<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/NCT03838679</url>
  </required_header>
  <id_info>
    <org_study_id>2019-02-0051</org_study_id>
    <nct_id>NCT03838679</nct_id>
  </id_info>
  <brief_title>Imaging of the Angiofibrotic Switch in Neovascular AMD</brief_title>
  <official_title>Multimodal Imaging of Subretinal Fibrosis in Neovascular AMD</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Medical University of Vienna</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Medical University of Vienna</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The content of this research project is to identify the angiofibrotic switch, the transition&#xD;
      from angiogenesis to fibrosis, in neovascular age-related macular degeneration (nAMD)&#xD;
      longitudinally. Despite optimal treatment about 50% of eyes with nAMD develop fibrosis within&#xD;
      2 years, causing irreversible damage to the retina and functional loss. Objective measurement&#xD;
      of fibrosis, however, is challenging, since clinical staging is subjective and current&#xD;
      imaging modalities such as color fundus photography (CFP), fluorescein angiography (FA) and&#xD;
      optical coherence tomography (OCT) often do not allow clear delineation. Novel imaging&#xD;
      modalities such as polarization-sensitive OCT (PS-OCT), OCT angiography (OCTA) and&#xD;
      adaptive-optics OCT (AO-OCT) offer identification of fibrous components and microvasculature&#xD;
      of fibrotic lesions non-invasively with highest precision and shall thus be used in this&#xD;
      study.&#xD;
&#xD;
      Hypotheses: The investigators hypothesize to detect and quantify subclinical (i.e. not&#xD;
      detectable on dilated fundus examination) areas of fibrosis using PS-OCT and determine the&#xD;
      rate and exact location within the neovascular lesion. Furthermore, the investigators expect&#xD;
      neuroretinal and microvascular changes, which will be assessed by AO-OCT and OCTA.&#xD;
&#xD;
      Methods: Eighty eyes of 80 patients with chronic nAMD will be included and examined cross-&#xD;
      sectionally to evaluate the accuracy of PS-OCT to detect and quantify fibrosis in comparison&#xD;
      to gold standard imaging modalities. In addition, OCTA and AO-OCT will be performed to&#xD;
      analyze the relationship between fibrous, neovascular and neuroretinal structures.&#xD;
      Furthermore, forty eyes of 40 participants with treatment-naïve nAMD will be included and&#xD;
      followed over 12 months with predefined follow-up intervals. Novel non-invasive imaging will&#xD;
      be applied to objectively determine the exact time and extent of the angiofibrotic switch in&#xD;
      nAMD during state-of-the- art therapy. This approach has not been done before and is&#xD;
      clinically relevant for multiple reasons: Firstly, only little is known about the development&#xD;
      of fibrosis in AMD during therapy. Secondly, the clinical diagnosis of subretinal fibrosis is&#xD;
      subjective and does not allow reliable quantification. Thirdly, current gold standard imaging&#xD;
      modalities (i.e. CFP and FA) for detection of fibrosis involve invasive and time-consuming&#xD;
      procedures and do not allow three-dimensional analysis. Finally, our study may identify&#xD;
      objective endpoints for future interventional trials.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Research questions/hypotheses: Age-related macular degeneration (AMD) is the main cause of&#xD;
      legal blindness among elderly patients in industrialized countries. The main reason for&#xD;
      severe and irreversible visual impairment among these patients is subretinal fibrosis (SF).&#xD;
      Large-scale interventional trials (e.g. CATT) have shown that half of all eyes affected by&#xD;
      choroidal neovascularization (CNV) develop clinically visible fibrotic scarring over two&#xD;
      years despite optimal treatment, causing irreversible retinal damage and functional loss.&#xD;
      Thus, prevention of fibrosis in AMD is currently the focus of researchers worldwide. Clearly&#xD;
      defined end points for interventional trials, however, are lacking because detection and&#xD;
      quantification of SF is challenging. Clinical staging of SF is subjective and current gold&#xD;
      standard imaging modalities such as color fundus photography (CFP), fluorescein angiography&#xD;
      (FA) and optical coherence tomography (OCT), even in concert, do not allow a distinct and&#xD;
      early delineation of SF. Novel imaging modalities such as polarization-sensitive OCT&#xD;
      (PS-OCT), OCT angiography (OCTA) and adaptive optics (AO)-OCT are promising means to&#xD;
      objectively detect SF and provide detailed insights into the biology of the microvascular and&#xD;
      neurosensory compartments. Our group recently demonstrated that PS-OCT offers automated&#xD;
      identification and quantification of SF in AMD based on tissue-specific contrast. Aim of the&#xD;
      proposed research project is to detect and characterize the angiofibrotic switch, i.e. the&#xD;
      transition from active and reversible neovascularization to irreversible fibrosis, in&#xD;
      neovascular AMD under anti-VEGF treatment. We hypothesize to detect the initiating events of&#xD;
      fibrotic conversion including even subclinical stages of fibrosis by non-invasive PS-OCT and&#xD;
      identify the association with fibrovascular and retinal changes by OCTA and AO-OCT,&#xD;
      respectively.&#xD;
&#xD;
      Scientific/scholarly innovation/originality of the project: The combination of PS-OCT, OCTA&#xD;
      and AO-OCTA to non-invasively detect pathognomonic features of fibrovascular conversion is a&#xD;
      novel and unprecedented approach towards objective visualization and quantification of&#xD;
      disease pathomechanisms. Outcomes of this study may provide clearly defined morphological&#xD;
      endpoints for future interventional trials.&#xD;
&#xD;
      Methods: Eighty eyes of 80 patients with chronic nAMD will be included and examined&#xD;
      cross-sectionally to evaluate the accuracy of PS-OCT to detect and quantify fibrosis in&#xD;
      comparison to gold standard imaging. In addition, OCTA and AO-OCT will be performed to&#xD;
      analyze the relationship between fibrous, vascular and retinal structures. Furthermore, forty&#xD;
      eyes of 40 participants with treatment-naïve nAMD will be included in a prospective study and&#xD;
      followed for one year under treatment. PS-OCT, AO-OCT and OCTA imaging will be performed&#xD;
      according to a standardized protocol at predefined visits. Gold standard imaging will be&#xD;
      performed for validation.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">May 1, 2019</start_date>
  <completion_date type="Anticipated">April 28, 2022</completion_date>
  <primary_completion_date type="Anticipated">April 28, 2022</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Detection of subretinal fibrosis by PS-OCT</measure>
    <time_frame>15 months</time_frame>
    <description>The primary objective is to determine how well the fibrosis present/not present classification of the novel PS-OCT imaging works compared to gold standard imaging techniques. To assess the primary objective, a 95% confidence interval for the proportion of correct fibrosis yes/no classifications by the novel PS-OCT imaging compared to the gold standard will be computed. To assess this objective, data from cohort 1 will be used.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Extension of fibrosis area quantified on PS-OCT and correlated to standard imaging modalities</measure>
    <time_frame>33 months</time_frame>
    <description>The secondary objective is to determine how well the fibrosis area detection of the novel PS-OCT imaging works compared to gold standard imaging techniques. To assess the secondary objective, a Bland-Altman plot will be drawn. Furthermore, a 95% confidence interval for the mean difference in detected area and the mean absolute difference in detected area will be computed. To assess this objective, two analysis sets will be used: Firstly, data from cohort 1 and baseline data of cohort 2, and secondly data from the 1 year follow-up examination of patients in cohort 2.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Correlation of fibrosis and co-localized vascular changes (comparison between OCTA and PS-OCT)</measure>
    <time_frame>36 months</time_frame>
    <description>In cohort 1 (eyes with a minimum history of 12 months of anti- VEGF), we will compare imaging data assessed by PS-OCT with image data from OCTA for morphological analyses. In cohort 2 the same analyses will be performed. Cohort 2 will provide detailed follow-up information about morphological changes over time. Outcome measures in eyes with and without fibrosis (vessel configuration in OCTA) will be compared using chi-square tests (categorical variables), t-tests (metric variables that can be assumed to be normally distributed) and Wilcoxon tests (metric variables that cannot be assumed to be normally distributed). ANOVA and paired t-tests will be used to investigate the longitudinal changes in cohort 2. P values &lt; 0.05 will be considered statistically significant. Due to the exploratory nature of these analyses, no correction for multiplicity will be used.</description>
  </other_outcome>
  <other_outcome>
    <measure>Correlation of fibrosis localization and co-localized retinal function (comparison between MP, PS-OCT, OCTA, OCT and AO-OCT)</measure>
    <time_frame>36 months</time_frame>
    <description>For a morphological-functional analysis areas of functional loss in microperimetry will be analyzed in detail using multimodal imaging (including PS-OCT, OCTA, OCT and AO-OCT) and relevant morphological changes associated with reduced retinal sensitivity will be assessed and described. In cohort 1 and cohort 2 the same analyses will be performed. Additionally, cohort 2 will provide detailed follow-up information about morphological and functional changes over time.</description>
  </other_outcome>
  <other_outcome>
    <measure>Correlation of morphology (fibrosis) and visual outcome (comparison between BCVA and PS-OCT, OCTA, AO-OCT, OCT)</measure>
    <time_frame>36 months</time_frame>
    <description>Descriptive analysis will be performed for patient demographics of both cohort 1 and cohort 2, as well as for morphological parameters and visual acuity (for metric variables mean, standard deviation, min, max, median and for categorical variables absolute and relative frequencies will be computed). Outcomes of BCVA testing in eyes with and without subretinal fibrosis will be analyzed cross-sectionally (cohort 1) and longitudinally (cohort 2).</description>
  </other_outcome>
  <other_outcome>
    <measure>Condition of the retinal pigment epithelium (RPE) assessed by PS-OCT in areas of fibrosis.</measure>
    <time_frame>36 months</time_frame>
    <description>Condition of the RPE assessed by PS-OCT will be graded as continuous, RPE porosity, focal RPE atrophy, RPE thickening or pigment migration in areas with and without fibrosis and described. RPE condition in eyes with and without subretinal fibrosis will be analyzed cross-sectionally (cohort 1) and longitudinally (cohort 2).</description>
  </other_outcome>
  <other_outcome>
    <measure>Correlation of fibrosis localization and co-localized photoreceptor status (comparison between AO-OCT and PS-OCT)</measure>
    <time_frame>36 months</time_frame>
    <description>Condition of the photoreceptor layer assessed by AO-OCT in areas with and without fibrosis (particularly areas at the border zone of subretinal fibrosis) will be assessed and described. RPE condition in eyes with and without subretinal fibrosis will be analyzed cross-sectionally (cohort 1) and longitudinally (cohort 2).</description>
  </other_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Anticipated">120</enrollment>
  <condition>Age-related Macular Degeneration</condition>
  <condition>Choroidal Neovascularization</condition>
  <arm_group>
    <arm_group_label>Cohort 1</arm_group_label>
    <description>80 participants with neovascular AMD and a minimum history of 12 months of anti- VEGF therapy will be included in cohort 1 and examined only once (1 study visit).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 2</arm_group_label>
    <description>40 participants with treatment-naive neovascular AMD receiving standardized anti- VEGF therapy will be included in cohort 2 and followed for 12 months (6 study visits).</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Best-corrected Visual acuity testing (BCVA)</intervention_name>
    <description>Best-corrected visual acuity (BCVA) will be measured using Early Treatment of Diabetic Retinopathy Study (ETDRS) charts at 4 meters and 1 meter, respectively.</description>
    <arm_group_label>Cohort 1</arm_group_label>
    <arm_group_label>Cohort 2</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Optical coherence tomography (OCT)</intervention_name>
    <description>Optical Coherence Tomography (OCT) is a non-invasive diagnostic technique that renders an in vivo cross sectional view of the retina.</description>
    <arm_group_label>Cohort 1</arm_group_label>
    <arm_group_label>Cohort 2</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Color fundus photography (CFP)</intervention_name>
    <description>Color fundus photography is a non-invasive, fast and reliable imaging method providing a true-to-life depiction of the ocular fundus.</description>
    <arm_group_label>Cohort 1</arm_group_label>
    <arm_group_label>Cohort 2</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Optical coherence tomography angiography (OCTA)</intervention_name>
    <description>OCTA, an extension of conventional OCT, offers noninvasive imaging of the retinal and choroidal vasculature.</description>
    <arm_group_label>Cohort 1</arm_group_label>
    <arm_group_label>Cohort 2</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Polarization-sensitive optical coherence tomography (PS-OCT)</intervention_name>
    <description>PS-OCT, a functional exten- sion of conventional OCT technology, enables differentiation of retinal layers based on their distinct interference with the polarization state of the probing light beam, as opposed to mere light intensity.</description>
    <arm_group_label>Cohort 1</arm_group_label>
    <arm_group_label>Cohort 2</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Microperimetry (MP)</intervention_name>
    <description>Microperimetry allows testing of retinal sensitivity at specific locations in the area of the fovea, parafovea or even more peipheral areas of the macula.</description>
    <arm_group_label>Cohort 1</arm_group_label>
    <arm_group_label>Cohort 2</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Adaptive-optics optical coherence tomography (AO-OCT)</intervention_name>
    <description>AO-OCT, an extension of conventional OCT, offers non-invasive imaging of the retina with improved lateral resolution of up to 2-3 μm.</description>
    <arm_group_label>Cohort 1</arm_group_label>
    <arm_group_label>Cohort 2</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Fluorescein angiography (FA)</intervention_name>
    <description>FA imaging is a standard imaging technique used for the diagnosis of vascular pathologies of the retina such as choroidal neovascularization.</description>
    <arm_group_label>Cohort 1</arm_group_label>
    <arm_group_label>Cohort 2</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        There will be two study cohorts in this trial:&#xD;
&#xD;
          1. 80 participants with neovascular AMD and a minimum history of 12 months of anti- VEGF&#xD;
             therapy will be included in cohort 1 and examined only once (1 study visit).&#xD;
&#xD;
          2. 40 participants with treatment-naive neovascular AMD receiving standardized anti- VEGF&#xD;
             therapy will be included in cohort 2 and followed for 12 months (6 study visits).&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Chronic neovascular AMD with anti-VEGF treatment of a minimum duration of 12 months&#xD;
             (cohort 1)&#xD;
&#xD;
          -  Treatment-naïve active neovascular AMD (cohort 2)&#xD;
&#xD;
          -  50 years of age or older&#xD;
&#xD;
          -  Visual acuity 20/25-20/320&#xD;
&#xD;
          -  At least one druse (&gt;63μm) in either eye or late AMD in the fellow eye&#xD;
&#xD;
          -  Fibrosis &lt;50% of total lesion area at baseline (cohort 2)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Previous treatment for CNV in the study eye (cohort 2)&#xD;
&#xD;
          -  Presence of other progressive retinal disease likely to affect visual acuity&#xD;
&#xD;
          -  Contraindications for treatment with anti-VEGF&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Dyslexia&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>50 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Philipp Roberts, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Medical University of Vienna</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Philipp Roberts, MD PhD</last_name>
    <phone>+4314040079400</phone>
    <email>philipp.roberts@meduniwien.ac.at</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Markus Schranz, MD</last_name>
    <phone>+4314040079400</phone>
    <email>markus.schranz@meduniwien.ac.at</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Medical University of Vienna</name>
      <address>
        <city>Vienna</city>
        <zip>1090</zip>
        <country>Austria</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Philipp Roberts, MD PhD</last_name>
      <phone>+4314040079400</phone>
      <email>philipp.roberts@meduniwien.ac.at</email>
    </contact>
    <contact_backup>
      <last_name>Markus Schranz, MD</last_name>
      <phone>+4314040079400</phone>
      <email>markus.schranz@meduniwien.ac.at</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Austria</country>
  </location_countries>
  <verification_date>February 2020</verification_date>
  <study_first_submitted>February 10, 2019</study_first_submitted>
  <study_first_submitted_qc>February 10, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 12, 2019</study_first_posted>
  <last_update_submitted>February 19, 2020</last_update_submitted>
  <last_update_submitted_qc>February 19, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">February 20, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Medical University of Vienna</investigator_affiliation>
    <investigator_full_name>Philipp Roberts</investigator_full_name>
    <investigator_title>Principal investigator</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Macular Degeneration</mesh_term>
    <mesh_term>Choroidal Neovascularization</mesh_term>
    <mesh_term>Neovascularization, Pathologic</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03838679
org study id: 2019-02-0051
nct id: NCT03838679
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The content of this research project is to identify the angiofibrotic switch, the transition
      from angiogenesis to fibrosis, in neovascular age-related macular degeneration (nAMD)
      longitudinally. Despite optimal treatment about 50% of eyes with nAMD develop fibrosis within
      2 years, causing irreversible damage to the retina and functional loss. Objective measurement
      of fibrosis, however, is challenging, since clinical staging is subjective and current
      imaging modalities such as color fundus photography (CFP), fluorescein angiography (FA) and
      optical coherence tomography (OCT) often do not allow clear delineation. Novel imaging
      modalities such as polarization-sensitive OCT (PS-OCT), OCT angiography (OCTA) and
      adaptive-optics OCT (AO-OCT) offer identification of fibrous components and microvasculature
      of fibrotic lesions non-invasively with highest precision and shall thus be used in this
      study.

      Hypotheses: The investigators hypothesize to detect and quantify subclinical (i.e. not
      detectable on dilated fundus examination) areas of fibrosis using PS-OCT and determine the
      rate and exact location within the neovascular lesion. Furthermore, the investigators expect
      neuroretinal and microvascular changes, which will be assessed by AO-OCT and OCTA.

      Methods: Eighty eyes of 80 patients with chronic nAMD will be included and examined cross-
      sectionally to evaluate the accuracy of PS-OCT to detect and quantify fibrosis in comparison
      to gold standard imaging modalities. In addition, OCTA and AO-OCT will be performed to
      analyze the relationship between fibrous, neovascular and neuroretinal structures.
      Furthermore, forty eyes of 40 participants with treatment-naïve nAMD will be included and
      followed over 12 months with predefined follow-up intervals. Novel non-invasive imaging will
      be applied to objectively determine the exact time and extent of the angiofibrotic switch in
      nAMD during state-of-the- art therapy. This approach has not been done before and is
      clinically relevant for multiple reasons: Firstly, only little is known about the development
      of fibrosis in AMD during therapy. Secondly, the clinical diagnosis of subretinal fibrosis is
      subjective and does not allow reliable quantification. Thirdly, current gold standard imaging
      modalities (i.e. CFP and FA) for detection of fibrosis involve invasive and time-consuming
      procedures and do not allow three-dimensional analysis. Finally, our study may identify
      objective endpoints for future interventional trials.
Research questions/hypotheses: Age-related macular degeneration (AMD) is the main cause of
      legal blindness among elderly patients in industrialized countries. The main reason for
      severe and irreversible visual impairment among these patients is subretinal fibrosis (SF).
      Large-scale interventional trials (e.g. CATT) have shown that half of all eyes affected by
      choroidal neovascularization (CNV) develop clinically visible fibrotic scarring over two
      years despite optimal treatment, causing irreversible retinal damage and functional loss.
      Thus, prevention of fibrosis in AMD is currently the focus of researchers worldwide. Clearly
      defined end points for interventional trials, however, are lacking because detection and
      quantification of SF is challenging. Clinical staging of SF is subjective and current gold
      standard imaging modalities such as color fundus photography (CFP), fluorescein angiography
      (FA) and optical coherence tomography (OCT), even in concert, do not allow a distinct and
      early delineation of SF. Novel imaging modalities such as polarization-sensitive OCT
      (PS-OCT), OCT angiography (OCTA) and adaptive optics (AO)-OCT are promising means to
      objectively detect SF and provide detailed insights into the biology of the microvascular and
      neurosensory compartments. Our group recently demonstrated that PS-OCT offers automated
      identification and quantification of SF in AMD based on tissue-specific contrast. Aim of the
      proposed research project is to detect and characterize the angiofibrotic switch, i.e. the
      transition from active and reversible neovascularization to irreversible fibrosis, in
      neovascular AMD under anti-VEGF treatment. We hypothesize to detect the initiating events of
      fibrotic conversion including even subclinical stages of fibrosis by non-invasive PS-OCT and
      identify the association with fibrovascular and retinal changes by OCTA and AO-OCT,
      respectively.

      Scientific/scholarly innovation/originality of the project: The combination of PS-OCT, OCTA
      and AO-OCTA to non-invasively detect pathognomonic features of fibrovascular conversion is a
      novel and unprecedented approach towards objective visualization and quantification of
      disease pathomechanisms. Outcomes of this study may provide clearly defined morphological
      endpoints for future interventional trials.

      Methods: Eighty eyes of 80 patients with chronic nAMD will be included and examined
      cross-sectionally to evaluate the accuracy of PS-OCT to detect and quantify fibrosis in
      comparison to gold standard imaging. In addition, OCTA and AO-OCT will be performed to
      analyze the relationship between fibrous, vascular and retinal structures. Furthermore, forty
      eyes of 40 participants with treatment-naïve nAMD will be included in a prospective study and
      followed for one year under treatment. PS-OCT, AO-OCT and OCTA imaging will be performed
      according to a standardized protocol at predefined visits. Gold standard imaging will be
      performed for validation.
observational model: Cohort
time perspective: Prospective
measure: Detection of subretinal fibrosis by PS-OCT
time frame: 15 months
description: The primary objective is to determine how well the fibrosis present/not present classification of the novel PS-OCT imaging works compared to gold standard imaging techniques. To assess the primary objective, a 95% confidence interval for the proportion of correct fibrosis yes/no classifications by the novel PS-OCT imaging compared to the gold standard will be computed. To assess this objective, data from cohort 1 will be used.
measure: Extension of fibrosis area quantified on PS-OCT and correlated to standard imaging modalities
time frame: 33 months
description: The secondary objective is to determine how well the fibrosis area detection of the novel PS-OCT imaging works compared to gold standard imaging techniques. To assess the secondary objective, a Bland-Altman plot will be drawn. Furthermore, a 95% confidence interval for the mean difference in detected area and the mean absolute difference in detected area will be computed. To assess this objective, two analysis sets will be used: Firstly, data from cohort 1 and baseline data of cohort 2, and secondly data from the 1 year follow-up examination of patients in cohort 2.
measure: Correlation of fibrosis and co-localized vascular changes (comparison between OCTA and PS-OCT)
time frame: 36 months
description: In cohort 1 (eyes with a minimum history of 12 months of anti- VEGF), we will compare imaging data assessed by PS-OCT with image data from OCTA for morphological analyses. In cohort 2 the same analyses will be performed. Cohort 2 will provide detailed follow-up information about morphological changes over time. Outcome measures in eyes with and without fibrosis (vessel configuration in OCTA) will be compared using chi-square tests (categorical variables), t-tests (metric variables that can be assumed to be normally distributed) and Wilcoxon tests (metric variables that cannot be assumed to be normally distributed). ANOVA and paired t-tests will be used to investigate the longitudinal changes in cohort 2. P values < 0.05 will be considered statistically significant. Due to the exploratory nature of these analyses, no correction for multiplicity will be used.
measure: Correlation of fibrosis localization and co-localized retinal function (comparison between MP, PS-OCT, OCTA, OCT and AO-OCT)
time frame: 36 months
description: For a morphological-functional analysis areas of functional loss in microperimetry will be analyzed in detail using multimodal imaging (including PS-OCT, OCTA, OCT and AO-OCT) and relevant morphological changes associated with reduced retinal sensitivity will be assessed and described. In cohort 1 and cohort 2 the same analyses will be performed. Additionally, cohort 2 will provide detailed follow-up information about morphological and functional changes over time.
measure: Correlation of morphology (fibrosis) and visual outcome (comparison between BCVA and PS-OCT, OCTA, AO-OCT, OCT)
time frame: 36 months
description: Descriptive analysis will be performed for patient demographics of both cohort 1 and cohort 2, as well as for morphological parameters and visual acuity (for metric variables mean, standard deviation, min, max, median and for categorical variables absolute and relative frequencies will be computed). Outcomes of BCVA testing in eyes with and without subretinal fibrosis will be analyzed cross-sectionally (cohort 1) and longitudinally (cohort 2).
measure: Condition of the retinal pigment epithelium (RPE) assessed by PS-OCT in areas of fibrosis.
time frame: 36 months
description: Condition of the RPE assessed by PS-OCT will be graded as continuous, RPE porosity, focal RPE atrophy, RPE thickening or pigment migration in areas with and without fibrosis and described. RPE condition in eyes with and without subretinal fibrosis will be analyzed cross-sectionally (cohort 1) and longitudinally (cohort 2).
measure: Correlation of fibrosis localization and co-localized photoreceptor status (comparison between AO-OCT and PS-OCT)
time frame: 36 months
description: Condition of the photoreceptor layer assessed by AO-OCT in areas with and without fibrosis (particularly areas at the border zone of subretinal fibrosis) will be assessed and described. RPE condition in eyes with and without subretinal fibrosis will be analyzed cross-sectionally (cohort 1) and longitudinally (cohort 2).
arm group label: Cohort 1
description: 80 participants with neovascular AMD and a minimum history of 12 months of anti- VEGF therapy will be included in cohort 1 and examined only once (1 study visit).
arm group label: Cohort 2
description: 40 participants with treatment-naive neovascular AMD receiving standardized anti- VEGF therapy will be included in cohort 2 and followed for 12 months (6 study visits).
intervention type: Diagnostic Test
intervention name: Best-corrected Visual acuity testing (BCVA)
description: Best-corrected visual acuity (BCVA) will be measured using Early Treatment of Diabetic Retinopathy Study (ETDRS) charts at 4 meters and 1 meter, respectively.
arm group label: Cohort 1
arm group label: Cohort 2
intervention type: Diagnostic Test
intervention name: Optical coherence tomography (OCT)
description: Optical Coherence Tomography (OCT) is a non-invasive diagnostic technique that renders an in vivo cross sectional view of the retina.
arm group label: Cohort 1
arm group label: Cohort 2
intervention type: Diagnostic Test
intervention name: Color fundus photography (CFP)
description: Color fundus photography is a non-invasive, fast and reliable imaging method providing a true-to-life depiction of the ocular fundus.
arm group label: Cohort 1
arm group label: Cohort 2
intervention type: Diagnostic Test
intervention name: Optical coherence tomography angiography (OCTA)
description: OCTA, an extension of conventional OCT, offers noninvasive imaging of the retinal and choroidal vasculature.
arm group label: Cohort 1
arm group label: Cohort 2
intervention type: Diagnostic Test
intervention name: Polarization-sensitive optical coherence tomography (PS-OCT)
description: PS-OCT, a functional exten- sion of conventional OCT technology, enables differentiation of retinal layers based on their distinct interference with the polarization state of the probing light beam, as opposed to mere light intensity.
arm group label: Cohort 1
arm group label: Cohort 2
intervention type: Diagnostic Test
intervention name: Microperimetry (MP)
description: Microperimetry allows testing of retinal sensitivity at specific locations in the area of the fovea, parafovea or even more peipheral areas of the macula.
arm group label: Cohort 1
arm group label: Cohort 2
intervention type: Diagnostic Test
intervention name: Adaptive-optics optical coherence tomography (AO-OCT)
description: AO-OCT, an extension of conventional OCT, offers non-invasive imaging of the retina with improved lateral resolution of up to 2-3 μm.
arm group label: Cohort 1
arm group label: Cohort 2
intervention type: Diagnostic Test
intervention name: Fluorescein angiography (FA)
description: FA imaging is a standard imaging technique used for the diagnosis of vascular pathologies of the retina such as choroidal neovascularization.
arm group label: Cohort 1
arm group label: Cohort 2
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 50 Years
maximum age: N/A
healthy volunteers: No
last name: Philipp Roberts, MD PhD
role: Principal Investigator
affiliation: Medical University of Vienna
last name: Philipp Roberts, MD PhD
phone: +4314040079400
email: philipp.roberts@meduniwien.ac.at
last name: Markus Schranz, MD
phone: +4314040079400
email: markus.schranz@meduniwien.ac.at
facility: 
status: Recruiting
contact: 
contact backup: 
country: Austria
responsible party type: Principal Investigator
investigator affiliation: Medical University of Vienna
investigator full name: Philipp Roberts
investigator title: Principal investigator
mesh term: Macular Degeneration
mesh term: Choroidal Neovascularization
mesh term: Neovascularization, Pathologic
sharing ipd: Undecided