NIRVANA: Navigated Laser In Branch Retinal Vein Occlusion Study

Sponsor

Odense University Hospital (Other)

Overall Status

Completed

CT.gov ID

NCT03651011

Collaborator

Danske Regioner (Other), Synoptik-Fonden (Other), Toyota-Fonden (Other), AP Moeller Foundation (Other), Yamagata University (Other), Queen's University, Belfast (Other), Zealand University Hospital (Other), Region Sjællands og Region Syddanmarks forskningspulje (Other)

Enrollment

Locations

Arms

37.8

Actual Duration (Months)

23.5

Patients Per Site

0.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Branch retinal vein occlusion (BRVO) is often complicated by macular edema, possibly leading to severe visual loss or blindness. Treatment is repeated, intravitreal injections of vascular endothelial growth factor (VEGF)-inhibitors like aflibercept. The treatment is effective, but a need for repetitive injections is a concern for patients as well as society due to risk of side effects, regular hospital visits and the price of the drug. Former treatment included macular grid pattern photocoagulation, but this technology was limited by a poorer visual outcome for the patient and a higher risk of side effects, including central visual loss.

A novel laser delivery system, called navigated laser photocoagulation, has proven effective, safe and precise, and has shown promising results in stabilising the effect of the VEGF-inhibitor treatment in similar diseases.

Thus, in a 12-month prospective, randomized 1:1 study of 60 patients with BRVO and macular edema the investigators aim to (1) Examine the treatment response of patients treated with intravitreal aflibercept (Eylea®) and navigated retinal laser (Navilas®)(Group 1) as compared to patients treated with intravitreal aflibercept only (Group 2), and (2) Identify non-invasive retinal biomarkers (retinal oxygen saturation, macular ischemia and retinal vascular arteriolar and venular calibre) for successful treatment outcome.

Condition or Disease	Intervention/Treatment	Phase
Branch Retinal Vein Occlusion Macular Edema	Drug: Aflibercept Injection [Eylea] Procedure: Navigated laser photocoagulation	N/A

Detailed Description

Purpose of the study

In a 12-month prospective, randomized 1:1 study of patients with branch retinal vein occlusion (BRVO) and macular edema, the investigators aim to

Examine the treatment response of patients treated with intravitreal aflibercept (Eylea®) and navigated retinal laser (Navilas®)(Group 1) as compared to patients treated with intravitreal aflibercept only (Group 2), and
Identify non-invasive retinal biomarkers (retinal oxygen saturation, macular ischemia and retinal vascular arteriolar and venular calibre) for successful treatment outcome.

Problem statement

Severe visual loss or blindness in BRVO is often caused by macular edema. Until a few years ago, treatment included observation or macular grid pattern laser photocoagulation. With this treatment it was often possible to stabilize the disease in a few treatment sessions. However, in recent years better visual outcome has been demonstrated with intravitreal injections of vascular endothelial growth factor (VEGF) inhibitors like ranibizumab or aflibercept. Even though this is encouraging, patients on average need nine injections in the first 12 months. The high number of repetitive treatments is a concern for patients as well as society due to the invasiveness of the treatment and the price of the drug. Hence, it is warranted to develop newer treatment regimens combining the efficacy of intravitreal anti-VEGF with the potential stabilizing effect of macular laser photocoagulation. This would be an approach that might minimize the number of injections and its side effects while still providing acceptable visual outcomes for the patients.

In addition to providing the optimal treatment, it is important to identify non-invasive markers of disease activity and treatment outcome in order to enable individualised and personalised treatment while providing novel research opportunity in this potentially blinding disease.

Theoretical foundation (Literature background)

Retinal vein occlusion (RVO) is a common cause of visual loss in the elderly with a 15-year incidence of 2.3% of the population. The condition is classified anatomically according to the site of the occlusion. Seventy eight percent of patients have an occlusion of a branch vein, which is often complicated by macular edema, leading to visual impairment.

Branch retinal vein occlusion is diagnosed based on intraretinal hemorrhages in the retinal sector drained by the affected vein. In time, hemorrhages often resorb, but vision-threatening complications may arise. The common link for these is ischemia, that leads to an upregulation of VEGF, which then causes neovascularization, vasodilation and increased vascular permeability, leading to macular edema, the most common reason for vision loss in BRVO.

With ischemia in mind, measurements of retinal oxygen saturation could provide important information regarding the metabolic status of the inner retina. The vascular oxygen saturation of the inner retina is a functional marker, that can be measured non-invasively by a spectrophotometric retinal oximeter. Even though this has only been studied on a very limited basis in BRVO, proof-of-concept has been established by Lin et al. and Hardarson et al., demonstrating cross-sectional changes in retinal oxygen saturation. However, they did not correlate these to treatment outcome.

Ischemia can also be evaluated as a structural marker. The most reliable way of evaluating this is to measure the area of retinal non-perfusion by fundus fluorescein angiography. Non-perfusion has been demonstrated as a strong marker of disease severity, but it is still uncertain if this is reversible, and if so, if this surrogate marker of VEGF-activity can potentially be used to guide the treatment.

Retinal vascular calibre is another non-invasive method of evaluating the retinal vascular system. The research unit have performed validated, semiautomatic measurements of the retinal arteriolar and venular diameters in studies of diabetic retinopathy, and demonstrated cross-sectional associations as well as longitudinal predictions of intra- and extraocular microvascular complications of type 1 diabetes. For instance, Broe et al. demonstrated that patients with narrower arterioles and wider venules had an independently higher risk of developing various microvascular complications in a 16-year prospective study. This emphasizes the importance of structural retinal changes in relation to the metabolic function. In BRVO, Youm et al. demonstrated that patients with BRVO had narrowing of retinal arterioles and venules, but any potential correlation to treatment outcome has not been examined.

Current state of the art In 1984 the Branch Vein Occlusion Study for macular edema demonstrated that 63% of patients treated with macular laser gained two or more lines of vision, compared to 36% of untreated eyes. Based on this, the standard treatment for many years was to perform macular laser photocoagulation if vision had not improved after 3-6 month of observation. However, the introduction of VEGF-inhibitors within the last decade has changed the landscape dramatically. Randomized, controlled studies like BRAVO and VIBRANT demonstrated a higher efficacy of ranibizumab and aflibercept versus sham and laser with 53-61% of patients gaining at least three lines of vision.

In Denmark, the present guidelines for treatment of BRVO with macular edema has been set in September 2015 by "Rådet for Anvendelse af Dyr Sygehusmedicin". The council recommended that intravitreal aflibercept or ranibizumab should be used as first line of treatment. However, the council also raised concern, stating that they expected an annual increment of approximately 600 new patients with RVO in Denmark putting both financial and societal burden on the individual and the healthcare system. With the chronic nature of the disease in mind, this is expected to put a significant weight on the healthcare system for the years to come.

Choice of methods

Navigated laser photocoagulation is the cornerstone of the present study. This is a novel laser delivery system that holds many advantages as compared to traditional macular laser photocoagulation. Navigated laser makes treatment easier to plan, perform and document.

Firstly, it includes an eye tracking system, which makes it safe to treat close to the foveal center. For a traditional laser it is recommended to keep a minimum distance of 500μm from the foveal center in order to limit the risk of severe visual loss. For safety reasons many physicians prefer to keep an even larger distance, which often limits the beneficial effect of the treatment. Secondly, the navigated laser system is automatic which improves the accuracy to target focal lesions by 27%. Thirdly, navigated laser makes it possible to import images from fluorescein angiographys and allows for clear delineation and consequent treatment of the diseased microvasculature.

Hypothesis

The investigators hypothesize that:

As compared to intravitreal aflibercept monotherapy, combination treatment with intravitreal aflibercept and navigated laser leads to a lesser number of intravitreal injections needed to stabilise vision in patients with BRVO and macular edema.
It is possible to use non-invasive retinal markers to predict disease activity and treatment outcome in patients with BRVO and macular edema. Regardless of treatment regimen, the investigators believe that patients who respond well to treatment will have (1) lower retinal venular oxygen saturation, (2) less macular ischemia, and (3) lower retinal venular calibre.

Study Design

Study Type:

Interventional

Actual Enrollment :

47 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Navigated Laser In Branch Retinal Vein Occlusion Study

Actual Study Start Date :

Aug 10, 2018

Actual Primary Completion Date :

Oct 5, 2021

Actual Study Completion Date :

Oct 5, 2021

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Aflibercept + Navigated laser Patients will receive intravitreal aflibercept at M0, M1 and M2 (loading phase) and in addition receive navigated retinal laser photocoagulation at M3. Patients will receive aflibercept according to pro re nata regimen from M3-M12.	Drug: Aflibercept Injection [Eylea] Intravitreal injection 2 mg Eylea every 4 weeks M0-M2 (loading phase). M3-M12: continue in a pro re nata treatment regimen. Procedure: Navigated laser photocoagulation Navigated laser photocoagulation planned from flourscein angiography. Other Names: Navilas
Active Comparator: Aflibercept only Patients will receive intravitreal aflibercept at M0, M1 and M2 (loading phase). Patients will receive aflibercept according to pro re nata regimen from M3-M12.	Drug: Aflibercept Injection [Eylea] Intravitreal injection 2 mg Eylea every 4 weeks M0-M2 (loading phase). M3-M12: continue in a pro re nata treatment regimen.

Arm

Intervention/Treatment

Active Comparator: Aflibercept + Navigated laser

Patients will receive intravitreal aflibercept at M0, M1 and M2 (loading phase) and in addition receive navigated retinal laser photocoagulation at M3. Patients will receive aflibercept according to pro re nata regimen from M3-M12.

Drug: Aflibercept Injection [Eylea]

Intravitreal injection 2 mg Eylea every 4 weeks M0-M2 (loading phase). M3-M12: continue in a pro re nata treatment regimen.

Procedure: Navigated laser photocoagulation

Navigated laser photocoagulation planned from flourscein angiography.

Other Names:

Navilas

Active Comparator: Aflibercept only

Patients will receive intravitreal aflibercept at M0, M1 and M2 (loading phase). Patients will receive aflibercept according to pro re nata regimen from M3-M12.

Drug: Aflibercept Injection [Eylea]

Intravitreal injection 2 mg Eylea every 4 weeks M0-M2 (loading phase). M3-M12: continue in a pro re nata treatment regimen.

Outcome Measures

Primary Outcome Measures

Patients with additional need for anti-VEGF after loading phase [Month 3 to Month 12]
Percentage of patients in Groups 1 and 2 that receive additional intravitreal aflibercept after the loading phase

Secondary Outcome Measures

Additional need for anti-VEGF after loading phase [Month 3 to Month 12]
Median number of additional intravitreal aflibercept after the loading phase
Change in BCVA according to treatment regimen [Month 12]
Median change in best-corrected visual acuity (BCVA) from baseline (BL) to month (M) 12 in Group 1 and 2.
Effect on macular edema according til treatment regimen [Month 12]
Ratio of patients without macular edema at M12 in Groups 1 and 2
Retinal oxygen saturation [Baseline]
Evaluation of retinal oxygen saturation at BL as marker of disease activity and successful treatment outcome (as defined by no need for intravitreal aflibercept at M11 and M12)
Macular ischemia (area of FAZ) [Baseline]
Evaluation of macular ischemia (as determined by area of the Foveal Avascular Zone (FAZ)) at BL as a marker of disease activity and successful treatment outcome (as defined by no need for intravitreal aflibercept at M11 and M12)
Vessel geometry [Baseline]
Evaluation of retinal venular calibre at BL as a marker of disease activity and successful treatment outcome (as defined by no need for intravitreal aflibercept at M11 and M12)
Visual field [Baseline and Month 12]
Change in central visual fields, as evaluated by microperimetry according to treatment regimen

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients with BRVO with foveal center-involved macular edema in the study eye.
Best-corrected visual acuity (BCVA) 35-80 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (0.1-0.8 Snellen equivalent) in the study eye at baseline (BL).
Age ≥18 years.
Central retinal thickness > 300 μm in the study eye at BL.
Onset ≤ 6 months prior to the study.

Exclusion Criteria:

Active retinal or iris neovascularizations in the study eye at any time.
Cataract, vitreous hemorrhage or other clouding conditions that prevent retinal laser photocoagulation in the study eye at M3.
Prior anti-VEGF treatment or macular laser photocoagulation in the study eye.
Macular edema and/or increased retinal thickness due to other potential causes than BRVO
Uncontrolled hypertension (blood pressure ≥ 160/110 mmHg).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Department of Ophthalmology, Odense University Hospital	Odense	Danmark	Denmark	5000
2	Department of Ophthalmology, Zealand University Hospital	Roskilde		Denmark	4000

Investigators

Principal Investigator: Katrine H Frederiksen, PhD-student, Research Unit of Ophthalmology, University of Southern Denmark
Study Director: Jakob Grauslund, DMSci,PhD, Research Unit of Ophthalmology, University of Southern Denmark
Study Chair: Torben L Sørensen, DMSci, Dept. of Ophthalmology, Zealand University Hospital
Study Chair: Jesper P Vestergaard, MD, Dept. of Ophthalmology, Odense University Hospital
Study Chair: Inger C Munch, PhD, Dept. of Ophthalmology, Zealand University Hospital
Study Chair: Tunde Peto, PhD, Queen's University, Belfast, England
Study Chair: Ryo Kawasaki, PhD, Yamagata, University, Japan