Official title: The Individually-Marked Panretinal Laser phoTocoagulation for Proliferative Diabetic Retinopathy Study: IMPETUS 2018 - TREAT
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Proliferative Diabetic Retinopathy
PDR
Diabetes
Lead sponsor: Odense University Hospital
Sponsor class: OTHER
Collaborators: name: University of Southern Denmark
name: Velux Fonden
First posted: 2017-04-13
Enrollment: 53
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Background Diabetic eye disease is the most frequent complication among the 320,000 Danes with diabetes. The formation of new vessels (PDR) in the inner part of the eye (retina) is a feared complication and a leading cause of blindness, since these vessels are fragile and often cause bleeding within the eye. Peripheral retinal laser treatment (PRP) halves the risk of blindness, but often comes with a high prize. The peripheral part of the retina is responsible for the visual field and the night vision, and PRP limits these abilities (i.e. loss of driving license).

The technique of PRP has principally been the same for the past 40 years with standard treatment given for all patients. With this one size fits all approach, a substantial number of patients will either be treated too much or too little. Too little treatment is inefficient, and disease progression may occur. Excessive treatment may cause side effects like loss of visual fields and decreased night vision. Therefore, it is important to test if treatment can be applied on an individual basis to give high efficacy treatment with minimal side effects.

IMPETUS 2018 - TREAT is the second of two studies aimed at making an individual design for retinal laser treatment. In IMPETUS 2018 - DETECT the investigators demonstrated that non-invasive examinations of the oxygen level and measurements of the retinal vascular tree provide important information of individual treatment response. For instance, if standard PRP led to three per cent higher retinal oxygen saturation, there was a 4-fold risk of disease progression despite treatment. Hence, such a patient would benefit from more treatment to avoid blindness. With these observations at hand, the investigators want to compare a less invasive treatment (individualized laser treatment) against the standard PRP.

Another essential aspect in the treatment of PDR is to be able to give the right diagnosis and to evaluate the efficacy of laser treatment. So far, this has been performed by fluorescein angiography. However, this examination are highly person-dependent and unpleasant to patients, and a more objective approach is needed. Optical coherent tomography angiography (OCT-A) is a quick, noninvasive scanning of the retina which is ideal to visualize moving objects like blood within the retinal vessels. The method has been successfully implemented in a number of retinal diseases, but it has never been validated in PDR.

Standard PRP is often performed in 3-4 sessions. However, it may be painful, and patients sometimes choose not to complete all sessions after the initial treatment has been given. There is insufficient knowledge of the patient-barriers to treatment, and it is important to address these in an individualized treatment design.

Aim In this 6-month 1:1 randomized, prospective study the investigators want to investigate 1) whether individualized retinal laser treatment compared with standard PRP has the same efficacy but less side effects, 2) whether OCT-A can be used as an objective marker for disease activity, and 3) to obtain a better understanding of patient-reported barriers to standard laser treatment PRP and whether these can be addressed with personalized retinal laser treatment.

Setup Fifty eight consecutively recruited patients (1 May 2017 - 30 April 2018) with newly diagnosed PDR referred to the Department of Ophthalmology, OUH, and randomly assigned to standard PRP (n=29) or individualized laser treatment (n=29).

Intervention Standard laser treatment is performed in all four quadrants of the retina. Individualized laser treatment is only performed in the part(s) of the retina with proliferation(s).

Both treatments are carried out at baseline (BL), and additional treatment is given at month three (M3) and/or (M6), if necessary.

Investigations Retinal digital images, fluorescein angiography, OCT-A (BL, M3, M6). Test of visual fields, dark adaptation and quality of life (BL, M6). Semi-structured interview will be performed with five patients who have received PRP in one eye and individualized laser treatment in the other eye. This will address treatment experience, potential barriers to treatment, etc.

What to measure:

Differences in need for retreatment, night blindness, visual fields, visual acuity, bleeding in the eye, surgery, and quality of life between the groups.

Detailed description: Introduction Diabetes mellitus is an epidemic disorder, which in Denmark alone is affecting 320,000 patients. Diabetic retinopathy (DR) is the most frequent long term complication to diabetes mellitus (1) and a feared cause of severe vision loss and blindness (2).

Proliferative diabetic retinopathy (PDR) is the major cause of severe visual loss. Lack of oxygen to the retina (retinal ischemia) results in up-regulation of, in particular, the growth factor vascular endothelial growth factor (VEGF) (3) followed by compensatory retinal proliferations. The neovasculature is fragile and often leads to vitreous hemorrhages or retinal detachment which makes the patient at high risk of irreversible vision loss (4).

In 1976 it was shown that patients with severe PDR can halve the risk of severe vision loss by peripheral retinal laser treatment (photocoagulation panretinal, PRP) (5). This treatment reduces the retina's oxygen demand, which makes the VEGF concentration decrease and the proliferations shrink (5).

PRP has largely been the same for the last 40 years. The standard treatment is basically the same for all patients (4 + 6), which leads to some patients being either over or under treated. If treatment is inadequate, patients are in risk of disease progression and thus difficult vision loss (7). On the other hand, the treatment may cause side effects in the form of loss of visual field (8-9), night vision loss (10) and accumulation of fluid in the eye's macula (diabetic macular edema) (11).

This study is a continuum of the clinical project IMPETUS 2018 - DETECT, which aimed to identify the factors that were important for a successful PRP treatment of PDR. In the study the investigators prospectively followed 65 patients with newly diagnosed PDR. All patients received baseline navigated PRP, as in Scandinavia only offered at Odense University Hospital (OUH). Navigated panretinal laser with a Navilas® laser ensures optimized treatment (12), shorter treatment (13) and increased patient comfort (12-14). Treatment effect was investigated at month three and six, and if necessary, treatment was supplied. All the patients venous retinal oxygen saturation was measured to study whether this had any therapeutic value.

The investigators observed that the retinal oxygen saturation was a strong predictor of treatment response. Compared to patients whose disease was slowed down after treatment, patients with progression three months after PRP had an increase in the venous retinal oxygen saturation (+ 4.1% vs. -1.8%, p = 0.02). Patients with an increase of at least 3.0% in venous retinal oxygen saturation had 4.0 times greater risk of disease progression than patients who were below this threshold (15). This observation is in line with another Danish study, which demonstrated that worsening of DR causes increased venous retinal oxygen saturation (16). By measuring if this increase in venous retinal oxygen saturation has slowed down, one can assess whether PRP treatment is sufficient.

PDR is traditionally perceived as an ischemic disease, which initially affects the entire retina. In our above mentioned study the investigators were able to confirm the results regarding the venous retinal oxygen saturation in the affected segment of the retina, in 24 of the patients in the study, who had only one peripheral proliferation. In these patients the oxygen saturation was increased with disease progression (+ 3.9% vs. -1.5%, p = 0.04). This indicates that the focal hypoxia are more important than previously thought, and thus the local treatment of the diseased area may be a treatment option that reduces the processing volume, thereby minimizing potential side effects.

Retinal proliferations are fragile and often leak contrast fluid. When initiating the study, the investigators expected the leakage of fluorescein over time would be the optimal method to assess disease activity, but had to realize that this method was difficult to objectify (17). As an alternative to this objective evaluation, it is possible to observe the structural conditions at the interface between the retina and vitreous body (18), but technological limitations have so far prevented the possibility of repeated evaluations of the same lesion over time. Optical coherency tomography (OCT)-angiography is, however, a new method that can visualize retinal structures and potential development of these in detail (19).

Purpose In a six-month randomized, prospective study of patients with newly diagnosed PDR the investigators want to investigate 1) whether individualized PRP compared with standard PRP has the same efficacy but less side effects and 2) whether OCT angiography can be used as a marker for disease activity in PDR.

Hypothesis The investigators expect that 1) individualized PDR provides the same effect but fewer side effects and better quality of life than traditional PDR, and 2) OCT angiography has better sensitivity and specificity than wide field fluorescein angiography (FA) for the evaluation of disease activity by PDR.

Methods

Setup:

* Six-months 1: 1 randomized, prospective study.
* 58 consecutively recruited patients with newly diagnosed PDR at the Department of Ophthalmology, University Hospital, included in the period 1 March 2017 to 28 February 2018.
* Patients will be randomized to either 1) standard PRP with Navilas® (n = 29) or individualized PRP with Navilas® (n = 29). To ensure the same degree of ischemic disease, the two groups are balanced in relation to the number of retinal quadrants with proliferations.

Intervention:

* Standard PRP: localized to all four retinal quadrants.
* Individualized PRP: localized to the affected quadrants.
* Both treatments are carried out at baseline (BL) and supplemented if there is increasing disease activity at month three (M3) and / or month six (M6).
* Indications for additional treatment:
* Progression of PDR in the form of subjective growing lesion (assessed by ophthalmoscopy and wide field fundus photo) or increasing leakage wide field FA (M3 or M6).
* Progression of PDR in terms of objectively progressive lesion (≥10% from BL) measured by spectral domain (SD) OCT or OCT angiography (M3 or M6).
* Increase in venous retinal oxygen saturation of at least + 3,0% between BL and M3.

Investigations:

* Demographics: age, sex, type of diabetes, diabetes duration, smoking, drugs (BL).
* Objectively: Blood pressure, height, weight (BL).
* Blood samples: HbA1c, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, P creatinine, eGFR (BL, M3, M6).
* Visual acuity (Best Corrected Early Treatment Diabetic Retinopathy Study standard) (BL, M3, M6).
* Intraocular pressure (BL, M3, M6).
* SD-OCT (Topcon 3D OCT 2000): macula and area(s) with PDR (BL, M3, M6).
* OCT angiography (Topcon DRI OCT Triton): region(s) with PDR (BL, M3, M6).
* Wide field fundus photo and FA (Optos) (BL, M3, M6).
* Retinal oximetry (Oxymap T1) (BL, M3, M6).
* Dark-adaptation (Goldmann-weeker adaptometer) (BL, M6).
* Perimetry (Humphrey 30-2) (BL, M6).
* Selected components of quality of life questionnaire (Danish translation of Visual Function Questionnaire-25) (BL, M6).

Endpoints

Primary:

* Need for retreatment between the groups (M3 and M6).
* Loss of visual fields between the groups (from BL to M6).
* Change in dark adaptation between the groups (from BL to M6).
* Sensitivity and specificity of OCT angiography as an expression of disease activity in PDR (BL, M3 and M6).

Secondary:

* Change in visual acuity between the groups (from BL to M6).
* Difference in proportion with the development of vitreous haemorrhage between the groups (from BL to M6).
* Need for surgical removal of the vitreous between the groups (from BL to M6)
* Change in quality of life between the groups (from BL to M6).

Eligibility criteria: Inclusion Criteria:

* Diabetes mellitus.
* Newly diagnosed, untreated PDR in one eye (the possibility of inclusion of both eyes by bilateral PDR).

Exclusion Criteria:

* Diabetic macular edema in the affected eye.
* Age \<18 years.
* Pregnancy.
* Ambiguities in refracting media on topical eye.

Primary outcomes:
measure: Need for retreatment between the groups
timeFrame: At month 3 and 6
measure: Loss of visual fields between the groups
timeFrame: From baseline to month 6
measure: Change in dark adaptation between the groups
timeFrame: From baseline to month 6
measure: Sensitivity and specificity of OCT angiography as an expression of disease activity in PDR
timeFrame: At month 6
Secondary outcomes:
measure: Change in visual acuity between the groups
timeFrame: From baseline to month 6
measure: Difference in proportion with the development of vitreous haemorrhage between the groups
timeFrame: From baseline to month 6
measure: Need for surgical removal of the vitreous between the groups
timeFrame: From baseline to month 6
measure: Change in quality of life between the groups
timeFrame: From baseline to month 6
Other outcomes:
Locations:
city: Odense
country: Denmark
facility: The Department of Ophthalmology, Odense University Hospital
state: The Region Of Southern Denmarj
Study officials:
affiliation: Odense University Hospital
name: Anna S Vergmann, M.D.
role: PRINCIPAL_INVESTIGATOR
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