xml: <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/NCT05976139</url>
    </required_header>
    <id_info>
      <org_study_id>Neu 01-23</org_study_id>
      <nct_id>NCT05976139</nct_id>
    </id_info>
    <brief_title>Micropulsed Laser in Patients With Macular Oedema in Retinal Dystrophies</brief_title>
    <official_title>Treatment of Macular Oedema in Patients With Hereditary Retinal Dystrophies by Applying the Micropulsed Subthreshold Laser</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Fondazione G.B. Bietti, IRCCS</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Fondazione G.B. Bietti, IRCCS</source>
    <oversight_info>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        The purpose of this study is to investigate whether subthreshold treatment with micropulsed&#xD;
        laser can be effective in resolving macular edema in patients with inherited retinal&#xD;
        dystrophy.&#xD;
  &#xD;
        Visits will be performed after 1, 3, 6, 9, 12, 18, and 24 months after treatment. Laser&#xD;
        treatment will be performed on the day of the first visit, and its repetition at subsequent&#xD;
        visits between months 3 and 12 will be evaluated.&#xD;
  &#xD;
        Evaluations of treatment effects will include:&#xD;
  &#xD;
          -  comprehensive ophthalmologic examination&#xD;
  &#xD;
          -  multifocal electroretinogram&#xD;
  &#xD;
          -  OCT examination&#xD;
  &#xD;
          -  OCT-angiography examination&#xD;
  &#xD;
          -  retinography&#xD;
  &#xD;
        Primary endpoint.&#xD;
  &#xD;
        - central retinal thickness, measured by OCT&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        BACKGROUND:&#xD;
  &#xD;
        Degenerative diseases of the visual system classified as rare and, in particular, those&#xD;
        affecting the retina (known as Inherited retinal dystrophies, IRDs) cause very severe&#xD;
        functional deficits. Their onset is in many cases particularly early with a consequent visual&#xD;
        impact of extreme severity. They constitute a heterogeneous group from a clinical point of&#xD;
        view, but in all of them the loss of photoreceptors causes progressive vision loss that can&#xD;
        result in complete blindness.&#xD;
  &#xD;
        These pathologies can be complicated by the presence of cataracts, epiretinal membrane and&#xD;
        macular oedema (10-50%), resulting in a worsening of visual acuity. While surgical treatment&#xD;
        is applicable for the first two complications, the treatment of macular oedema can make use&#xD;
        of several options. Oral or topical diuretics (Acetazolamide) are still the first therapeutic&#xD;
        approach and, if oedema persists despite treatment, intravitreal corticosteroid injection has&#xD;
        been used in various reports. The injection of anti-Vascular Endothelial Growth Factor (VEGF)&#xD;
        drugs and vitrectomy have also been proposed but with conflicting results. The use of topical&#xD;
        non-steroidal drugs has been studied and proven to be valuable, although inferior to diuretic&#xD;
        treatment in terms of visual recovery. The use of intravitreal corticosteroids is also not&#xD;
        without possible further complications such as ocular hypertension and early onset of&#xD;
        cataracts.&#xD;
  &#xD;
        Despite some improvement in retinal oedema by taking the above-mentioned diuretics, relapses&#xD;
        can be observed at the end of therapy, reason for taking longer periods (&gt;12 weeks) of&#xD;
        therapy. However, the same chronic continuation of diuretic therapy is not always desirable&#xD;
        considering its possible adverse events such as tingling sensation, malaise, altered taste&#xD;
        sensation and gastrointestinal disorders.&#xD;
  &#xD;
        RATIONALE:&#xD;
  &#xD;
        The application of the micropulsed subthreshold retinal laser to reduce retinal oedema in&#xD;
        various diseases (diabetic oedema, central serous chorioretinopathy, age-related macular&#xD;
        degeneration and retinal vein occlusion) has recently gained wide acceptance.&#xD;
  &#xD;
        Retinal threshold refers to the tendency of the laser to cause tissue bleaching resulting in&#xD;
        retinal cell death, the term sub-threshold implies that the laser uses such a small amount of&#xD;
        energy that it does not cause irreversible damage to retinal structures. The term&#xD;
        'micropulsed' derives from the fact that the laser does not use a continuous wave but has a&#xD;
        sub-100% duty cycle and the use of 'off' times is what distinguishes this type of laser from&#xD;
        conventional lasers and allows the tissue to cool down, preventing laser-induced retinal&#xD;
        damage.&#xD;
  &#xD;
        The main characteristics of this type of laser are therefore that it does not cause visible&#xD;
        retinal damage and that it has therapeutic effects.&#xD;
  &#xD;
        One theory of how this type of laser works is through the action of the molecular protective&#xD;
        mechanisms of the Heat Shock Protein (Hsp) family in the retina, including protein chaperone&#xD;
        activity, stabilisation of the cytoskeleton and prevention of apoptosis mainly through&#xD;
        inhibition of cytochrome C release through the phenomenon of 'resetting'. Another theory&#xD;
        hypothesized the activation of leucocyte recruitment or remodeling of the extracellular&#xD;
        matrix in the choroid and retina. Possible mechanisms of increased trophic factors (CNTF and&#xD;
        FGF-2)14 and up-regulation of other factors (MMP-2, MMP-3, TNFα and Nos2) are covered.&#xD;
  &#xD;
        TRIAL DESIGN:&#xD;
  &#xD;
        Prospective, interventional, single-centre, open-label study involving consecutive enrolment&#xD;
        (see sample size in section &quot;Statistics&quot;) of patients with macular oedema in retinal&#xD;
        dystrophies.&#xD;
  &#xD;
        Each patient referred to the Outpatient Clinical and Research Center of Neuro-ophthalmology&#xD;
        and Genetic and Rare Diseases with IRD and macular oedema treated for 3 months with diuretics&#xD;
        and draining food supplements and without improvement of macular oedema or increase of the&#xD;
        same (reduction of post-therapy CRT ≤20% compared to pre-therapy CRT) will be duly informed&#xD;
        about the therapeutic option of this study protocol. After verification of the criteria for&#xD;
        inclusion in the study and after signing of the informed consent, the patient will be&#xD;
        considered eligible for treatment with micropulsed laser by the physicians of the Clinical&#xD;
        and Research Center of Neuro-ophthalmology and Genetic and Rare Diseases and Medical Retina.&#xD;
        The patient enrolled in the study will be clinically analysed with the instrumentation&#xD;
        indicated below at regular intervals (screening/baseline, follow-up 1 [FU1] (1 month), FU2 (3&#xD;
        months), FU3 (6 months), FU4 (9 months), FU5 (12 months), FU6 (18 months) and FU7 (24&#xD;
        months).&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Recruiting</overall_status>
    <start_date type="Actual">September 6, 2023</start_date>
    <completion_date type="Anticipated">July 30, 2025</completion_date>
    <primary_completion_date type="Anticipated">July 30, 2025</primary_completion_date>
    <phase>N/A</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>N/A</allocation>
      <intervention_model>Sequential Assignment</intervention_model>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
      <masking_description>no masking</masking_description>
    </study_design_info>
    <primary_outcome>
      <measure>assessment of significative change in retinal oedema compared to baseline</measure>
      <time_frame>up to 24 months</time_frame>
      <description>assessment of central retinal thickness by macular SD-OCT</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>To study changes in visual acuity between before and after treatment</measure>
      <time_frame>up to 24 months</time_frame>
      <description>LogMAr visual acuity values</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>To study the retinal function in the macular area before and after treatment.</measure>
      <time_frame>up to 24 months</time_frame>
      <description>response amplitude density, measured in nV/dg2 and analysed using multifocal electroretinogram, assessing the amplitude in 5 concentric rings centred on the fovea.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>To study the retinal perfusion of the macular area by OCT-angiography before and after treatment.</measure>
      <time_frame>up to 24 months</time_frame>
      <description>vascular density (expressed as Retinal Vessel Density) before and after treatment, using OCT-angiography</description>
    </secondary_outcome>
    <number_of_arms>1</number_of_arms>
    <enrollment type="Anticipated">10</enrollment>
    <condition>Macular Edema</condition>
    <condition>Inherited Retinal Dystrophy</condition>
    <condition>Laser Retinopathy</condition>
    <arm_group>
      <arm_group_label>inherited retinal dystrophies with macular oedema</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Laser treatment will be performed in patients with macular edema in IRD (experimental arm) who:&#xD;
  underwent treatment with diuretics or nutritional drainage products for 3 months and subsequent 'wash-out' of one month 17,18 and had no reduction in macular oedema, in terms of central retinal thickness, of at least 20% compared with the initial assessment&#xD;
  they have had an intravitreal injection of anti-VEGF or steroids, and after 3 months there is no reduction in central retinal thickness (CRT) of at least 20% compared to the initial assessment&#xD;
  have after 3 months a thickness reduction &lt;10% compared to baseline assessment, following initial treatment with micropulsed laser, and may be candidates for repeating treatment;&#xD;
  are not eligible for diuretic therapy due to the presence of comorbidities.</description>
    </arm_group>
    <intervention>
      <intervention_type>Device</intervention_type>
      <intervention_name>subthreshold treatment with micropulsed laser</intervention_name>
      <description>The laser instrument used is the Q 577® Laser System, Iridex, wavelength 577 yellow. The standard pattern used is:&#xD;
  Power: 5% Duty Cycle&#xD;
  Power 250 mw&#xD;
  Pulse duration 200 ms&#xD;
  Spot size 100 micron&#xD;
  Pattern spacing 0.0 confluente, griglie 7x7</description>
      <arm_group_label>inherited retinal dystrophies with macular oedema</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Patients with inherited retinal disease&#xD;
  &#xD;
            -  Age between 18 and 80 years&#xD;
  &#xD;
            -  Conclusive molecular genetic study for IRD&#xD;
  &#xD;
            -  Male or female patient&#xD;
  &#xD;
            -  Presence of macular oedema assessed by sd-OCT with reduction ≤ 20% after 3 months of&#xD;
               diuretics or draining supplements or 4 months after last anti-VEGF or steroid&#xD;
               injection&#xD;
  &#xD;
            -  Phakic and pseudophakic patients&#xD;
  &#xD;
            -  Central Retinal thickness &gt; 320 microns in men and &gt; 305 microns in women&#xD;
  &#xD;
            -  Informed consent freely granted and acquired before the start of the study&#xD;
  &#xD;
            -  Participant has the ability to understand and willingness to follow study instructions&#xD;
               and is likely to complete all required visits and procedures.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Patients with cataract extraction prior to 6 months&#xD;
  &#xD;
            -  Patients with IOP ≥ 20 mmHg&#xD;
  &#xD;
            -  Patients with a clinical diagnosis of retinal dystrophy of unproven genetic origin&#xD;
  &#xD;
            -  Patients with diabetes&#xD;
  &#xD;
            -  Patients with central serous chorioretinosis, retinal vein occlusion, age-related&#xD;
               degeneration&#xD;
  &#xD;
            -  Patients with current or previous vitreo-retinal pathology or with indication for&#xD;
               vitreo-retinal surgical therapy (tractional oedema)&#xD;
  &#xD;
            -  Patients with a lack of target fixation at 32 cm&#xD;
  &#xD;
            -  Pregnant women&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>80 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Lucia Ziccardi, MD, PhD</last_name>
      <role>Principal Investigator</role>
      <affiliation>IRCCS Fondazione G.B. Bietti</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Lucia Ziccardi, MD, PhD</last_name>
      <phone>+390684009486</phone>
      <email>neuger@fondazionebietti.it</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Federica Petrocchi, Orthoptist</last_name>
      <phone>+390684009486</phone>
      <email>neuger@fondazionebietti.it</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>IRCSS Fondazione G:B:Bietti</name>
        <address>
          <city>Rome</city>
          <state>RM</state>
          <zip>00194</zip>
          <country>Italy</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Lucia Ziccardi, MD, PhD</last_name>
        <phone>+390684009486</phone>
        <email>neuger@fondazionebietti.it</email>
      </contact>
      <contact_backup>
        <last_name>Federica Petrocchi, Orthoptist</last_name>
        <phone>+390684009486</phone>
        <email>neuger@fondazionebietti.it</email>
      </contact_backup>
      <investigator>
        <last_name>Lucilla Barbano</last_name>
        <role>Sub-Investigator</role>
      </investigator>
      <investigator>
        <last_name>Mariacristina Parravano</last_name>
        <role>Principal Investigator</role>
      </investigator>
      <investigator>
        <last_name>Lucia Ziccardi</last_name>
        <role>Principal Investigator</role>
      </investigator>
    </location>
    <location_countries>
      <country>Italy</country>
    </location_countries>
    <link>
      <url>https://www.retinalphysician.com/issues/2017/october-2017/hereditary-retinal-degenerations-and-cystoid-macul</url>
      <description>Hereditary Retinal Degenerations and Cystoid Macular Edema</description>
    </link>
    <link>
      <url>https://pubmed.ncbi.nlm.nih.gov/26697211/</url>
      <description>Photothermal Stimulation with a Micropulse Laser</description>
    </link>
    <link>
      <url>https://www.ncbi.nlm.nih.gov/books/NBK564379/</url>
      <description>Retinal Distrophies</description>
    </link>
    <reference>
      <citation>Olivares-Gonzalez L, Velasco S, Campillo I, Rodrigo R. Retinal Inflammation, Cell Death and Inherited Retinal Dystrophies. Int J Mol Sci. 2021 Feb 20;22(4):2096. doi: 10.3390/ijms22042096.</citation>
      <PMID>33672611</PMID>
    </reference>
    <reference>
      <citation>Bakthavatchalam M, Lai FHP, Rong SS, Ng DS, Brelen ME. Treatment of cystoid macular edema secondary to retinitis pigmentosa: a systematic review. Surv Ophthalmol. 2018 May-Jun;63(3):329-339. doi: 10.1016/j.survophthal.2017.09.009. Epub 2017 Oct 5.</citation>
      <PMID>28987613</PMID>
    </reference>
    <reference>
      <citation>Hong Y, Li H, Sun Y, Ji Y. A Review of Complicated Cataract in Retinitis Pigmentosa: Pathogenesis and Cataract Surgery. J Ophthalmol. 2020 Dec 21;2020:6699103. doi: 10.1155/2020/6699103. eCollection 2020.</citation>
      <PMID>33489339</PMID>
    </reference>
    <reference>
      <citation>Ikeda Y, Yoshida N, Murakami Y, Nakatake S, Notomi S, Hisatomi T, Enaida H, Ishibashi T. Long-term Surgical Outcomes of Epiretinal Membrane in Patients with Retinitis Pigmentosa. Sci Rep. 2015 Aug 13;5:13078. doi: 10.1038/srep13078.</citation>
      <PMID>26268934</PMID>
    </reference>
    <reference>
      <citation>Sahel J, Bonnel S, Mrejen S, Paques M. Retinitis pigmentosa and other dystrophies. Dev Ophthalmol. 2010;47:160-167. doi: 10.1159/000320079. Epub 2010 Aug 10.</citation>
      <PMID>20703049</PMID>
    </reference>
    <reference>
      <citation>Lemos Reis RF, Moreira-Goncalves N, Estrela Silva SE, Brandao EM, Falcao-Reis FM. Comparison of topical dorzolamide and ketorolac treatment for cystoid macular edema in retinitis pigmentosa and Usher's syndrome. Ophthalmologica. 2015;233(1):43-50. doi: 10.1159/000368052. Epub 2014 Nov 26.</citation>
      <PMID>25428176</PMID>
    </reference>
    <reference>
      <citation>Orzalesi N, Pierrottet C, Porta A, Aschero M. Long-term treatment of retinitis pigmentosa with acetazolamide. A pilot study. Graefes Arch Clin Exp Ophthalmol. 1993 May;231(5):254-6. doi: 10.1007/BF00919100.</citation>
      <PMID>8319913</PMID>
    </reference>
    <reference>
      <citation>Moore SM, Chao DL. Application of subthreshold laser therapy in retinal diseases: a review. Expert Rev Ophthalmol. 2018;13(6):311-320. doi: 10.1080/17469899.2018.1555035. Epub 2018 Dec 11.</citation>
      <PMID>31692951</PMID>
    </reference>
    <reference>
      <citation>Franklin TB, Krueger-Naug AM, Clarke DB, Arrigo AP, Currie RW. The role of heat shock proteins Hsp70 and Hsp27 in cellular protection of the central nervous system. Int J Hyperthermia. 2005 Aug;21(5):379-92. doi: 10.1080/02656730500069955.</citation>
      <PMID>16048836</PMID>
    </reference>
    <reference>
      <citation>Caballero S, Kent DL, Sengupta N, Li Calzi S, Shaw L, Beli E, Moldovan L, Dominguez JM 2nd, Moorthy RS, Grant MB. Bone Marrow-Derived Cell Recruitment to the Neurosensory Retina and Retinal Pigment Epithelial Cell Layer Following Subthreshold Retinal Phototherapy. Invest Ophthalmol Vis Sci. 2017 Oct 1;58(12):5164-5176. doi: 10.1167/iovs.16-20736.</citation>
      <PMID>29049716</PMID>
    </reference>
    <reference>
      <citation>Chidlow G, Shibeeb O, Plunkett M, Casson RJ, Wood JP. Glial cell and inflammatory responses to retinal laser treatment: comparison of a conventional photocoagulator and a novel, 3-nanosecond pulse laser. Invest Ophthalmol Vis Sci. 2013 Mar 28;54(3):2319-32. doi: 10.1167/iovs.12-11204.</citation>
      <PMID>23439603</PMID>
    </reference>
    <reference>
      <citation>Flaxel C, Bradle J, Acott T, Samples JR. Retinal pigment epithelium produces matrix metalloproteinases after laser treatment. Retina. 2007 Jun;27(5):629-34. doi: 10.1097/01.iae.0000249561.02567.fd.</citation>
      <PMID>17558327</PMID>
    </reference>
    <reference>
      <citation>Chalam KV, Bressler SB, Edwards AR, Berger BB, Bressler NM, Glassman AR, Grover S, Gupta SK, Nielsen JS; Diabetic Retinopathy Clinical Research Network. Retinal thickness in people with diabetes and minimal or no diabetic retinopathy: Heidelberg Spectralis optical coherence tomography. Invest Ophthalmol Vis Sci. 2012 Dec 13;53(13):8154-61. doi: 10.1167/iovs.12-10290.</citation>
      <PMID>23132803</PMID>
    </reference>
    <reference>
      <citation>Elman MJ, Bressler NM, Qin H, Beck RW, Ferris FL 3rd, Friedman SM, Glassman AR, Scott IU, Stockdale CR, Sun JK; Diabetic Retinopathy Clinical Research Network. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2011 Apr;118(4):609-14. doi: 10.1016/j.ophtha.2010.12.033.</citation>
      <PMID>21459214</PMID>
    </reference>
    <reference>
      <citation>Marashi A, Zazo A. Hybrid threshold laser to treat diabetic macular edema: A retrospective analysis single center cohort study. Ann Med Surg (Lond). 2022 Jul 31;80:104222. doi: 10.1016/j.amsu.2022.104222. eCollection 2022 Aug.</citation>
      <PMID>36045820</PMID>
    </reference>
    <verification_date>July 2023</verification_date>
    <study_first_submitted>July 19, 2023</study_first_submitted>
    <study_first_submitted_qc>July 27, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 4, 2023</study_first_posted>
    <last_update_submitted>September 12, 2023</last_update_submitted>
    <last_update_submitted_qc>September 12, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 13, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Fondazione G.B. Bietti, IRCCS</investigator_affiliation>
      <investigator_full_name>lucia ziccardi</investigator_full_name>
      <investigator_title>Principal Investigator</investigator_title>
    </responsible_party>
    <keyword>Visual Acuity</keyword>
    <keyword>Retinal Function</keyword>
    <keyword>IRD</keyword>
    <keyword>Macular Edema</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Macular Edema</mesh_term>
      <mesh_term>Retinal Dystrophies</mesh_term>
      <mesh_term>Edema</mesh_term>
    </condition_browse>
    <patient_data>
      <sharing_ipd>Yes</sharing_ipd>
      <ipd_description>At the end of the research, within 6 months after the end of the study, a Final Clinical Report of the study containing clinical comments based on the data generated by the statistical processing will be prepared by the Investigator and/or delegated person. This report will be structured as an &amp;#34;integrated statistical clinical report&amp;#34; containing the clinical comments based on the data generated by the statistical report.</ipd_description>
      <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
      <ipd_time_frame>Six months after the end of the study</ipd_time_frame>
      <ipd_access_criteria>On demand</ipd_access_criteria>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT05976139
  org study id: Neu 01-23
  nct id: NCT05976139
  lead sponsor: 
  is fda regulated drug: No
  is fda regulated device: No
  The purpose of this study is to investigate whether subthreshold treatment with micropulsed
        laser can be effective in resolving macular edema in patients with inherited retinal
        dystrophy.
  
        Visits will be performed after 1, 3, 6, 9, 12, 18, and 24 months after treatment. Laser
        treatment will be performed on the day of the first visit, and its repetition at subsequent
        visits between months 3 and 12 will be evaluated.
  
        Evaluations of treatment effects will include:
  
          -  comprehensive ophthalmologic examination
  
          -  multifocal electroretinogram
  
          -  OCT examination
  
          -  OCT-angiography examination
  
          -  retinography
  
        Primary endpoint.
  
        - central retinal thickness, measured by OCT
  BACKGROUND:
  
        Degenerative diseases of the visual system classified as rare and, in particular, those
        affecting the retina (known as Inherited retinal dystrophies, IRDs) cause very severe
        functional deficits. Their onset is in many cases particularly early with a consequent visual
        impact of extreme severity. They constitute a heterogeneous group from a clinical point of
        view, but in all of them the loss of photoreceptors causes progressive vision loss that can
        result in complete blindness.
  
        These pathologies can be complicated by the presence of cataracts, epiretinal membrane and
        macular oedema (10-50%), resulting in a worsening of visual acuity. While surgical treatment
        is applicable for the first two complications, the treatment of macular oedema can make use
        of several options. Oral or topical diuretics (Acetazolamide) are still the first therapeutic
        approach and, if oedema persists despite treatment, intravitreal corticosteroid injection has
        been used in various reports. The injection of anti-Vascular Endothelial Growth Factor (VEGF)
        drugs and vitrectomy have also been proposed but with conflicting results. The use of topical
        non-steroidal drugs has been studied and proven to be valuable, although inferior to diuretic
        treatment in terms of visual recovery. The use of intravitreal corticosteroids is also not
        without possible further complications such as ocular hypertension and early onset of
        cataracts.
  
        Despite some improvement in retinal oedema by taking the above-mentioned diuretics, relapses
        can be observed at the end of therapy, reason for taking longer periods (>12 weeks) of
        therapy. However, the same chronic continuation of diuretic therapy is not always desirable
        considering its possible adverse events such as tingling sensation, malaise, altered taste
        sensation and gastrointestinal disorders.
  
        RATIONALE:
  
        The application of the micropulsed subthreshold retinal laser to reduce retinal oedema in
        various diseases (diabetic oedema, central serous chorioretinopathy, age-related macular
        degeneration and retinal vein occlusion) has recently gained wide acceptance.
  
        Retinal threshold refers to the tendency of the laser to cause tissue bleaching resulting in
        retinal cell death, the term sub-threshold implies that the laser uses such a small amount of
        energy that it does not cause irreversible damage to retinal structures. The term
        'micropulsed' derives from the fact that the laser does not use a continuous wave but has a
        sub-100% duty cycle and the use of 'off' times is what distinguishes this type of laser from
        conventional lasers and allows the tissue to cool down, preventing laser-induced retinal
        damage.
  
        The main characteristics of this type of laser are therefore that it does not cause visible
        retinal damage and that it has therapeutic effects.
  
        One theory of how this type of laser works is through the action of the molecular protective
        mechanisms of the Heat Shock Protein (Hsp) family in the retina, including protein chaperone
        activity, stabilisation of the cytoskeleton and prevention of apoptosis mainly through
        inhibition of cytochrome C release through the phenomenon of 'resetting'. Another theory
        hypothesized the activation of leucocyte recruitment or remodeling of the extracellular
        matrix in the choroid and retina. Possible mechanisms of increased trophic factors (CNTF and
        FGF-2)14 and up-regulation of other factors (MMP-2, MMP-3, TNFα and Nos2) are covered.
  
        TRIAL DESIGN:
  
        Prospective, interventional, single-centre, open-label study involving consecutive enrolment
        (see sample size in section "Statistics") of patients with macular oedema in retinal
        dystrophies.
  
        Each patient referred to the Outpatient Clinical and Research Center of Neuro-ophthalmology
        and Genetic and Rare Diseases with IRD and macular oedema treated for 3 months with diuretics
        and draining food supplements and without improvement of macular oedema or increase of the
        same (reduction of post-therapy CRT ≤20% compared to pre-therapy CRT) will be duly informed
        about the therapeutic option of this study protocol. After verification of the criteria for
        inclusion in the study and after signing of the informed consent, the patient will be
        considered eligible for treatment with micropulsed laser by the physicians of the Clinical
        and Research Center of Neuro-ophthalmology and Genetic and Rare Diseases and Medical Retina.
        The patient enrolled in the study will be clinically analysed with the instrumentation
        indicated below at regular intervals (screening/baseline, follow-up 1 [FU1] (1 month), FU2 (3
        months), FU3 (6 months), FU4 (9 months), FU5 (12 months), FU6 (18 months) and FU7 (24
        months).
  allocation: N/A
  intervention model: Sequential Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  masking description: no masking
  measure: assessment of significative change in retinal oedema compared to baseline
  time frame: up to 24 months
  description: assessment of central retinal thickness by macular SD-OCT
  measure: To study changes in visual acuity between before and after treatment
  time frame: up to 24 months
  description: LogMAr visual acuity values
  measure: To study the retinal function in the macular area before and after treatment.
  time frame: up to 24 months
  description: response amplitude density, measured in nV/dg2 and analysed using multifocal electroretinogram, assessing the amplitude in 5 concentric rings centred on the fovea.
  measure: To study the retinal perfusion of the macular area by OCT-angiography before and after treatment.
  time frame: up to 24 months
  description: vascular density (expressed as Retinal Vessel Density) before and after treatment, using OCT-angiography
  arm group label: inherited retinal dystrophies with macular oedema
  arm group type: Experimental
  description: Laser treatment will be performed in patients with macular edema in IRD (experimental arm) who:
  underwent treatment with diuretics or nutritional drainage products for 3 months and subsequent 'wash-out' of one month 17,18 and had no reduction in macular oedema, in terms of central retinal thickness, of at least 20% compared with the initial assessment
  they have had an intravitreal injection of anti-VEGF or steroids, and after 3 months there is no reduction in central retinal thickness (CRT) of at least 20% compared to the initial assessment
  have after 3 months a thickness reduction <10% compared to baseline assessment, following initial treatment with micropulsed laser, and may be candidates for repeating treatment;
  are not eligible for diuretic therapy due to the presence of comorbidities.
  intervention type: Device
  intervention name: subthreshold treatment with micropulsed laser
  description: The laser instrument used is the Q 577® Laser System, Iridex, wavelength 577 yellow. The standard pattern used is:
  Power: 5% Duty Cycle
  Power 250 mw
  Pulse duration 200 ms
  Spot size 100 micron
  Pattern spacing 0.0 confluente, griglie 7x7
  arm group label: inherited retinal dystrophies with macular oedema
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: 80 Years
  healthy volunteers: No
  last name: Lucia Ziccardi, MD, PhD
  role: Principal Investigator
  affiliation: IRCCS Fondazione G.B. Bietti
  last name: Lucia Ziccardi, MD, PhD
  phone: +390684009486
  email: neuger@fondazionebietti.it
  last name: Federica Petrocchi, Orthoptist
  phone: +390684009486
  email: neuger@fondazionebietti.it
  facility: 
  status: Recruiting
  contact: 
  contact backup: 
  investigator: 
  investigator: 
  investigator: 
  country: Italy
  url: https://www.retinalphysician.com/issues/2017/october-2017/hereditary-retinal-degenerations-and-cystoid-macul
  description: Hereditary Retinal Degenerations and Cystoid Macular Edema
  url: https://pubmed.ncbi.nlm.nih.gov/26697211/
  description: Photothermal Stimulation with a Micropulse Laser
  url: https://www.ncbi.nlm.nih.gov/books/NBK564379/
  description: Retinal Distrophies
  citation: Olivares-Gonzalez L, Velasco S, Campillo I, Rodrigo R. Retinal Inflammation, Cell Death and Inherited Retinal Dystrophies. Int J Mol Sci. 2021 Feb 20;22(4):2096. doi: 10.3390/ijms22042096.
  PMID: 33672611
  citation: Bakthavatchalam M, Lai FHP, Rong SS, Ng DS, Brelen ME. Treatment of cystoid macular edema secondary to retinitis pigmentosa: a systematic review. Surv Ophthalmol. 2018 May-Jun;63(3):329-339. doi: 10.1016/j.survophthal.2017.09.009. Epub 2017 Oct 5.
  PMID: 28987613
  citation: Hong Y, Li H, Sun Y, Ji Y. A Review of Complicated Cataract in Retinitis Pigmentosa: Pathogenesis and Cataract Surgery. J Ophthalmol. 2020 Dec 21;2020:6699103. doi: 10.1155/2020/6699103. eCollection 2020.
  PMID: 33489339
  citation: Ikeda Y, Yoshida N, Murakami Y, Nakatake S, Notomi S, Hisatomi T, Enaida H, Ishibashi T. Long-term Surgical Outcomes of Epiretinal Membrane in Patients with Retinitis Pigmentosa. Sci Rep. 2015 Aug 13;5:13078. doi: 10.1038/srep13078.
  PMID: 26268934
  citation: Sahel J, Bonnel S, Mrejen S, Paques M. Retinitis pigmentosa and other dystrophies. Dev Ophthalmol. 2010;47:160-167. doi: 10.1159/000320079. Epub 2010 Aug 10.
  PMID: 20703049
  citation: Lemos Reis RF, Moreira-Goncalves N, Estrela Silva SE, Brandao EM, Falcao-Reis FM. Comparison of topical dorzolamide and ketorolac treatment for cystoid macular edema in retinitis pigmentosa and Usher's syndrome. Ophthalmologica. 2015;233(1):43-50. doi: 10.1159/000368052. Epub 2014 Nov 26.
  PMID: 25428176
  citation: Orzalesi N, Pierrottet C, Porta A, Aschero M. Long-term treatment of retinitis pigmentosa with acetazolamide. A pilot study. Graefes Arch Clin Exp Ophthalmol. 1993 May;231(5):254-6. doi: 10.1007/BF00919100.
  PMID: 8319913
  citation: Moore SM, Chao DL. Application of subthreshold laser therapy in retinal diseases: a review. Expert Rev Ophthalmol. 2018;13(6):311-320. doi: 10.1080/17469899.2018.1555035. Epub 2018 Dec 11.
  PMID: 31692951
  citation: Franklin TB, Krueger-Naug AM, Clarke DB, Arrigo AP, Currie RW. The role of heat shock proteins Hsp70 and Hsp27 in cellular protection of the central nervous system. Int J Hyperthermia. 2005 Aug;21(5):379-92. doi: 10.1080/02656730500069955.
  PMID: 16048836
  citation: Caballero S, Kent DL, Sengupta N, Li Calzi S, Shaw L, Beli E, Moldovan L, Dominguez JM 2nd, Moorthy RS, Grant MB. Bone Marrow-Derived Cell Recruitment to the Neurosensory Retina and Retinal Pigment Epithelial Cell Layer Following Subthreshold Retinal Phototherapy. Invest Ophthalmol Vis Sci. 2017 Oct 1;58(12):5164-5176. doi: 10.1167/iovs.16-20736.
  PMID: 29049716
  citation: Chidlow G, Shibeeb O, Plunkett M, Casson RJ, Wood JP. Glial cell and inflammatory responses to retinal laser treatment: comparison of a conventional photocoagulator and a novel, 3-nanosecond pulse laser. Invest Ophthalmol Vis Sci. 2013 Mar 28;54(3):2319-32. doi: 10.1167/iovs.12-11204.
  PMID: 23439603
  citation: Flaxel C, Bradle J, Acott T, Samples JR. Retinal pigment epithelium produces matrix metalloproteinases after laser treatment. Retina. 2007 Jun;27(5):629-34. doi: 10.1097/01.iae.0000249561.02567.fd.
  PMID: 17558327
  citation: Chalam KV, Bressler SB, Edwards AR, Berger BB, Bressler NM, Glassman AR, Grover S, Gupta SK, Nielsen JS; Diabetic Retinopathy Clinical Research Network. Retinal thickness in people with diabetes and minimal or no diabetic retinopathy: Heidelberg Spectralis optical coherence tomography. Invest Ophthalmol Vis Sci. 2012 Dec 13;53(13):8154-61. doi: 10.1167/iovs.12-10290.
  PMID: 23132803
  citation: Elman MJ, Bressler NM, Qin H, Beck RW, Ferris FL 3rd, Friedman SM, Glassman AR, Scott IU, Stockdale CR, Sun JK; Diabetic Retinopathy Clinical Research Network. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2011 Apr;118(4):609-14. doi: 10.1016/j.ophtha.2010.12.033.
  PMID: 21459214
  citation: Marashi A, Zazo A. Hybrid threshold laser to treat diabetic macular edema: A retrospective analysis single center cohort study. Ann Med Surg (Lond). 2022 Jul 31;80:104222. doi: 10.1016/j.amsu.2022.104222. eCollection 2022 Aug.
  PMID: 36045820
  responsible party type: Principal Investigator
  investigator affiliation: Fondazione G.B. Bietti, IRCCS
  investigator full name: lucia ziccardi
  investigator title: Principal Investigator
  mesh term: Macular Edema
  mesh term: Retinal Dystrophies
  mesh term: Edema
  sharing ipd: Yes
  ipd description: At the end of the research, within 6 months after the end of the study, a Final Clinical Report of the study containing clinical comments based on the data generated by the statistical processing will be prepared by the Investigator and/or delegated person. This report will be structured as an &#34;integrated statistical clinical report&#34; containing the clinical comments based on the data generated by the statistical report.
  ipd info type: Clinical Study Report (CSR)
  ipd time frame: Six months after the end of the study
  ipd access criteria: On demand