<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02243878</url>
  </required_header>
  <id_info>
    <org_study_id>UKCRN ID 18040</org_study_id>
    <secondary_id>ISRCTN12884465</secondary_id>
    <secondary_id>EME-Project:12/66/22</secondary_id>
    <nct_id>NCT02243878</nct_id>
  </id_info>
  <brief_title>Stereotactic Radiotherapy for Wet AMD (STAR)</brief_title>
  <acronym>STAR</acronym>
  <official_title>StereoTactic Radiotherapy for Wet Age-Related Macular Degeneration (STAR): A Randomised, Double-masked, Sham-controlled, Clinical Trial Comparing Low-voltage X-ray Irradiation With as Needed Ranibizumab, to as Needed Ranibizumab Monotherapy.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>King's College Hospital NHS Trust</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>King's College London</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>King's College Hospital NHS Trust</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study investigates the use of radiation to treat wet age-related macular degeneration&#xD;
      (AMD). The radiation is delivered using a robotically controlled device that projects&#xD;
      overlapping beams of radiation onto the macula, the part of the eye that is affected by wet&#xD;
      AMD. Participants will be randomized to receive radiation (stereotactic radiotherapy) or&#xD;
      simulated placebo treatment (sham control). They will be followed up regularly for two years,&#xD;
      and then again at the end of three and four years for a safety visit. Participants will also&#xD;
      receive injections of ranibizumab (Lucentis) into their eye if their wet AMD is active.&#xD;
      Ranibizumab is the standard anti-VEGF agent that is used to treat wet AMD. The study aims to&#xD;
      determine if stereotactic radiosurgery can maintain vision and reduce the need for such&#xD;
      regular anti-VEGF injections.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Age-related macular degeneration (AMD) leads more people to go blind than all other eye&#xD;
      diseases combined. 'Wet' AMD occurs when abnormal new blood vessels grow into the macula. The&#xD;
      macula is an area inside the back of the eye, which is tightly packed with the&#xD;
      light-sensitive cells that give fine central vision for driving, reading, facial recognition&#xD;
      etc. Most patients are treated with repeated injections of ranibizumab (Lucentis),&#xD;
      bevacizumab (Avastin) , or aflibercept (Eylea) into the eye (these drugs suppresses the new&#xD;
      vessel growth). Unsurprisingly, the need for hospital visits every 1-2 months, and regular&#xD;
      injections into the eye, is not favoured by patients.&#xD;
&#xD;
      The proposed study investigates the use of radiation to treat wet AMD. Radiation&#xD;
      preferentially damages proliferating cells, such as those forming the abnormal new blood&#xD;
      vessels. It has the potential to kill off the abnormal cells, unlike the injections which&#xD;
      just suppress the disease.&#xD;
&#xD;
      The radiation is delivered using a robotically controlled device that aims three beams of&#xD;
      radiation in through the white of eye, to overlap at the macula. Initial studies of&#xD;
      stereotactic radiotherapy (SRT) were promising, and established the best dose of radiation.&#xD;
      They showed that radiation has the potential to significantly reduce the need for injections.&#xD;
      Each injection costs the National Health Service (NHS) approximately £600, hence the&#xD;
      potential cost savings are substantial. For those who respond well, disease activity is&#xD;
      reduced, and injections can be eliminated or greatly reduced.&#xD;
&#xD;
      Eye charities have run focus groups of people with wet AMD to help set priorities, and&#xD;
      participants identified the burden of treating wet AMD as one of their most pressing&#xD;
      concerns, as it greatly restricts their freedom and quality of life. Repeated injections also&#xD;
      carry risks of rare but blinding complications, and long term they may possibly lead to other&#xD;
      eye diseases such as glaucoma and atrophy of the macula.&#xD;
&#xD;
      The preliminary SRT studies were not designed to determine if the visual outcome was the&#xD;
      same, better, or worse than standard injection therapy, and follow up was too short to&#xD;
      determine long term risks. A larger study is therefore required to confirm that SRT reduces&#xD;
      the number of injections and to determine if the visual outcomes are acceptable. There is&#xD;
      also a need for longer term safety monitoring, as radiation damage typically has a delayed&#xD;
      onset.&#xD;
&#xD;
      STAR will use ranibizumab as the anti-VEGF agent in both the treatment and control arms.&#xD;
      Ranibizumab was chosen over bevacizumab as it is licensed for use in the eye, and at present&#xD;
      bevacizumab is used in only a small minority of NHS hospitals, such that the results with&#xD;
      bevacizumab may be less generalisable. Bevacizumab may slow recruitment if prospective&#xD;
      participants are anxious about swapping to an off label treatment, and preliminary&#xD;
      discussions with prospective sites indicated some investigators would prefer to use&#xD;
      ranibizumab. Further, ranibizumab was used in the phase II INTREPID study (detailed below),&#xD;
      which helps inform the STAR statistical analysis. Aflibercept's mandated dosing in year 1&#xD;
      means it is not possible to determine if radiation reduces the need for anti-VEGF treatment,&#xD;
      the primary outcome measure.&#xD;
&#xD;
      Participants will be randomly allocated to dummy SRT (0 Gray dose) or live SRT (16 Gray).&#xD;
      Neither the treating doctor nor participant will know if a 0 or 16 Gray dose was given. SRT&#xD;
      will be performed in approximately 3 national treatment centres, but 25 NHS recruiting&#xD;
      hospitals will refer patients for SRT, and then review them afterwards, treating them with&#xD;
      ranibizumab as needed.&#xD;
&#xD;
      Participants will attend for examination monthly for two years. They will then revert to&#xD;
      standard NHS care, but with two further study visits - one at the end of year 3 and one at&#xD;
      the end of year 4. These two late safety visits are to exclude delayed radiation damage. At&#xD;
      the 24 monthly visits participants will have their vision tested on an eye chart, and a laser&#xD;
      scan (OCT) of their macula. If the vision drops or the OCT shows disease activity, then they&#xD;
      will receive an injection of ranibizumab. Participants will have imaging of the blood vessels&#xD;
      in the macula (angiography) at baseline and yearly thereafter for 4 years. The images will be&#xD;
      interpreted by an independent, specialist reading centre to quantify the effect of treatment,&#xD;
      to study the interaction of radiation and wet AMD, to look for subtle radiation damage, and&#xD;
      to subclassify disease to determine who responds best to SRT.&#xD;
&#xD;
      We predict that SRT will produce a similar, or possibly better vision than ranibizumab alone,&#xD;
      but with fewer injections. With 411 participants we will have 90% certainty that our results&#xD;
      are valid.&#xD;
&#xD;
      Participants will provide feedback using established questionnaires about how acceptable they&#xD;
      found SRT, their visual function, and their overall quality of life. Experienced health&#xD;
      economists will then look at the cost of treatment in relation to any improvement in quality&#xD;
      of life, to see if SRT is cost-effective.&#xD;
&#xD;
      The main outcomes we will monitor are the number of eye injections and visual function on an&#xD;
      eye chart, but several other observations will be made. In particular, we will monitor the&#xD;
      safety of treatment, any collateral damage caused by radiation, and the interactions between&#xD;
      radiation and diseased eye tissue.&#xD;
&#xD;
      If proven to be effective, SRT has the potential to save the NHS money, but more importantly,&#xD;
      it may reduce the burden of care faced by more than 250,000 people with wet AMD.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date>December 2014</start_date>
  <completion_date type="Anticipated">June 2024</completion_date>
  <primary_completion_date type="Actual">December 2021</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of as required (prn) ranibizumab injections during the first 24 months</measure>
    <time_frame>24 months</time_frame>
    <description>Monitor the number of eye injections</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Mean Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity (VA) at 24 months.</measure>
    <time_frame>24 months</time_frame>
    <description>Measure the visual function on an eye chart</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">411</enrollment>
  <condition>Neovascular (Wet) Age-related Macular Degeneration (AMD)</condition>
  <arm_group>
    <arm_group_label>Arm A (treatment)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will receive Stereotactic radiotherapy, a 16 Gy dose of radiation, delivered to the macula.&#xD;
Participants will receive intravitreal injections of 0.5 mg ranibizumab at baseline, and then administered 'as required' (PRN) up to monthly, if predefined retreatment criteria are met.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm B (control)</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>Participants will receive a sham treatment.&#xD;
Participants will receive intravitreal injections of 0.5 mg ranibizumab at baseline, and then administered 'as required' (PRN) up to monthly, if predefined retreatment criteria are met.</description>
  </arm_group>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Stereotactic radiotherapy (16 Gray or Sham)</intervention_name>
    <description>Participants will be allocated in a 2:1 ratio to either 16 Gray SRT (IRay, Oraya, Newark,USA) delivered in a single session, or sham SRT.</description>
    <arm_group_label>Arm A (treatment)</arm_group_label>
    <arm_group_label>Arm B (control)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>0.5 mg ranibizumab</intervention_name>
    <description>Both arms will receive intravitreal injections of 0.5 mg ranibizumab at baseline, and then administered 'as required' (PRN) up to monthly, if predefined retreatment criteria are met.</description>
    <arm_group_label>Arm A (treatment)</arm_group_label>
    <arm_group_label>Arm B (control)</arm_group_label>
    <other_name>Lucentis®</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria&#xD;
&#xD;
          1. Participants must have neovascular AMD in the study eye, for which they have received&#xD;
             at least 3 prior intravitreal injections of either bevacizumab (Avastin), aflibercept&#xD;
             (Eylea), ranibizumab (Lucentis), or pegaptanib (Macugen).&#xD;
&#xD;
          2. Participants must have received an anti-VEGF injection in the study eye within 3&#xD;
             months prior to enrolment.&#xD;
&#xD;
          3. Participants must require treatment with anti-VEGF therapy at the time of enrolment,&#xD;
             due to OCT evidence of subretinal fluid and/or cystoid macular oedema, and have a&#xD;
             macular volume that is greater than the 95th percentile of normal for the SD-OCT&#xD;
             machines used in the investigational sites.&#xD;
&#xD;
          4. Participants must be at least 50 years of age.&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
          1. Disciform scarring that involves the fovea, in the study eye.&#xD;
&#xD;
          2. Visual acuity worse than 6/96 (24 ETDRS letters) in the study eye.&#xD;
&#xD;
          3. Lesion size greater than 4 mm in greatest linear dimension, or greater than 2 mm from&#xD;
             the centre of the fovea to the furthest point on the lesion perimeter.&#xD;
&#xD;
          4. An axial length of less than 20 mm, or greater than 26 mm, in the study eye.&#xD;
&#xD;
          5. Contraindication or sensitivity to contact lens application, including recurrent&#xD;
             corneal erosions, in the study eye.&#xD;
&#xD;
          6. Type 1 or Type 2 diabetes mellitus.&#xD;
&#xD;
          7. Retinopathy in the study eye.&#xD;
&#xD;
          8. Prior or current therapies in the study eye for age-related macular degeneration,&#xD;
             other than anti-VEGF agents, including submacular surgery, subfoveal thermal laser&#xD;
             photocoagulation, photodynamic therapy (PDT), or transpupillary thermotherapy (TTT).&#xD;
&#xD;
          9. Presence of an intravitreal device in the study eye.&#xD;
&#xD;
         10. Previous radiation therapy to the study eye, head, or neck with the exception of&#xD;
             radio-iodine treatment for hyperthyroidism, epimacular brachytherapy to the non-study&#xD;
             eye, or Oraya SRT to the non-study eye.&#xD;
&#xD;
         11. Inadequate pupillary dilation or significant media opacities in the study eye,&#xD;
             including cataract, which may interfere with visual acuity testing, the clinical&#xD;
             evaluation of the posterior segment, or fundus imaging.&#xD;
&#xD;
         12. Study eyes with CNV due to causes other than AMD, including presumed ocular&#xD;
             histoplasmosis syndrome (POH), angioid streaks, multifocal choroiditis, choroidal&#xD;
             rupture, and pathological myopia (greater than 8 Dioptres spherical equivalent).&#xD;
             Participants with retinal angiomatous proliferation (RAP) or idiopathic polypoidal&#xD;
             choroidal vasculopathy (IPCV) are not excluded.&#xD;
&#xD;
         13. Known allergy to intravenous fluorescein, ICG or intravitreal ranibizumab.&#xD;
&#xD;
         14. Intraocular surgery or laser-assisted in situ keratomileusis (LASIK) in the study eye&#xD;
             within 12 weeks prior to enrolment.&#xD;
&#xD;
         15. Prior pars plana vitrectomy in the study eye.&#xD;
&#xD;
         16. Current participation in another interventional clinical trial, or participation in&#xD;
             such a clinical trial within the last six months.&#xD;
&#xD;
         17. Unwilling, unable, or unlikely to return for scheduled follow-up for the duration of&#xD;
             the trial.&#xD;
&#xD;
         18. Women who are pregnant at the time of radiotherapy.&#xD;
&#xD;
         19. Participants with an implantable cardioverter defibrillator (ICD) or pacemaker implant&#xD;
             (or any implanted device) where the device labelling specifically contraindicates&#xD;
             patients undergoing X-ray.&#xD;
&#xD;
         20. Any other condition, which in the judgment of the investigator, would prevent the&#xD;
             participant from granting informed consent or completing the study, such as dementia,&#xD;
             and mental illness (including generalized anxiety disorder and claustrophobia).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>50 Years</minimum_age>
    <maximum_age>110 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Timothy L Jackson, PhD FRCOphth</last_name>
    <role>Principal Investigator</role>
    <affiliation>King's College Hospital, London</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hinchingbrooke Hospital</name>
      <address>
        <city>Huntingdon</city>
        <state>Cambridgeshire</state>
        <zip>PE29 6NT</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Princess Alexandra Hospital</name>
      <address>
        <city>Harlow</city>
        <state>Essex</state>
        <zip>CM20 1QX</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Maidstone Hospital</name>
      <address>
        <city>Maidstone</city>
        <state>Kent</state>
        <zip>ME16 9QQ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ashford William Harvey Hospital</name>
      <address>
        <city>Willesborough</city>
        <state>Kent</state>
        <zip>TN24 0LZ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>James Paget University Hospital</name>
      <address>
        <city>Great Yarmouth</city>
        <state>Norfolk</state>
        <zip>NR31 6LA</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Hallamshire Hospital</name>
      <address>
        <city>Sheffield</city>
        <state>South Yorkshire</state>
        <zip>S10 2JF</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Frimley Park Hospital</name>
      <address>
        <city>Frimley</city>
        <state>Surrey</state>
        <zip>GU16 7UJ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stoke Mandeville Hospital</name>
      <address>
        <city>Aylesbury</city>
        <zip>HP21 8AL</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Heart Of England NHS Foundation Trust</name>
      <address>
        <city>Birmingham</city>
        <zip>B75 7RR</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Blackburn Hospital</name>
      <address>
        <city>Blackburn</city>
        <zip>BB2 3HH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sussex Eye Hospital</name>
      <address>
        <city>Brighton</city>
        <zip>BN2 5BE</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Bristol Eye Hospital</name>
      <address>
        <city>Bristol</city>
        <zip>BS1 2LX</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Addenbrooke's Hospital</name>
      <address>
        <city>Cambridge</city>
        <zip>CB2 0QQ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Essex County Hospital</name>
      <address>
        <city>Colchester</city>
        <zip>C03 3NB</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Leighton Hospital</name>
      <address>
        <city>Crewe</city>
        <zip>CW1 4QJ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Derby Hospital</name>
      <address>
        <city>Derby</city>
        <zip>DE22 3NE</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dorset County Hospital</name>
      <address>
        <city>Dorchester</city>
        <zip>DT1 2JY</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Calderdale Royal Hospital</name>
      <address>
        <city>Halifax</city>
        <zip>HX3 0PW</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Whipps Cross Hospital</name>
      <address>
        <city>Leytonstone</city>
        <zip>E11 1NR</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lincoln Country Hospital</name>
      <address>
        <city>Lincoln</city>
        <zip>LN2 5QY</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Central Middlesex Hospital</name>
      <address>
        <city>London</city>
        <zip>NW10 7NS</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>King's College Hospital NHS Foundation Trust</name>
      <address>
        <city>London</city>
        <zip>SE5 9RS</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Epsom and St. Helier Hospital</name>
      <address>
        <city>London</city>
        <zip>SM5 1AA</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Manchester Royal Eye Hospital</name>
      <address>
        <city>Manchester</city>
        <zip>M13 9WL</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Norfolk &amp; Norwich University Hospital</name>
      <address>
        <city>Norwich</city>
        <zip>NR47UY</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Queen's Hospital</name>
      <address>
        <city>Romford</city>
        <zip>RM7 0AG</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Salisbury District Hospital</name>
      <address>
        <city>Salisbury</city>
        <zip>SP2 8BJ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hillingdon Hospital</name>
      <address>
        <city>Uxbridge</city>
        <zip>UB8 3 NN</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>New Cross Hospital</name>
      <address>
        <city>Wolverhampton</city>
        <zip>WV10 0QP</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Yeovil District Hospital</name>
      <address>
        <city>Yeovil</city>
        <zip>BA21 4AT</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <link>
    <url>http://www.starstudy.org.uk</url>
    <description>Study Website</description>
  </link>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>September 8, 2014</study_first_submitted>
  <study_first_submitted_qc>September 17, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 18, 2014</study_first_posted>
  <last_update_submitted>July 3, 2023</last_update_submitted>
  <last_update_submitted_qc>July 3, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 5, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Macular Degeneration</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ranibizumab</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02243878
org study id: UKCRN ID 18040
secondary id: ISRCTN12884465
secondary id: EME-Project:12/66/22
nct id: NCT02243878
lead sponsor: 
collaborator: 
has dmc: Yes
This study investigates the use of radiation to treat wet age-related macular degeneration
      (AMD). The radiation is delivered using a robotically controlled device that projects
      overlapping beams of radiation onto the macula, the part of the eye that is affected by wet
      AMD. Participants will be randomized to receive radiation (stereotactic radiotherapy) or
      simulated placebo treatment (sham control). They will be followed up regularly for two years,
      and then again at the end of three and four years for a safety visit. Participants will also
      receive injections of ranibizumab (Lucentis) into their eye if their wet AMD is active.
      Ranibizumab is the standard anti-VEGF agent that is used to treat wet AMD. The study aims to
      determine if stereotactic radiosurgery can maintain vision and reduce the need for such
      regular anti-VEGF injections.
Age-related macular degeneration (AMD) leads more people to go blind than all other eye
      diseases combined. 'Wet' AMD occurs when abnormal new blood vessels grow into the macula. The
      macula is an area inside the back of the eye, which is tightly packed with the
      light-sensitive cells that give fine central vision for driving, reading, facial recognition
      etc. Most patients are treated with repeated injections of ranibizumab (Lucentis),
      bevacizumab (Avastin) , or aflibercept (Eylea) into the eye (these drugs suppresses the new
      vessel growth). Unsurprisingly, the need for hospital visits every 1-2 months, and regular
      injections into the eye, is not favoured by patients.

      The proposed study investigates the use of radiation to treat wet AMD. Radiation
      preferentially damages proliferating cells, such as those forming the abnormal new blood
      vessels. It has the potential to kill off the abnormal cells, unlike the injections which
      just suppress the disease.

      The radiation is delivered using a robotically controlled device that aims three beams of
      radiation in through the white of eye, to overlap at the macula. Initial studies of
      stereotactic radiotherapy (SRT) were promising, and established the best dose of radiation.
      They showed that radiation has the potential to significantly reduce the need for injections.
      Each injection costs the National Health Service (NHS) approximately £600, hence the
      potential cost savings are substantial. For those who respond well, disease activity is
      reduced, and injections can be eliminated or greatly reduced.

      Eye charities have run focus groups of people with wet AMD to help set priorities, and
      participants identified the burden of treating wet AMD as one of their most pressing
      concerns, as it greatly restricts their freedom and quality of life. Repeated injections also
      carry risks of rare but blinding complications, and long term they may possibly lead to other
      eye diseases such as glaucoma and atrophy of the macula.

      The preliminary SRT studies were not designed to determine if the visual outcome was the
      same, better, or worse than standard injection therapy, and follow up was too short to
      determine long term risks. A larger study is therefore required to confirm that SRT reduces
      the number of injections and to determine if the visual outcomes are acceptable. There is
      also a need for longer term safety monitoring, as radiation damage typically has a delayed
      onset.

      STAR will use ranibizumab as the anti-VEGF agent in both the treatment and control arms.
      Ranibizumab was chosen over bevacizumab as it is licensed for use in the eye, and at present
      bevacizumab is used in only a small minority of NHS hospitals, such that the results with
      bevacizumab may be less generalisable. Bevacizumab may slow recruitment if prospective
      participants are anxious about swapping to an off label treatment, and preliminary
      discussions with prospective sites indicated some investigators would prefer to use
      ranibizumab. Further, ranibizumab was used in the phase II INTREPID study (detailed below),
      which helps inform the STAR statistical analysis. Aflibercept's mandated dosing in year 1
      means it is not possible to determine if radiation reduces the need for anti-VEGF treatment,
      the primary outcome measure.

      Participants will be randomly allocated to dummy SRT (0 Gray dose) or live SRT (16 Gray).
      Neither the treating doctor nor participant will know if a 0 or 16 Gray dose was given. SRT
      will be performed in approximately 3 national treatment centres, but 25 NHS recruiting
      hospitals will refer patients for SRT, and then review them afterwards, treating them with
      ranibizumab as needed.

      Participants will attend for examination monthly for two years. They will then revert to
      standard NHS care, but with two further study visits - one at the end of year 3 and one at
      the end of year 4. These two late safety visits are to exclude delayed radiation damage. At
      the 24 monthly visits participants will have their vision tested on an eye chart, and a laser
      scan (OCT) of their macula. If the vision drops or the OCT shows disease activity, then they
      will receive an injection of ranibizumab. Participants will have imaging of the blood vessels
      in the macula (angiography) at baseline and yearly thereafter for 4 years. The images will be
      interpreted by an independent, specialist reading centre to quantify the effect of treatment,
      to study the interaction of radiation and wet AMD, to look for subtle radiation damage, and
      to subclassify disease to determine who responds best to SRT.

      We predict that SRT will produce a similar, or possibly better vision than ranibizumab alone,
      but with fewer injections. With 411 participants we will have 90% certainty that our results
      are valid.

      Participants will provide feedback using established questionnaires about how acceptable they
      found SRT, their visual function, and their overall quality of life. Experienced health
      economists will then look at the cost of treatment in relation to any improvement in quality
      of life, to see if SRT is cost-effective.

      The main outcomes we will monitor are the number of eye injections and visual function on an
      eye chart, but several other observations will be made. In particular, we will monitor the
      safety of treatment, any collateral damage caused by radiation, and the interactions between
      radiation and diseased eye tissue.

      If proven to be effective, SRT has the potential to save the NHS money, but more importantly,
      it may reduce the burden of care faced by more than 250,000 people with wet AMD.
allocation: Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Number of as required (prn) ranibizumab injections during the first 24 months
time frame: 24 months
description: Monitor the number of eye injections
measure: Mean Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity (VA) at 24 months.
time frame: 24 months
description: Measure the visual function on an eye chart
arm group label: Arm A (treatment)
arm group type: Experimental
description: Participants will receive Stereotactic radiotherapy, a 16 Gy dose of radiation, delivered to the macula.
Participants will receive intravitreal injections of 0.5 mg ranibizumab at baseline, and then administered 'as required' (PRN) up to monthly, if predefined retreatment criteria are met.
arm group label: Arm B (control)
arm group type: Sham Comparator
description: Participants will receive a sham treatment.
Participants will receive intravitreal injections of 0.5 mg ranibizumab at baseline, and then administered 'as required' (PRN) up to monthly, if predefined retreatment criteria are met.
intervention type: Radiation
intervention name: Stereotactic radiotherapy (16 Gray or Sham)
description: Participants will be allocated in a 2:1 ratio to either 16 Gray SRT (IRay, Oraya, Newark,USA) delivered in a single session, or sham SRT.
arm group label: Arm A (treatment)
arm group label: Arm B (control)
intervention type: Drug
intervention name: 0.5 mg ranibizumab
description: Both arms will receive intravitreal injections of 0.5 mg ranibizumab at baseline, and then administered 'as required' (PRN) up to monthly, if predefined retreatment criteria are met.
arm group label: Arm A (treatment)
arm group label: Arm B (control)
other name: Lucentis®
criteria: 
gender: All
minimum age: 50 Years
maximum age: 110 Years
healthy volunteers: No
last name: Timothy L Jackson, PhD FRCOphth
role: Principal Investigator
affiliation: King's College Hospital, London
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country: United Kingdom
url: http://www.starstudy.org.uk
description: Study Website
responsible party type: Sponsor
mesh term: Macular Degeneration
mesh term: Ranibizumab