Macular EpiRetinal Brachytherapy Versus Lucentis® Only Treatment (MERLOT) (MERLOT)

• ClinicalTrials.gov Identifier: NCT01006538
• Recruitment Status: Completed
• First Posted: November 3, 2009
• Results First Posted: July 22, 2019
• Last Update Posted: December 7, 2020
• Sponsor: King's College Hospital NHS Trust
• Information provided by (Responsible Party): King's College Hospital NHS Trust

Study Description

Brief Summary:

Wet age-related macular degeneration is the most common cause of blind registration in the United Kingdom (UK). Standard treatment involves regular eye injections of a drug called ranibizumab (Lucentis). For most patients, ranibizumab maintains their vision but the effect of the drug is temporary, and they therefore require monthly hospital visits and typically six injections into the eye every year, probably for life.

This study tests a new surgical device that delivers a focal dose of radiation (epimacular brachytherapy) to the macula (the part inside the back of the eye that gives fine central vision), to try and reduce or eliminate the need for ongoing, regular eye injections. The trial compares epimacular brachytherapy to ongoing standard treatment with ranibizumab.

Whereas most studies of this new surgical device target patients who have not yet commenced any treatment, this study targets those who are requiring frequent eye injections, as there are limited surgical resources and these resources are best directed to those who have not fully responded to ranibizumab therapy, or whose response is shortlived. These patients have the most to gain from a device that may reduce their burden of treatment. The findings in untreated disease cannot be extrapolated to this discrete subset of patients, hence the need for a study that targets refractory disease.

It is hypothesised that epimacular brachytherapy will reduce the frequency of Lucentis® (ranibizumab) re-treatment that patients require, whilst maintaining visual acuity.

Condition or disease	Intervention/treatment	Phase
Macular Degeneration	Device: Epimacular Brachytherapy; Drug: Ranibizumab	Phase 4

Detailed Description:

The eye is designed like a camera, with a lens at the front and a film at the back. Using this analogy, the retina is the film in the camera. In the center of the retina is the macula, the region that absorbs focused light from the lens and creates an image of the outside world that is then transmitted to the brain.

The commonest cause of irreversible blindness in developed nations is age related macular degeneration (AMD). There are two types, 'dry' and 'wet' AMD. Wet AMD is also called neovascular AMD: It is the most damaging type and can blind people in a matter of weeks. Neovascular AMD is due to the growth of blood vessels under the retina, similar to a wound healing process. The blood vessels grow in two patterns, classic (15%) and occult (85%); these can be visualized with fluorescein angiography, a commonly used technique that photographs the macula after a fluorescent dye is injected into the arm. In most research on AMD, vision is assessed using the Early Treatment of Diabetic Retinopathy Study (ETDRS) vision chart, with results quantified in numbers of letters read correctly, from 0 (very poor vision) to 100 (very good vision).

A new treatment has recently been licensed in the UK called ranibizumab (trade name, Lucentis). This is an antibody that reduces the effect of vascular endothelial growth factor (VEGF), a chemical that mediates new blood vessel growth. This drug is injected into the eye at regular intervals (up to 12 a year, and typically 6 a year). Patients receiving 12 ranibizumab injections per year have a greater than 90% chance of maintaining their vision over 12 months (1-2). Another drug called bevacizumab (Avastin) has been used off label (without a licence) in the UK, USA and other countries, and this also targets VEGF. In non-randomized trials it showed similar results to ranibizumab, and is currently being assessed in head-to-head trials with ranibizumab in the UK and the USA.

One of the drawbacks of ranibizumab therapy is that patients require regular injections into the eye. In the UK, the National Institute for Health and Care Excellence (NICE) recommends patient with newly diagnosed wet AMD receive three consecutive monthly injections of ranibizumab, followed by 'as required' therapy based on disease activity. They estimate that patients receive eight injections in the first year, six in the second, and ongoing treatment thereafter. Patients require monthly hospital visits for life and each injection caries a small but cumulative risk of complications such as bleeding inside the eye, infection, detachment of the retina, raised eye pressure, and systemic effects such as stroke. A treatment that produced a more durable reduction in disease activity might reduce these risks, be more cost effective for the health service, and reduce the considerable burden of treatment for patients and their carers, with the prospect of fewer hospital visits. It would also give patients an alternative choice, should they not wish to undergo such regular eye injections.

Radiation has the potential to produce a more durable therapeutic effect, by targeting the proliferating cells that cause visual damage in wet AMD. It is well known that radiation can modify the wound healing process, which is a biological process similar to neovascular AMD. Previous studies with external beam radiation have shown an effect on the progression of macular degeneration. However vision was not improved - possibly due to the type of radiation used, the accuracy of delivery, and collateral damage to neighbouring structures.

Epimacular brachytherapy delivers local, controlled radiation 1-3 mm into the macula, during an operation called a vitrectomy. The proposed device will be CE marked (Conformité Européene - approved for clinical use) and is manufactured by NeoVista Inc, who have completed preliminary trials to assess the safety and feasibility of treating naive (newly diagnosed) neovascular AMD with a single application of brachytherapy. Initial data showed that epiretinal treatment stabilised vision for most patients with neovascular AMD. Phase II trials using the device with two concomitant doses of bevacizumab showed promising results with 91% of patients maintaining vision (losing fewer than 15 ETDRS letters), with an average improvement of 8.9 ETDRS letters (3). The percentage of patients whose visual acuity improved by more than 3 lines (15 letters on the ETDRS scale) was 38%. These results are similar to the large studies of monthly ranibizumab. A mean gain of 8.9 letters is more than twice the visual gain reported in large studies (HORIZON) of 'as required' dosing, as occurs in the UK.

A large, international, randomized, multicentre study of the device, used with two concomitant injections of ranibizumab, is now underway (the CABERNET study). Recruitment is occuring in the hospital of the applicant, and two other UK sites, with more sites to follow. The CABERNET study uses the device in treatment naive disease and was favourably reviewed by the Southwest Research Ethics Committee (07/H0206/50).

Whilst the CABERNET study will provide high quality data in treatment naive disease, it is not possible to rely on this study in relation to previously treated disease. Prior therapy with ranibizumab modifies the disease process, and those that respond poorly to injections differ from the majority, suggesting differences in the underlying disease process. It is therefore necessary to study the subset of patients with refractory disease, if valid clinical conclusions are to be reached. Furthermore, because there is limited vitreoretinal surgical capacity it is logical to offer surgical intervention to patients who have not responded fully to ranibizumab, rather than aim to treat all patients presenting with wet-AMD. To this end, an uncontrolled study (MERITAGE) using the device in refractory, previously treated disease has commenced, having received a favourable opinion from the Southwest Research Ethics Committee (07/H0206/55). The present randomised controlled trial (MERLOT) follows on from the Phase II MERITAGE study. It targets previously treated disease, and patients that are receiving regular ranibizumab, to determine if the device benefits this large subset of patients.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 363 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomised Controlled Trial of Epimacular Brachytherapy Versus Ranibizumab Monotherapy for the Treatment of Subfoveal Choroidal Neovascularisation Associated With Wet Age-related Macular Degeneration in Patients Who Have Commenced Anti-VEGF Therapy
• Study Start Date: November 2009
• Actual Primary Completion Date: March 2015
• Actual Study Completion Date: December 2016

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm A (treatment); Arm A: A single surgical procedure with epimacular brachytherapy using the VIDION® System, with Lucentis® (0.5 mg) administered on a monthly basis as required.	Device: Epimacular Brachytherapy; Strontium-90. The device delivers 24 Gray of beta radiation to the choroidal neovascular membrane (CNV) lesion. Each device is calibrated for a set duration.; Other Names: Vidion System; EpiRetinal Brachytherapy; Drug: Ranibizumab; intravitreal injection of Ranibizumab (0.5 mg) administered on a monthly basis as required, using the re-treatment criteria; Other Names: Lucentis; Anti-VEGF therapy
Active Comparator: Arm B (control): Arm B: Lucentis® (0.5 mg) administered on a monthly basis as required, using the re-treatment criteria below.	Drug: Ranibizumab; intravitreal injection of Ranibizumab (0.5 mg) administered on a monthly basis as required, using the re-treatment criteria; Other Names: Lucentis; Anti-VEGF therapy

Outcome Measures

Primary Outcome Measures :

1. Mean Change in Early Treatment for Diabetic Retinopathy Study (ETDRS) Best-corrected Visual Acuity (BCVA) From Baseline to Month 12 [ Time Frame: 12 months ]

   Manifest refraction and BCVA measurements were performed according to the standard procedure originally developed for Early Treatment for Diabetic Retinopathy Study (ETDRS) and adapted for the Age Related Eye Disease Study (AREDS) protocol. Visual acuity testing was measured at a distance of 4 meters and, for subjects with sufficiently reduced vision, at 1 meter. The ETDRS charts consist of 14 lines, each comprising a series of 5 letters of equal difficulty, with standardized spacing between letters and rows (total 70 letters). Minimum is 0 (no letters read at 1 m) and maximum possible is 100 (70 letters read at 4 m + 30). If visual acuity is so poor that the subject cannot read any of the largest letters at 1 meter count fingers (CF), hand movements (HM) and light perception (PL) are tested.

   The mean change in ETDRS BCVA was calculated from baseline to month 12.

2. Mean Number of Re-treatment Injections of Lucentis® Per Patient, Per Year. [ Time Frame: 12 months ]

Secondary Outcome Measures :

1. Percentage of Subjects Losing < 15 ETDRS Letters [ Time Frame: 12 months ]

   Manifest refraction and BCVA measurements were performed according to the standard procedure originally developed for Early Treatment for Diabetic Retinopathy Study (ETDRS) and adapted for the Age Related Eye Disease Study (AREDS) protocol. Visual acuity testing was measured at a distance of 4 meters and, for subjects with sufficiently reduced vision, at 1 meter. The ETDRS charts consist of 14 lines, each comprising a series of 5 letters of equal difficulty, with standardized spacing between letters and rows (total 70 letters). Minimum is 0 (no letters read at 1 m) and maximum possible is 100 (70 letters read at 4 m + 30). If visual acuity is so poor that the subject cannot read any of the largest letters at 1 meter count fingers (CF), hand movements (HM) and light perception (PL) are tested.

   Participants with worsening in BCVA by less than 15 EDTRS letters at month 12 compared with baseline were considered for this outcome measure.

2. Percentage of Subjects Gaining ≥ 0 ETDRS Letters [ Time Frame: 12 months ]

   Manifest refraction and BCVA measurements were performed according to the standard procedure originally developed for Early Treatment for Diabetic Retinopathy Study (ETDRS) and adapted for the Age Related Eye Disease Study (AREDS) protocol. Visual acuity testing was measured at a distance of 4 meters and, for subjects with sufficiently reduced vision, at 1 meter. The ETDRS charts consist of 14 lines, each comprising a series of 5 letters of equal difficulty, with standardized spacing between letters and rows (total 70 letters). Minimum is 0 (no letters read at 1 m) and maximum possible is 100 (70 letters read at 4 m + 30). If visual acuity is so poor that the subject cannot read any of the largest letters at 1 meter count fingers (CF), hand movements (HM) and light perception (PL) are tested.

   Participants with an improvement in BCVA by more than 0 EDTRS letters at month 12 compared with baseline were considered for this outcome measure.

3. Percentage of Subjects Gaining ≥ 15 ETDRS Letters [ Time Frame: 12 months ]

   Manifest refraction and BCVA measurements were performed according to the standard procedure originally developed for Early Treatment for Diabetic Retinopathy Study (ETDRS) and adapted for the Age Related Eye Disease Study (AREDS) protocol. Visual acuity testing was measured at a distance of 4 meters and, for subjects with sufficiently reduced vision, at 1 meter. The ETDRS charts consist of 14 lines, each comprising a series of 5 letters of equal difficulty, with standardized spacing between letters and rows (total 70 letters). Minimum is 0 (no letters read at 1 m) and maximum possible is 100 (70 letters read at 4 m + 30). If visual acuity is so poor that the subject cannot read any of the largest letters at 1 meter count fingers (CF), hand movements (HM) and light perception (PL) are tested.

   Participants with an improvement in BCVA by more than 15 EDTRS letters at month 12 compared with baseline were considered for this outcome measure.

4. Change in Total Lesion Size by Fluorescein Angiography From Baseline to Month 12 [ Time Frame: 12 months ]
5. Change in Total Choroidal Neovascular Membrane (CNV) Size by Fluorescein Angiography From Baseline to Month 12 [ Time Frame: 12 months ]
6. Foveal Thickness Measured Using Optical Coherence Tomography (OCT) From Baseline to Month 12 [ Time Frame: 12 months ]

Eligibility Criteria

• Ages Eligible for Study: 50 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Subjects with subfoveal choroidal neovascularisation associated with wet age-related macular degeneration. Retinal Angiomatous Proliferation (RAP) lesions not directly involving the fovea must be associated with contiguous foveal leakage demonstrated on fundus examination, optical coherence tomography (OCT), or fluorescein angiography;
2. Subjects must have received anti-VEGF induction treatment, defined as the first three months of anti-VEGF therapy. Following this induction period, subjects must have received at least 4 additional injections of Lucentis® in no more than 12 months preceding enrolment, or 2 additional injections of Lucentis® in no more than 6 months preceding enrolment, given on an as needed basis;

3. At the time subjects commenced anti-VEGF therapy for wet age-related macular degeneration they were aged 50 years or older and met the NICE treatment criteria for Lucentis® therapy, as outlined in the Final Appraisal Determination (FAD). This states that all of the following circumstances must apply in the eye to be treated:

   • the best-corrected visual acuity is between 6/12 and 6/96 (24 to 69 ETDRS letters)
   • there is no permanent structural damage to the central fovea
   • the lesion size is less than or equal to 12 disc areas in greatest linear dimension
   • there is evidence of recent presumed disease progression (blood vessel growth, as indicated by fluorescein angiography, or recent visual acuity changes)

Exclusion Criteria:

1. Patients who have not been treated in accordance with NICE guidance;
2. Visual acuity worse than 6/96 at the time of study enrolment;
3. Subjects with prior or concurrent subfoveal CNV therapy with agents, surgery or devices (other than Macugen®, Avastin®, or Lucentis®) including thermal laser photocoagulation (with or without photographic evidence), photodynamic therapy, intravitreal or subretinal steroids, and transpupillary thermotherapy (TTT);
4. Subfoveal scarring;
5. Subjects with active concomitant disease in the study eye, including uveitis, presence of pigment epithelial tears or rips, acute ocular or periocular infection;
6. Subjects who have been previously diagnosed with Type 1 or Type 2 Diabetes Mellitus. Subjects who do not have a documented diagnosis, but have retinal findings consistent with Type 1 or Type 2 Diabetes Mellitus;
7. Subjects with advanced glaucoma (greater than 0.8 cup:disk) or intraocular pressure ≥ 30 mmHg in the study eye;
8. Previous glaucoma filtering surgery in the study eye;
9. Subjects with inadequate pupillary dilation or significant media opacities in the study eye, including cataract, which may interfere with visual acuity or the evaluation of the posterior segment;
10. Current vitreous haemorrhage in the study eye;
11. History of rhegmatogenous retinal detachment or macular hole in the study eye;
12. Subjects who present with CNV due to causes other than AMD, including subjects with known or suspected idiopathic polypoidal choroidal vasculopathy (IPCV), ocular histoplasmosis syndrome, angioid streaks, multifocal choroiditis, choroidal rupture, or pathologic myopia (spherical equivalent ≥ 8 Dioptre or axial length ≥ 25mm);
13. Subjects who have undergone any intraocular surgery in the study eye within 12 weeks prior to the screening visit, with the exception of cataract surgery as discussed in the Exclusion Criteria #14
14. Previous cataract surgery within 2 months prior to enrolment into the study;
15. Subjects with known serious allergies to fluorescein dye used in angiography;
16. Subjects with known sensitivity or allergy to Lucentis®;
17. Subjects who underwent previous radiation therapy to the eye, head or neck;
18. Subjects with an intravitreal device or drug in the study eye;
19. Subjects with any other condition, which in the judgment of the investigator would prevent the subject from completing the study (e.g. documented diagnosis of dementia or serious mental illness);
20. Current participation in another drug or device clinical trial, or participation in such a clinical trial within the last year;
21. History of use of drugs with known retinal toxicity, including: chloroquine (Aralen - an anti-malarial drug), hydroxychloroquine (Plaquenil), phenothiazines, chlorpromazine (Thorazine), thioridazine (Mellaril), fluphenazine (Prolixin), perphenazine (Trilafon), and trifluoperazine (Stelazine);
22. Subjects who are unwilling or unable to return for scheduled treatment and follow-up examinations for three years;
23. Women must be post-menopausal more than 1 year unless surgically sterilised

Contacts and Locations

Locations

United Kingdom

Royal Devon and Exeter Hospital

Exeter, Devon, United Kingdom, EX2 5DW

Plymouth Royal Eye Infirmary

Plymouth, Devon, United Kingdom, PL4 6PL

Torbay Hospital

Torquay, Devon, United Kingdom, TQ2 7AA

Royal Bournemouth Hospital

Bournemouth, Dorset, United Kingdom, BH7 7DW

Sussex Eye Hospital

Brighton, East Sussex, United Kingdom, BN2 5BF

Hull and East Yorks Hospital

Hull, East Yorkshire, United Kingdom, HU3 2JZ

Essex County Hospital

Colchester, Essex, United Kingdom, CO3 3SP

Southend Hospital

Westcliff-on-Sea,, Essex, United Kingdom, SS0 0RY

Manchester Royal Eye Hospital

Manchester, Greater Manchester, United Kingdom, M13 9WH

Queen Alexandra Hospital

Portsmouth, Hampshire, United Kingdom, PO6 3LY

Maidstone Hospital

Maidstone, Kent, United Kingdom, ME16 9QQ

Ashford William Harvey Hospital

Willesborough, Kent, United Kingdom, TN24 0LZ

Royal Liverpool Hospital

Liverpool, Merseyside, United Kingdom, L7 8XP

Arrowe Park Hospital

Upton, Merseyside, United Kingdom, CH49 5PE

James Cook Hospital

Middlesborough, North Yorkshire, United Kingdom, TS4 3BW

Royal Hallamshire Hospital

Sheffield, South Yorkshire, United Kingdom, S10 2JF

Southampton Hospital

Shirley, Southampton, United Kingdom, SO16 6YD

Royal Victoria Infirmary

Newcastle, Tyne And Wear, United Kingdom, NE1 4LP

Sunderland Eye Infimary

Sunderland, Tyne And Wear, United Kingdom, SR2 9HP

Warwick Hospital Eye Unit

Warwick, Warwickshire, United Kingdom, CV34 5BW

St James University Hospital

Leeds, West Yorkshire, United Kingdom, LS9 7TF

Bristol Eye Hospital

Bristol, United Kingdom, BS1 2LX

Darlington Memorial Hospital

Darlington, United Kingdom, DL3 6HX

King's College Hospital

London, United Kingdom, SE5 9RS

Sponsors and Collaborators

King's College Hospital NHS Trust

Investigators

• Principal Investigator: Timothy L Jackson, PhD FRCOphth; King's College Hospital NHS Trust

More Information

Additional Information:

MERLOT Study website with information for Patients and Investigators 

Website for King's College Hospital (Study Sponsor Site) 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Jackson TL, Soare C, Petrarca C, Simpson A, Neffendorf JE, Petrarca R, Muldrew KA, Peto T, Chakravarthy U, Membrey L, Haynes R, Costen M, Steel DHW, Desai R; MERLOT Study Group. Epimacular brachytherapy for previously treated neovascular age-related macular degeneration: month 36 results of the MERLOT randomised controlled trial. Br J Ophthalmol. 2022 Feb 25:bjophthalmol-2021-320620. doi: 10.1136/bjophthalmol-2021-320620. Online ahead of print.

Evans JR, Igwe C, Jackson TL, Chong V. Radiotherapy for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2020 Aug 26;8(8):CD004004. doi: 10.1002/14651858.CD004004.pub4.

Jackson TL, Soare C, Petrarca C, Simpson A, Neffendorf JE, Petrarca R, Muldrew A, Peto T, Chakravarthy U, Membrey L, Haynes R, Costen M, Steel D, Desai R; MERLOT Study Group. Evaluation of Month-24 Efficacy and Safety of Epimacular Brachytherapy for Previously Treated Neovascular Age-Related Macular Degeneration: The MERLOT Randomized Clinical Trial. JAMA Ophthalmol. 2020 Aug 1;138(8):835-842. doi: 10.1001/jamaophthalmol.2020.2309.

Jackson TL, Dugel PU, Bebchuk JD, Smith KR, Petrarca R, Slakter JS, Jaffe GJ, Nau JA; CABERNET Study Group. Epimacular brachytherapy for neovascular age-related macular degeneration (CABERNET): fluorescein angiography and optical coherence tomography. Ophthalmology. 2013 Aug;120(8):1597-603. doi: 10.1016/j.ophtha.2013.01.074. Epub 2013 Mar 13.

• Responsible Party: King's College Hospital NHS Trust
• ClinicalTrials.gov Identifier: NCT01006538
• Other Study ID Numbers: 09/HO206/20; 2009-012509-20 ( EudraCT Number )
• First Posted: November 3, 2009
• Results First Posted: July 22, 2019
• Last Update Posted: December 7, 2020
• Last Verified: May 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by King's College Hospital NHS Trust:

Wet Age-related Macular Degeneration; Predominantly classic; Minimally classic; Occult with no classic; Retinal Angiomatous Proliferation (RAP) lesions

Additional relevant MeSH terms:

Macular Degeneration; Retinal Degeneration; Retinal Diseases; Eye Diseases; Ranibizumab; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors; Antineoplastic Agents