Navigated Laser In Branch Retinal Vein Occlusion Study (NIRVANA)

April 18, 2022 updated by: Katrine Hartmund Frederiksen, Odense University Hospital

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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

  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.

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:

  1. 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.
  2. 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 Type

Interventional

Enrollment (Actual)

47

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Denmark
      • Roskilde, Denmark, 4000
        • Department of Ophthalmology, Zealand University Hospital
    • Danmark
      • Odense, Danmark, Denmark, 5000
        • Department of Ophthalmology, Odense University Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Patients with additional need for anti-VEGF after loading phase
Time Frame: Month 3 to Month 12
Percentage of patients in Groups 1 and 2 that receive additional intravitreal aflibercept after the loading phase
Month 3 to Month 12

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Additional need for anti-VEGF after loading phase
Time Frame: Month 3 to Month 12
Median number of additional intravitreal aflibercept after the loading phase
Month 3 to Month 12
Change in BCVA according to treatment regimen
Time Frame: Month 12
Median change in best-corrected visual acuity (BCVA) from baseline (BL) to month (M) 12 in Group 1 and 2.
Month 12
Effect on macular edema according til treatment regimen
Time Frame: Month 12
Ratio of patients without macular edema at M12 in Groups 1 and 2
Month 12
Retinal oxygen saturation
Time Frame: 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)
Baseline
Macular ischemia (area of FAZ)
Time Frame: 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)
Baseline
Vessel geometry
Time Frame: 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)
Baseline
Visual field
Time Frame: Baseline and Month 12
Change in central visual fields, as evaluated by microperimetry according to treatment regimen
Baseline and Month 12

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Odense University Hospital

Collaborators

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

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 10, 2018

Primary Completion (Actual)

October 5, 2021

Study Completion (Actual)

October 5, 2021

Study Registration Dates

First Submitted

August 24, 2018

First Submitted That Met QC Criteria

August 28, 2018

First Posted (Actual)

August 29, 2018

Study Record Updates

Last Update Posted (Actual)

April 20, 2022

Last Update Submitted That Met QC Criteria

April 18, 2022

Last Verified

April 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NIRVANA (Alias Study Number)
  • S-20170084 (Other Identifier: The Regional Committees on Health Research Ethics)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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