Combination of Ranibizumab and Targeted Laser Photocoagulation (CoRaLaII)

• ClinicalTrials.gov Identifier: NCT04444492
• Recruitment Status: Recruiting
• First Posted: June 23, 2020
• Last Update Posted: October 8, 2020
• Sponsor: University of Leipzig
• Information provided by (Responsible Party): Matus Rehak, MD, Ph.D., University of Leipzig

Study Description

Brief Summary:

Intravitreal injections of Ranibizumab will be applied in all patients according to treatment guidelines. The experimental group will receive additional targeted laser photocoagulation of the peripheral areas of capillary non-perfusion (up to 4 laser treatments within 1st year of the study). Based on the long-term observation after CoRaLa I study an importantly shorter duration of treatment and a relevant reduction of the total number of re-injections in RL patients is expected.

Condition or disease	Intervention/treatment	Phase
Central Retinal Vein Occlusion With Macular Edema	Drug: Ranibizumab Injection; Device: Laser photocoagulation	Phase 3

Detailed Description:

Retinal vein occlusion (RVO) is the second most common retinal vascular disease leading to visual impairment. Main cause for visual impairment in CRVO (Central Retinal Vein Occlusion) is macular edema (ME) while neovascularization of the retina and/or the anterior segment is the most serious complication leading to vitreous hemorrhage, retinal detachment and neovascular glaucoma. In serious cases loss of vision is imminent. To date, no causal treatment has been proven to be effective in large trials. Intravitreal injections of drugs that inhibit the vascular endothelial growth factor (VEGF) and other inflammatory factors are the current treatments of choice for ME due to CRVO. Two different anti-VEGF drugs (ranibizumab and aflibercept), and a biodegradable dexamethasone implant are approved by the EMA (European Medicines Agency). Based on data from confirmatory studies anti-VEGF-drugs are recommended as a treatment of first choice in patients with RVO. All intravitreal drugs provide only a temporary effect with need for re-treatment for recurrences of ME. Mean number of ranibizumab application needed in CRVO patients was found to be 7.4 to 10.2 injections in 12 months. A significant number of CRVO patients require treatment over several years. Need for repetitive treatments and ophthalmic controls are a major burden for patients (and their relatives who are required for driving the patients to ophthalmologists) despite of only few adverse events and generally well-tolerated injections. Endophthalmitis is the most severe ocular complication which can be eye-sight-threatening. The more injections are administered, the higher is the cumulative risk of complications. Due to high costs (>1000 € per injection) treatment with repeated injections over years is of significant socio-economic importance, too. Therefore, treatments concepts which would lead to permanent reduction of ME and/or significantly reduce the number of re-injections over long-term periods are the major currently unmet need in patients with RVO.

Until now, several studies evaluated the impact of the additional pan-retinal laser photocoagulation in patients undergoing the anti-VEGF-treatment for the ME due to retinal vein occlusions. However, most of the studies are limited by retrospective design, small number of evaluated patients or lack of the randomization. None of the available prospective randomized studies had sufficient power to finally clarify the benefit of the additional laser treatment. Therefore, there is an unmet need for a large randomized, prospective, multicentric trials.

The proposed study will be the first sufficiently powered trial evaluating the long-term effect of targeted laser photocoagulation performed selectively (targeted) in peripheral areas of non-perfusion in combination with standard anti-VEGF treatment (ranibizumab injections) on the duration of the required intravitreal treatment over time period of 2 years.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 110 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Masking Description: blinded BCVA assessor
• Primary Purpose: Treatment
• Official Title: Long-term Need of Ranibizumab Injections With or Without Early Targeted Peripheral Laser Photocoagulation for Treatment of Macular Edema Due to Central Retinal Vein Occlusion
• Actual Study Start Date: August 25, 2020
• Estimated Primary Completion Date: July 30, 2024
• Estimated Study Completion Date: July 30, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Ranibizumab+Laser-arm; Ranibizumab injections and additional targeted laser	Drug: Ranibizumab Injection; initial three injections of Ranibizumab - afterwards pro re nata monthly; Other Name: Lucentis; Device: Laser photocoagulation; Areas of capillary non-perfusion will be treated with photocoagulation upto 4 times
Active Comparator: Ranibizumab-arm; Only Ranibizumab injections	Drug: Ranibizumab Injection; initial three injections of Ranibizumab - afterwards pro re nata monthly; Other Name: Lucentis

Outcome Measures

Primary Outcome Measures :

1. Efficacy endpoint is the time to treatment success [ Time Frame: up-to 29 months ]
   Time from randomisation until the date of last criteria-based intravitreal injection in case that thereafter a treatment-free period for (at least) 6 months was observed.

Secondary Outcome Measures :

1. Best corrected visual acuity (BCVA) [ Time Frame: Month 29 ]
   Best corrected visual acuity (BCVA) in number of ETDRS letters (Early Treatment of Diabetes Retinopathy Study) per visit
2. Central subfield thickness (CST) [ Time Frame: Month 29 ]
   Central subfield thickness (CST) measured by OCT per visit
3. Number of ranibizumab injections [ Time Frame: Month 29 ]
   Number of ranibizumab injections required until treatment success and up to the end of Observation.

Other Outcome Measures:

1. Development of neovascularization(s) [ Time Frame: Month 24 ]
   Proportion of subjects developing neovascularization(s) of retina, optic disc, and/or in anterior segment over the total period of observation.
2. The area of non-perfusion [ Time Frame: Month 24 ]
   The area of non-perfusion (assessed by FA) will be quantified as sum of all areas identified
3. Vessel density [ Time Frame: Month 24 ]
   Assessed by OCT-angiography, will be quantified by a metric measure with the range [0;1]
4. Potential visual field loss [ Time Frame: Month 4 and Month 24 ]
   The change between the two timepoints (Months 4 and 24) per arm will be used to characterize the both groups and be compared between treatment arms.
5. The number of laser treatments and the laser spots given in the experimental group (RL-arm). [ Time Frame: Month 24 ]
   The number of visits with applied laser treatment and the laser spots applied in the experimental group (RL-arm) will be counted for descriptive reasons and be compared between treatment arms.
6. Health-related quality of life (QoL): Visual Function Questionnaire VFQ25 [ Time Frame: Baseline, Month 12 and Month 24 ]
   Measured by the Visual Function Questionnaire VFQ25
7. Areal of foveal avascular zone [ Time Frame: Month 24 ]
   Area of the foveal avascular zone (FAZ, assessed by OCT-angiography, will be quantified in [mmm²])

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Diagnosis of macular edema due to central retinal vein occlusion foveal thickness > 250 μm (measured by OCT)
• Age > 18 years
• Written informed consent of the patient
• BCVA score in the study eye between 24 letters (20/320) and 78 letters (20/25) measured in ETDRS chart
• History of CRVO no longer than 6 months
• Presence of capillary non-perfusion in peripheral retina larger than 5 disc areas documented in ultra wide-field fluorescein angiography
• Ability and willingness to attend all scheduled visits and assessments

Exclusion Criteria:

• CRVO with ischemic maculopathy defined as diameter of the foveolar avascular zone larger than 2 optic disc diameters
• Macular edema due to another etiology than retinal vein occlusion (e.g. diabetic maculopathy, uveitis, age related macular degeneration, Irvine-Gass syndrome)
• History of idiopathic central serous chorioretinopathy
• Presence of vitreoretinal interface disease (e.g. vitreomacular traction, epiretinal membrane), either on clinical examination or in OCT
• An eye that, in the investigator's opinion, would not benefit from resolution of macular edema, such as eyes with foveal atrophy, dense pigmentary changes, or dense subfoveal hard exudates
• Aphakia in the study eye
• Scatter laser photocoagulation or macular photocoagulation in the study eye prior to study entry
• Intraocular or periocular injection of steroids in the study eye prior to study entry
• Previous use of an anti-VEGF drug in the study eye
• Cataract surgery or any other intraocular surgery in the study eye within 3 months prior to study entry
• Uncontrolled glaucoma (defined as intraocular pressure ≥ 30 mm Hg despite treatment with maximal anti-glaucoma medications)
• History of stroke, myocardial infarction, transient ischemic attacks within 3 months prior to the study
• Pregnancy (positive urine pregnancy test) or lactation
• The presence of active malignancy, including lymphoproliferative disorders.
• History of allergy to fluorescein or any component of the ranibizumab formulation
• Active intraocular infection
• Participation in another simultaneous interventional medical investigation or trial
• Women with child bearing potency without effective contraception (i. e. implants, injectables, combined oral contraceptives, some IUDs or vasectomised partner) during the conduct of the trial.

Contacts and Locations

Contacts

Contact: Matus Rehak, Professor; 0049 341 97 21 650; matus.rehak@medizin.uni-leipzig.de

Contact: Marizel Schwarzkopf, Dr.; 0049 341 97 16 254; marizel.schwarzkopf@zks.uni-leipzig.de

Locations

Germany

Universitätsklinikum Carl Gustav Carus Dresden Klinik und Polyklinik für Augenheilkunde; Not yet recruiting

Dresden, Germany, 01307

Contact: Dirk Sandner, Dr.

Universitätsklinikum Klinik für Augenheilkunde Freiburg; Not yet recruiting

Freiburg, Germany, 79106

Contact: Hansjürgen Agostini, Prof.

Hannover MHH Universitätsklinik für Augenheilkunde; Not yet recruiting

Hannover, Germany, 30625

Contact: Amelie Pielen, PD. Dr.

University Hospital of Leipzig Department of Ophthalmology; Recruiting

Leipzig, Germany, 04103

Contact: Matus Rehak, Prof. MUDr.

Klinikum der Stadt Ludwigshafen Augenklinik; Not yet recruiting

Ludwigshafen, Germany, 67063

Contact: Lars-Olof Hattenbach, Prof.

Universitätsklinikum Gießen und Marburg GmbH, Standort Marburg Klinik für Augenheilkunde; Not yet recruiting

Marburg, Germany, 35043

Contact: Walter Sekundo, Prof.

Augenzentrum am St. Franziskus-Hospital Münster; Not yet recruiting

Münster, Germany, 48145

Contact: Georg Spital, Dr.

Universitätsklinikum Klinik für Augenheilkunde; Not yet recruiting

Münster, Germany, 48149

Contact: Nicole Eter, Prof.

Sponsors and Collaborators

University of Leipzig

Investigators

• Study Director: Matus Rehak, Professor; Department of Ophthalmology University Hospital of Leipzig

More Information

• Responsible Party: Matus Rehak, MD, Ph.D., Prof. Dr., University of Leipzig
• ClinicalTrials.gov Identifier: NCT04444492
• Other Study ID Numbers: CoRaLaII
• First Posted: June 23, 2020
• Last Update Posted: October 8, 2020
• Last Verified: October 2020

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Macular Edema; Retinal Vein Occlusion; Macular Degeneration; Retinal Degeneration; Retinal Diseases; Eye Diseases; Venous Thrombosis; Thrombosis; Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases; Ranibizumab; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors; Antineoplastic Agents