About MERLOT

Macular EpiRetinal Brachytherapy versus Lucentis Only Treatment (MERLOT)

Objective of the MERLOT study

To evaluate the safety and efficacy of focal delivery of radiation for the treatment of subfoveal choroidal neovascularization (CNV) associated with established wet age-related macular degeneration (AMD) previously treated with anti-VEGF therapy. It is hypothesised that epimacular brachytherapy will reduce the frequency of ranibizumab (Lucentis®) re-treatment that patients require, whilst maintaining visual acuity.

The objective of the MERLOT Trial is to evaluate the safety and efficacy of focal delivery of radiation for the treatment of subfoveal CNV associated with established wet AMD previously treated with anti-VEGF therapy.

The MERLOT Study is part of the National Institute for Health Research (NIHR) Clinical Research Network Portfolio

Indication for use

Epimacular brachytherapy (VIDION® System*) is indicated for the treatment of subjects with subfoveal CNV associated with wet AMD.

* Epimacular brachytherapy (VIDION® System) is manufactured by NeoVista Inc. in the US and distributed in the UK by Carleton Ltd

Study design

The MERLOT Trial is a multi-centre, randomised, controlled clinical study of the VIDION® System for the treatment of subfoveal CNV associated with wet AMD in patients who have been previously treated with Lucentis®. It is designed to test the hypothesis that epimacular brachytherapy will reduce the frequency of Lucentis® re-treatment that patients require, whilst maintaining visual acuity.

A total of 363 patients who are receiving regular Lucentis® treatment will be randomised in a 2:1 ratio to Arm A or Arm B:

Arm A: A single surgical procedure with epimacular brachytherapy using the VIDION® System, with Lucentis® (0.5 mg) administered as required, using the re-treatment criteria below.

Arm B: Lucentis® (0.5 mg) administered as required, using the re-treatment criteria below

Both groups will receive ongoing Lucentis® treatment administered as required, based on pre-defined retreatment criteria.

Efficacy endpoints

The co-primary outcome measures of efficacy are:

  1. Mean change in ETDRS best-corrected visual acuity.
  2. The mean number of re-treatment injections of Lucentis® per patient, per year.

Secondary efficacy parameters that will be assessed will be the following:

Safety assessment

Safety parameters to be evaluated include incidence and severity of adverse events and ocular adverse events identified by eye examination. This will include the incidence of cataract changes and the incidence of radiation induced toxicity.

Radiation toxicity to the retina and ocular structures will be monitored throughout this study by both the Chief Investigator, and Principal Investigators at each site. . Radiation retinopathy is well described in the literature and typically occurs between 6 months and 3 years. The most common clinical signs associated with "radiation retinopathy" are:

Many of these clinical signs are also associated with the natural progression of AMD and should be followed carefully and documented as adverse events as per Section 10 of this protocol.

Study population

The population to be studied will comprise 363 men and women = 50 years of age with a diagnosis of subfoveal choroidal neovascularisation associated with wet age-related macular degeneration, who have commenced treatment with intravitreal Lucentis® in accordance with NICE guidance. It is anticipated that subjects will have been referred for treatment with epimacular brachytherapy by their treating ophthalmologist, or be under the care of the Investigator prior to screening.

Inclusion criteria

1. Subjects with subfoveal choroidal neovascularisation associated with wet age-related macular degeneration;

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:

Exclusion criteria

1. Patients who have not been treated in accordance with NICE guidance;

2. Visual acuity worse than 6/96 at 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 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), hydroxychloriquine (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 ³1 year unless surgically sterilised.

Treatment

Patients will be treated with either:

a single surgical procedure with epimacular brachytherapy using the VIDION® System, with Lucentis® (0.5 mg) administered as required, using the re-treatment criteria below.

or

Lucentis® (0.5 mg) administered as required, using predefined re-treatment criteria below

Both groups will receive ongoing Lucentis® treatment administered as required, based on pre-defined retreatment criteria.

Re-Treatment Criteria

Lucentis® should be administered if any of the following four conditions are met:

Lucentis® should be administered at Baseline for subjects in both Arm A (VIDION®) and Arm B (Lucentis® monotherapy) if the above re-treatment criteria apply. To determine if there is new disease activity or loss of visual acuity, Baseline and Screening observations should be compared to recent clinical observations.

If the treating ophthalmologist decides that Lucentis® re-treatment would be beneficial for persisting subretinal, intraretinal, or sub-RPE fluid confirmed on OCT, but the re-treatment criteria are not fulfilled, then he or she may administer Lucentis®, but this should be recorded as a deviation.

If the eye does not show a decrease in fluid after three consecutive monthly injections, the treating ophthalmologist may choose to suspend treatment. Treatment may be re-initiated if the subretinal, intraretinal, or sub-RPE fluid becomes worse (relative to the visit when treatment was suspended) on OCT.