Influence of Ranibizumab versus laser photocoagulation on radiation retinopathy (RadiRet) - a prospective randomized controlled trial

Purpose To demonstrate superiority of intravitreal ranibizumab 0.5 mg compared to focal and peripheral laser treatment in patients with radiation retinopathy for choroidal melanoma. Methods Inclusion criteria were as follows: patients with radiation retinopathy and visual acuity impairment due to radiation maculopathy accessible for laser therapy, age ≥ 18 years, and BCVA less than 20/32. The main objective was to study the change in best-corrected visual acuity (BCVA) over 6 months from ranibizumab 0.5 mg (experimental) compared to focal laser of the macula and panretinal laser treatment of the ischemic retina (control) in patients with radiation retinopathy in choroidal melanoma. The secondary objectives of the radiation retinopathy study were to compare functional and anatomical results between ranibizumab and laser group over 12 months and to measure the frequency of vitreous hemorrhage and rubeosis iridis. Results The intention-to-treat analysis included 31 patients assigned to ranibizumab (n = 15) or laser treatment (n = 16). In terms of BCVA at month 6, ranibizumab was superior to laser treatment, with an advantage of 0.14 logMAR, 95% CI 0.01 to 0.25, p = 0.030. The positive effect of ranibizumab disappeared after treatment was discontinued. Similar results without statistically significant difference were found with respect to macular thickness. In both groups, no change was observed at month 6 in the size of ischemia in the macula or periphery compared to baseline. There was 1 case of vitreous hemorrhage in the laser group and no case of rubeosis iridis over time. Conclusions This study showed a statistically significant improvement in visual acuity and clear superiority of ranibizumab compared to laser treatment up to 26 weeks, but this effect disappeared at week 52 after completion of intravitreal treatment. Ranibizumab and PRP are considered equivalent in terms of the non-appearance of proliferative radiation retinopathy during the study. Trial registration EudraCT Number: 2011-004463-69 Electronic supplementary material The online version of this article (10.1007/s00417-020-04618-7) contains supplementary material, which is available to authorized users.


Introduction
Uveal melanoma (UM) is the most common primary intraocular tumour in adults and occurs in 7-10 cases per million people per year in Caucasian populations (Wilkes 1979).
In case of a primary UM, different treatments are available. Tumors with a thickness < 8 mm can be treated with proton beam therapy, stereotactic irradiation, or by a combination of radiation therapy and local resection or a combination with transpupillary thermotherapy (TTT).
Several complications are related to radiation therapy, including radiation retinopathy.
Radiation retinopathy is a delayed-onset disease of retinal blood vessels due to alterations in the vessel structure and their permeability after radiation. Retinal ischemia and leaking vessels are the two most significant clinical characteristics of radiation retinopathy.
Unfortunately, treatment options that will stop or reverse vision loss due to radiation retinopathy are very limited. There is no "standard of care" ( In cases of primary UM, there is a variety of available treatments. For tumors with a thickness of > 8 mm, enucleation is often the first choice, proton beam therapy could be an alternative. Small to medium-sized tumors with a prominence < 8 mm can be treated with proton beam therapy, stereotactic irradiation, or by sandwich therapy, a combination of radiation and laser therapy, using a plaque containing radioactive material which is placed on the sklera overlying the tumor.
Proton beam irradiation is the only method that allows the accurate sparing of structures close to the tumor such as the optical nerve and macula.
Radiation therapy results in destruction of the intraocular tumor, either through the direct damage of tumor cell DNA, thus preventing further cell division and growth (Goodman 1986, Char 1982, 1983, 1989, or through damage to capillary endothelium, leading to ischemia and tumor necrosis (Gragoudas 1980, Goodman 1986, Char 1989). Proton therapy is a highly effective local therapy, leading to a local tumor control in more than 95% of patients and a rate of enucleation lower than 14% (Höcht 2004 changes such as macular edema, capillary non-perfusion, cotton wool spots, capillary   telangiectasia, retinal neovascularization, micro-aneurysms, retinal hemorrhages, intraretinal exudation, and neuronal changes such as disc edema, disc pallor, optic nerve atrophy, and neovascularization of the disk (Guyer 1992).
Clinically, these signs are often identical to the findings seen in diabetic retinopathy. Patients with radiation retinopathy can suffer a loss of vision through any of these complications.
Currently, there is no treatment to reverse visual loss from ischemic maculopathy due to capillary nonperfusion (Guyer 1992).
The threshold for radiation retinopathy depends on the total dose delivered, the volume of irradiated retina, the fractionation scheme, and individual factors. In general, a greater total dose results in earlier, more severe and more pronounced radiation retinopathy (Harris 1976). Doses of more than 45 Gy imply an increased risk, and must be expected with doses over 65 Gy (Parsons 1994 (Höcht et. al.2004).
To date, there is no effective therapy to cure vision loss due to radiation retinopathy. Cystoid macular edema may benefit from a macular grid treatment. If there are localized capillary changes causing exudative retinopathy, the focal laser treatment of these areas may decrease macular edema. In many patients, maculopathy after radiation progresses from a leaking exudative phase to an occlusive phase, and focal grid photocoagulation might serve only as a temporary measure. Panretinal photocoagulation appears to be beneficial in reducing neovascularization of the disc and retina as well as rubeosis iridis (Gass 1968, Chaudhuri 1981, Finger 2005.
Retinal ischemia and leaking vessels are the two most significant factors in radiation retinopathy. Neovascularization, like leaking vessels, depends on the balance between angiogenic stimulators and inhibitors. Microangiopathy impairs vascularization of the retina, which causes subsequent permanent damage neuroretinal structures due to ischemia. As a consequence, the production of angiogenic stimulating factors will increase (Ferrara 1997, Neufeld 1999, Witmer 2003 There is an increase in visual acuity over the first year that is maintained over 3 years. The group receiving laser treatment initially received randibizumag in the second and third year of the study with a considerable improvement in visual acuity:

Implications
Approximately 30-40% of patients develop a deterioration of visual acuity within 5 years after treatment of uveal melanoma using radiation therapy due to radiation retinopathy (Shields 2002, Bartlema 2003). By administration of either Lucentis® we hope to treat complications of radiation therapy, by demonstrating a lack of further decrease in best-corrected visual acuity and a reduced amount of macular edema and vascular leakage. Additionally, we hope to obtain a better understanding of the pathophysiologic processes involved, by demonstrating a possible relation between high levels of angiogenic factors (VEGF) in the anterior chamber fluid, and radiation retinopathy. In conclusion, we hope to provide evidence for a new therapy in patients with retinopathy, due to radiation in uveal melanoma. There is no scientifically proven treatment available at this time although laser photocoagulation is considered the standard of care.

Primary objective
Approximately 30-40% of patients develop a deterioration of visual acuity within 5 years after the radiotherapy of uveal melanoma due to radiation retinopathy (Shields 2002, Bartlema 2003).
By administration of Lucentis® (ranibizumab) we hope to demonstrate a relevantly improved visual acuity and a reduced amount of macular edema and vascular leakage within a period of 12 6 months as compared to laser coaguagulation alone. Additionally, we hope to obtain a better understanding of the pathophysiologic processes involved, by demonstrating a possible relation between high levels of angiogenic factors (VEGF) in the anterior chamber fluid and radiation retinopathy. In conclusion, we hope to provide evidence for a new and effective treatment for uveal melanoma patients with retinopathy following radiotherapy, where no scientifically proven treatment yet exists.
1. VEGF plays an important role in pathological angiogenesis and vessel leakage. The hypothesis is that application of a VEGF inhibitor, specifically Lucentis®, will have a Study protocol v4-02-F of 04 December 2012 Charité Berlin, University of Cologne beneficial effect on reducing the neovascularization and leakage of vessels in radiation retinopathy, similar to its proven effect in age-related macular degeneration.
2. Photocoagulation is the standard of care in radiation retinopathy. The effect on maular edema is limited and needs to be analyzed against treatment with Lucentis®.
The study aims are therefore: 1. To demonstrate a positive effect of a new treatment for patients with retinopathy, due to radiation in uveal melanoma on formation of the avascular zone and macular edema. There is no scientifically proven treatment available at this time.
2. To obtain a preservation and/or improvement of visual acuity in patients with radiation retinopathy after treatment.
Primary objective / Hypothesis: To demonstrate superiority of ranibizumab 0.5 mg to laser treatment regarding change from baseline in BCVA over a 6-month treatment period.

Secondary and other objectives
The secondary objectives of the trial are: To evaluate whether ranibizumab 0.5 mg as monotherapy is superior to laser treatment with regard to • Change from baseline in macular thickness and the size of areas of macular and peripheral capillary drop out over 6 months (area under the curve / 6 months) • Change from baseline in BCVA, macular thickness and the size of areas of macular and peripheral capillary drop out over 12 months (area under the curve / 12 months) • Proportion of patients with improvement of visual acuity after 6 and 12 months

Data Monitoring Committee
There will be no Data Monitoring Committee set up in this clinical trial.

Steering Committee
There will be no Steering Committee set up in this clinical trial.

Advisory Committee
There will be no Advisory Committee set up in this clinical trial.

Review Board
Best corrected visual acuity (BCVA), size of areas of macular and peripheral capillary dropout, macula thickness will be analyzed in a blinded fashion by Dr. Florian Heussen and Dr.

Study laboratories and other technical services
There are no other tasks that will be performed by other service providers.

Investigators and trial sites
This clinical trial will be carried out as observer-masked trial at two trial sites in Germany. If necessary, further qualified trial sites may be recruited to the trial.
A list of trial sites involved, including information on the principal investigators, further investigators, and trial staff, will be kept and continuously updated. A list of the trial sites with names of the principal investigators is given in Appendix 11.1.

Requirements for investigators and trial sites
The investigators should be familiar with intravitreal injection procedures as well as macular laser. The invesigators and trial sites have to proof knowledge of regulatory procedures, and invectigator herself has to be an investigator and must have at least 2 years of experience in the clinical testing of pharmaceutical preparations.

Financing
This investigator initiated trial is financially supported by Novartis Pharma, Nürnberg, Germany. Trial Sponsorship is taken over by Charité University Medicine Berlin.

General aspects of trial design
This is a bi-centre, phase II, two-arm, randomised, parallel-group, observer-masked, controlled clinical trial.   Baseline examination (BCVA, macular thickness, capillary dropout)

Discussion of trial design
Selection bias is minimised by concealed random assignment of trial treatments. Balance of parallel treatment groups regarding important prognostic characteristics is assured by Pocock's minimisation procedure with random element (dynamic allocation). Observermasking (assessment of BCVA, macular thickness, capillary drop-out) is done to guard against detection bias. Though sham procedures for intraocular injection and retinal laser treatment are possible (in order to mask patients), these will/can not be implemented in this phase II trial. Generally patients feel the difference between sham injections and true injections as well as between sham laser and true laser treatment due to pain perception.
Thus, patients and treating physicians are very likely to guess what has actually been done.
Performance bias is thus to be reduced by strict standardisation of trial procedures. Attrition bias will be minimised by active follow-up of trial patients by a dedicated study nurse / physician (telephone, mail and in-person contact).

Selection of trial population
Reasons for gender distribution We expect a homogenous (1:1) gender distribution. There is no evidence of difference by gender in the incidence of choroidal melanoma, nor in the development of radiation retinopathy, nor in the response to anti-VEGF agents or laser treatment.

Inclusion criteria
• Patients with retinopathy, due to radiation of uveal melanoma

Dosage and administration of Ranibizumab
Ranibizumab will be administered intravitreally in a multiple-dose regimen of 0.5 mg of ranibizumab every month (Days 0, 30, 60) for a total of 3 injections and as a PRN Treatment thereafter. Subsequent injections if visual acuity drops by > 5 letters from best observed on treatment (including baseline) value or evidence of macular or optic disc edema.
Injection is discontinued when

Ranibizumab Injection
Procedures will be implemented to minimise the risk of potential adverse events associated with serial intraocular injections (e.g., endophthalmitis). Aseptic technique must be observed by clinic staff involved in the injection tray assembly, anesthetic preparation and administration, and study drug preparation and administration. In addition to the procedures outlined in the protocol, added safety measures in adherence to specific institutional policies associated with intraocular injections should be observed.
Ranibizumab will be administered in the study eye only. Intravitreal injection must be performed by the injecting physician(s) following the slitlamp examination and in accordance to standard treatment precautions and aseptic techniques.
A 30-gauge, ½-inch needle, attached to a low-volume (e.g., tuberculin) syringe containing 50 µL of study drug solution, will be inserted through the pre-anesthetized conjunctiva and sclera, approximately 3.5-4.0 mm posterior to the limbus, avoiding the horizontal meridian and aiming toward the center of the globe. Immediately following the intraocular injection, standard topical treatment for intraocular injections is administered and will be continued by the patient according to standards.
In the laser group, laser treatment using an Argon Green Laser will be performed to the macula and periphery in areas of ischemia. In the periphery PRP is performed according to the use of PRP in diabetic patients. In the macular area, a modified grid technique is used sparing the fovea; additional treatment at intervals of not less than 3 months if visual acuity drops by >5 letters from best observed on treatment (including baseline) value and evidence of ischemic areas, macular or optic disc edema is present.

Description of investigational medicinal product
The investigational drug is ranibizumab (see above). Ranibizumab is provided by Novartis. It is approved for intravitreal injection in wet age related macula degeneration, diabetic retinopathy and retinal vein occlusions. The drug supplied for this study will be manufactured by Novartis.

Labelling of investigational medicinal product
The drug supplied for this study will be labeled by Novartis.

Storage of investigational medicinal product
The trial medication will be kept separate from the normal medication distribution. The medication is provided by Novartis Pharma and will be distributed to the respective hospital pharmacies that are responsible for storage of the medication in accordance to the study protocol and applicable laws. The IMP will be stored in a secure, limited-access location according to the summary of product characteristics (SMPC).

Compliance with treatment / Dispensing and return of investigational medicinal product
The local coordinating investigator or his/her designee of each trial site will document inventoried and disposed IMP for each site and subject. Destruction of IMPs will be performed by the trial sites and will be documented. In the event that the IMP is received in a damaged condition (i.e. after shipment) or the expiration date of the IMP has past, the study drug should be held in quarantine and not dispensed to patients. In this case the local pharmacy should be informed by the trial site personal and additional drug supplies will be requested for the trial site.

Assignment of trial subjects to treatment groups
Patients will be dynamically allocated to treatment arms using Pocock's minimisation method with random element (Pocock 1975) as implemented by 24/7 Internet service. Minimisation factors include radiation dose to the macula and disc, tumor location (anterior / equator / posterior) and study centre (Berlin / Essen).

Blinding
Observer-masking (assessment of BCVA, macular thickness, capillary drop-out) is done to guard against detection bias. Though sham procedures for intraocular injection and retinal laser treatment are possible (in order to mask patients), these will/can not be implemented in this phase II due to the high likelihood of the patient knowing by a short local pain sensation during each treatment whether it is a sham treatment or a real therapy.
Study protocol v4-02-F of 04 December 2012 Charité Berlin, University of Cologne Unblinding Not applicable (treatment not blinded)

Previous and concomitant medication
Permitted concomitant therapies include cataract surgery for radiation induced cataracts.
Other surgical therapies, e.g. vitrectomy are not permitted during the study and will be considered adverse events and treatment failure.
Similarly, other pharmacological treatments for macular edema, e.g. triamcinolone or other steroids are not permitted during the study period.

Rescue therapy for emergencies
There is no current standard treatment for radiation retinopathy. Laser treatment for peripheral and central ischemia in the injection group will be considered rescue treatment.
In cases of severe vitreous hemorrhage, vitrectomy and intraoperative laser treatment will be performed as a rescue treatment.

Continuation of treatment after the end of the clinical trial
It is expected that active radiation retinopathy is transitory disease.

Primary variable
Study protocol v4-02-F of 04 December 2012 Charité Berlin, University of Cologne

Measurement of ischemic maculopathy by Fluorescein Angiography
Standardized angiography is performed by fluorescein angiography using a confocal scanning laser ophthalmoscope (Spectralis, Heidelberg Engineering). Besides central images of the macula, the periphery will be covered in an 8 field scheme. The angiograms follow a standardised protocol.
Fluorescein angiograms will include pre-injection reflectance images using the green illumination (514 nm) and autofluorescence images using the blue (488 nm) illumination. Angiographic images will be taken within the first second after dye inflow, and thereafter in 1 second intervals for 15 seconds, 30 seconds, 60 seconds, 120 seconds, 300 seconds, and 600 seconds, after injection. For all central images, the 30° mode will be used. Angiographic images will be recorded with a resolution of 256x256 pixels within the first minute after injection. Thereafter, the 512x512 resolution will be used. Subsequently, peripheral images are taken.

Safety analysis
Safety paramters that will be assessed: • Intraocular pressure

Rationale for assessment procedures
Macula edema is assessed both anatomically (OCT and FAG) and functionally (visual acuity). Further the ophthalmological assessment includes the tumor control.
From other indications of ranibizumab the duration of the treatment effect was determined as 4 weeks. Thus the intervals for clinical assessment in the current trial were set to 4 weeks. The trial sites will be monitored to ensure the quality of the data collected. The objectives of the monitoring procedures are to ensure that the trial subject's safety and rights as a study participant are respected, that accurate, valid and complete data are collected, and that the trial is conducted in accordance with the trial protocol, the principles of GCP and local legislation.

Pharmacokinetics/Determination of drug levels
All investigators agree that the monitor regularly visits the trial site and assure that the monitor will receive appropriate support in their activities at the trial site, as agreed in The exact extent of the monitoring procedures is described in a separate monitoring manual.

Audits/Inspections
As part of quality assurance, the sponsor has the right to audit the trial sites and any other institutions involved in the trial. The aim of an audit is to verify the validity, accuracy and completeness of data, to establish the credibility of the clinical trial, and to check whether the trial subject's rights and trial subject safety are being maintained. The sponsor may assign these activities to persons otherwise not involved in the trial (auditors). These persons are allowed access to all trial documentation (especially the trial protocol, case report forms, trial subjects' medical records, drug accountability documentation, and trial-related correspondence).
The sponsor and all trial sites involved undertake to support auditors and inspections by the competent authorities at all times and to allow the persons charged with these duties access to the necessary original documentation.
All persons conducting audits undertake to keep all trial subject data and other trial data confidential.

Documentation
All data relevant to the trial are documented soon after measurement by the investigator responsible in the electronic case report form supplied. Entering data may be delegated to members of the trial team. The CRFs are signed by the investigator.

Data management
The IT infrastructure and data management staff will be supplied by the ZKS Cologne. The trial database will be developed and validated before data entry based on standard operating Study protocol v4-02-F of 04 December 2012 Charité Berlin, University of Cologne procedures at the ZKS Cologne. The data management system is based on commercial trial software and stores the data in a database. All changes made to the data are documented in an audit trail. The trial software has a user and role concept that can be adjusted on a trialspecific basis. The database is integrated into a general IT infrastructure and safety concept with a firewall and backup system. The data are backed up daily. After completion and cleaning of data, the database is locked and the data exported for statistical analysis.
The data will be entered online at the trial sites via the Internet. Plausibility checks are run during data entry, thereby detecting many discrepancies immediately. The ZKS Cologne Data Management will conduct further checks for completeness and plausibility and will clarify any questions with the trial sites electronically via the trial software. These electronic queries have to be answered by the trial site without unreasonable delay. Further details will be specified in the data management manual.

Archiving
All eCRFs, informed consent forms and other important trial materials will be archived for at least 10 years in accordance with §13 Sec. 10 of the GCP Regulations. Trial subject identification lists at each trial site will be stored separately from trial documentation.

Independent ethics committee
The clinical trial will not be started before approval of the competent ethics committee.
In each trial site, the clinical study will not be started before approval of the competent local ethics committee concerning the suitability of the trial site and the qualifications of the investigators.

Ethical basis for the clinical trial
The present trial protocol and any amendments were and will be prepared in accordance with the Declaration of Helsinki in the version of October 1996 (48th General Assembly of the World Medical Association, Somerset West, Republic of South Africa).

Legislation and guidelines used for preparation
The present clinical trial will be conducted in accordance with the published principles of the

Notification of the authorities, approval and registration
Before the start of the clinical trial, all necessary documentation will be submitted to the competent supreme federal authority for approval (Paul Ehrlich Institute, Paul-Ehrlich-Institut [PEI]). The state authorities in each federal state in which the trial will be conducted will also be notified.
Before the trial is started, it will be registered under Current Controlled Trials (www.controlled-trials.com) or another trial register approved by the World Health Organisation (WHO) (http://www.who.int/ictrp/en/).

Obtaining informed consent from trial subjects
Trial subjects may not be enrolled into the present trial unless they have consented to take part in the trial after having been informed verbally and in writing in comprehensible language of the nature, scope and possible consequences by a trial investigator. Together with the consent to take part in the trial, the trial subject must also agree to representatives of the sponsor (e.g. monitors or auditors) or the competent supervisory or federal authorities having access to the data recorded within the framework of the clinical trial. The trial subject will be informed of the potential benefit and possible side effects of the IMP, It must be clear to trial subjects that he or she can withdraw his or her consent at any time without giving reasons and without jeopardizing his / her further course of treatment.
The originally signed consent form is archived in the investigator site file. Trial subjects receive copies of the written information sheet, confirmation of insurance with conditions, and the signed informed consent form. A copy of the written information sheet and the signed informed consent form will be filed in the patient's record.
The patient information sheet and informed consent form are supplied as anin Appendix.
The patient information sheet, informed consent form, all other documents handed out to the trial subject and any recruitment advertisements must be submitted for approval before use to the ethics committee. Part of the monitoring activities are to check that the most recent informed consent form was used before the trial subject was enrolled and that it was dated and signed by the trial subject himself or herself.

Insurance of trial subjects
All trial subjects enrolled are insured in accordance with § 40 AMG under the group insurance contract of Charité University Medicine with HDI Gerling Versicherung (insurance company). The headquarters, policy number and telephone and fax number will be included in the patient information sheet.

Data protection
The provisions of data protection legislation will be observed. It is assured by the sponsor that all investigational materials and data will be pseudonymised in accordance with data protection legislation before scientific processing.
Trial subjects will be informed that their pseudonymised data will be passed on in accordance with provisions for documentation and notification pursuant to § 12 and § 13 of the GCP Regulations to the recipients described there. Subjects who do not agree that the information may be passed on in this way will not be enrolled into the trial.

Statistical and analytical plan
This is a phase II therapeutic-exploratory clinical trial with 60 patients randomly assigned to two treatment arms. Though the primary analysis is done at increase significance level (i.e. 10% one-sided), the conclusions can be strengthened if the observed significance level is lower (e.g. than 5% one-sided or even two-sided). The essentials of the statistical analysis are outlined below. Further details will be layed down in the statistical analysis plan.

Trial populations
All analyses will be conducted on three trial populations: The primary dataset for analysis is derived from the intention-to-treat (ITT) population. This dataset includes all trial subjects enrolled into the trial and randomised -no exclusions.
The secondary dataset for analysis is derived from the per-protocol (PP) population. This dataset includes all trial subjects who were treated according to protocol (i.e. they received at least 3 injections of ranibizumab or at least one laser treatment as planned) and reached/provided the endpoints of main interest (i.e. after 6 months of follow-up).
The tertiary dataset for analysis is the safety population. This population includes all trial subjects who received any ranibizumab or laser treatment.

Description of trial subject groups
Demographic variables (including minimisation variables) and baseline values of study endpoints will be summarised by treatment group. Differences in location will be assessed by statistical hypothesis tests (i.e. chisquare-or t-tests).

Primary target variable
The primary variable change from baseline over 6 months (area under curve / 6 months) will be analysed by analysis of covariance with baseline and minimisation variables as covariates (type II SS). Missing values are imputed by the last observed value (possibly baseline).
Robustness of results to various imputation approaches (best case, worst case, multiple imputation and pooling) are investigated in sensitivity analyses. MMRM analyses are to complement the findings.
Moreover, These will also include (A)a corresponding mixed models for repeated measures (MMRM) analysis will be performed (assuming missing at random, MAR (Gueorguieva 2004) and (B) permutation tests (Kalish 1985;Scott 2002).). The robustness of results due to various imputation scenarios will be assessed by sensitivity analysis (worst/best case, multiple imputation).

Secondary target variables
Analyses of secondary variables / endpoints follow the same lines as that of the primary variable. Safety data are summarized (multple-way contingency tables) and listed.

Interim analysis
Not applicable power (δ/σ≈0.6). Note, this is a phase II therapeutic-exploratory trial. Randomisation will be stratified by radiation dose, tumor location and study centre. In order to account for stratification and drop-out, 27/0.9=30 patients will be randomised per treatment arm using

Sample size calculation
Pocock's minimisation method with random element (Pocock 1975). Thus, altogether, 60 patients will be included in the trial. Power for the secondary endpoints (macular thickness, capillary dropout) may be much higher. All events occurring after the first administration of the IMP until 30 days after the patient has stopped the study must be documented, The following events are excepted from reporting obligations and not considered as (S)AE: • Injuries or trauma unrelated to the eye

Concomitant diseases
The deterioration of a preexisting illness is also an AE in the context of a clinical trial. The following, however, is not regarded as an AE: a preexisting disease that led to a planned treatment measure before the start of the clinical trial, e.g. admission to hospital as an inpatient. This should be made clear in the trial subject's medical records and should also be documented in the CRF (see Section 7.1.3).

Pregnancy
For reasons of drug safety, the occurrence of a pregnancy during the conduct of this trial is to be regarded as an AE.
The investigator will inform the ZKS without delay about any pregnancy that occurs during the trial at latest within 24 hours of being made aware of it. This will be documented on a separate report form, "Pregnancy Report Form Part I". After delivery a "Pregnancy Report Form Part II" has to be filled in and must be sent to ZKS by the investigator within 24 hours of Study protocol v4-02-F of 04 December 2012 Charité Berlin, University of Cologne awareness of childbirth. ZKS will forward these informations to the coordinating principle investigator. The pregnant women will be asked to give separate informed consent for pregnancy follow up. For tracing health of the newborn baby after delivery both parents have to give an informed consent.
In case of pregnancy study medication has to be stopped immediately.

Adverse drug reaction
An adverse drug reaction (ADR) is any noxious and unintended response to an investigational medicinal product (IMP) related to any dose with at least a reasonably possible causal relationship with the IMP.

Serious adverse events and serious adverse reactions
A serious AE (SAE) or serious ADR (SADR) is any untoward medical occurrence that at any If an AE is classified as an SAE, this is documented on a separate SAE sheet in addition to the standard AE documentation. The authorities must be notified of SAEs by law (for procedure, see 7.3).

Unexpected adverse drug reaction
An unexpected ADR is an ADR which, the nature or severity of which is not consistent with the applicable product information available for the IMP. Expected ADRs are listed in the appropriate reference documents (For Lucentis: Information Sheet for Health Professionals,. SmPC or other scientific (Up to Date) product information documents, if applicable)

Suspected unexpected serious adverse reactions
A suspected unexpected serious adverse reaction (SUSAR) is an adverse event the nature or severity of which is not consistent with the product information available for the IMP, is regarded as serious, and has at least a possible causal relationship with the IMP.

Other possible trial-specific complications or risks
As the trial concerns patients with choroidal melanoma, there is a theoretical possibility of recurrent melanoma during the trial.
• If a choroidal melanoma is documented to expand after radiation treatment, therapy is considered to have failed. The  Tumor expansion is considered in two stages: 1. suspected growth 2. documented growth criteria for each of the parameters defining the stages are: Suspected growth: Confirmation of either of the following changes is considered adequate to define "suspected growth": • A 15% increase in tumor height, as determined from standardized echography • A 250-micron expansion of any tumor boundary, as judged from fundus photography Follow-up examinations at more frequent intervals are required after suspected growth.
For proton beam irradiation suspected growth during the first year is to be expected due to edema in the target tissue. However, thereafter no further increase in tumor size should be present.
Documented growth: Tumors first have been ovserved to have changes that fulfill the criteria for suspected growth.
Confirmation of either of the following changes within one year after suspected growth if confirmed is considered to be documented expansion: • An additional 15% increase in tumor height, as determined from standardized echography.
• A further 250-micron growth of any tumor boundary, as judged from fundus photography.
If either of these criteria is met, radiation therapy is considered to have failed, and the eye should be managed to the discretion of the ophthalmologist.
Patients with documented tumor growth will receive the appropriate treatment to ascertain tumor control (e.g. radiation or transpupillary thermo therapy).

Documentation and follow-up of adverse events
The sponsor ensures that all persons involved in the treatment of trial subjects are adequately informed of the responsibilities and actions required when AEs occur. Trial subjects will be asked at each visit whether they have experienced AEs or SAEs. AEs will be documented in the trial subject's medical records and in the CRF.
For the procedure of SAE-reporting see section 7.3, and section 4.7.1.3 for safety analyses.

Documentation of adverse events and adverse drug reactions
All AEs occurring during the defined reporting period will be documented in the CRF including all information listed below. Exempted are those AEs explicitly mentioned in Preexisting diseases (before administration of the IMP) are not documented as adverse events but as concomitant diseases. New diseases and preexisting diseases that worsen during the trial are documented as AEs.

Severity of the adverse event
The investigator will classify the severity of AEs as follows: • Mild: clinical symptoms or signs that are well tolerated

Unblinding when treatment is blinded
There is no blinded treatment in this trial.

Notification of ethics committee and competent supreme federal authority
Every SUSAR that becomes known in a clinical trial will be reported by the sponsor or PCI to the competent supreme federal authority, the responsible ethics committee, all principle investigators involved in the study and Novartis Pharma..
A CIOMS-1 format shall be used for submitting expedited reports to the above mentioned partners.

Fatal and life-threatening SUSARs
The competent supreme federal authority and the ethics committee responsible must be informed by the sponsor or PCI of all fatal or life-threatening SUSARs. This must be done without delay, at the latest 7 calendar days after becoming aware of the minimum criteria for reporting. In all cases, attempts must be made to obtain further relevant information which must be supplied to the competent supreme federal authority and the ethics committee within a further 8 days. Furthermore, if a trial subject dies, this information must be passed on to the ethics committee responsible for the region in which the death occurred.
SUSARs that are not fatal or life-threatening The competent supreme federal authority and the ethics committee responsible will be informed without delay by the sponsor or PCI of all SUSARs, at the latest within 15 calendar days of becoming aware of the minimum criteria for reporting. Further relevant details will be passed on as soon as possible.
If the information at the time of reporting is incomplete, further information to enable adequate assessment of the case will be requested from the reporter or other available sources.

Review and reporting of changes in the risk-benefit ratio
Without delay, and at the latest within 15 days of the decision for the need to do so, the sponsor or PCI will inform the competent supreme federal authority, the ethics committee Study protocol v4-02-F of 04 December 2012 Charité Berlin, University of Cologne responsible and the competent authorities of all other member states of the EU or EEA where the trial is being conducted, of any events or factors that mean that the risk-benefit ratio of the IMP has to be reviewed. These consist of especially: • Individual reports of expected serious ADRs with an unexpected outcome

Informing the investigators
The sponsor or PCI will inform all principal investigators of each site of all SUSARs including all relevant further information within the periods set by the supreme federal authority. The principal investigator is responsible for disclosure of this information at the site.
If new information becomes known that is different from the scientific information given to the investigator, all investigators will be informed.

Informing the marketing authorisation holder
Novartis Pharmaceuticals will be notified for SAEs. The sponsor or PCI will also inform the marketing authorization holder about all SUSARs including information reported to the competent supreme authority and ethics committee in accordance with contractual agreements.

Annual safety report of trial subjects
Once per year, the sponsor or PCI will supply a report on the safety of trial subjects with all available relevant information concerning patient safety during the reference period to the competent supreme federal authority and the competent authorities of all other member states of the EU or EEA where the trial is being conducted. This report will also be supplied to the responsible ethics committee.
The annual safety report will be compiled according to the corresponding ICH guideline E2F "Development Safety Update Report -DSUR" The data lock point for the patient data to be included and analyzed is 30.06.2006/ the last day before the date of approval of the first clinical trial investigating Lucentis by Novartis Pharma.
The sponsor or PCI will supply the report within 60 days of one year after the reference date

Final report
The competent authority and ethics committee will be informed within 90 days that the trial has officially ended.
Within one year of the completion of the trial, the competent federal authority and the ethics committee will be supplied with a summary of the final report on the clinical trial containing the principle results.

Publication
It is planned to publish the trial results, in mutual agreement with the PCI, in a scientific journal and at German or international congresses. Publication of the results of the trial as a whole is intended. Any publication will take account of the 'Uniform requirements for manuscripts submitted to biomedical journals (International Committee of Medical Journal Editors' (ICMJE) [JAMA 1997;277:927-34]).
The trial will also be registered in a public register in accordance with the recommendations of the ICMJE (see also Section 5.3).
Any published data will observe data protection legislation covering the trial subject and investigators. Success rates or individual findings at individual trial sites are known only to the sponsor.
Study protocol v4-02-F of 04 December 2012 Charité Berlin, University of Cologne Publications or lectures on the findings of the present clinical trial either as a whole or at individual investigation sites must be approved by the sponsor in advance, and the sponsor reserves the right to review and comment on such documentation before publication.
By signing the contract to participate in this trial, the investigator declares that he or she agrees to submission of the results of this trial to national and international authorities for approval and surveillance purposes, and to the Federal Physicians Association, the Association of Statutory Health Fund Physicians and to statutory health fund organisations, if required. At the same time, the investigator agrees that his or her name, address, qualifications and details of his or her involvement in the clinical trial may be made known to these bodies.
The support by the ZKS is to be mentioned in any publication. ZKS staff will be included as coauthors as applicable and the Grant number oft the ZKS (01KN1106) is mentioned in an acknowledgement. A copy of all publications will be sent to the ZKS.

Amendments to the trial protocol
To ensure that comparable conditions are achieved as far as possible at individual trial sites and in the interests of a consistent and valid data analysis, changes to the provisions of this trial protocol are not planned. In exceptional cases, however, changes may be made to the trial protocol. Such changes can only be made if agreed by the sponsor, sponsor's representative, the PCI and biometrician, and all Authors of this trial protocol. Any changes to the trial procedures must be made in writing and must be documented with reasons and signed by all Authors of the original trial protocol.
Amendments made in accordance with § 10 Secs. 1 and 4 GCP Regulations that require approval are submitted to the ethics committee and the supreme federal authority and will not be implemented until approved. Exceptions to this are amendments made to avoid immediate dangers.