<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/NCT03763721</url>
  </required_header>
  <id_info>
    <org_study_id>NL64392.041.17</org_study_id>
    <nct_id>NCT03763721</nct_id>
  </id_info>
  <brief_title>The ADVISE Study: Advanced Visualization In Corneal Surgery Evaluation</brief_title>
  <acronym>ADVISE</acronym>
  <official_title>The ADVISE Study: Advanced Visualization In Corneal Surgery Evaluation Intra-operative Optical Coherence Tomography in Posterior Lamellar Keratoplasty</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>UMC Utrecht</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Maastricht University Medical Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Universitaire Ziekenhuizen KU Leuven</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Carl Zeiss Surgical GmbH</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>UMC Utrecht</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Rationale: Intra-operative optical coherence tomography (iOCT) is a new technology that&#xD;
      incorporates advanced imaging techniques in the ophthalmic operating theatre. This allows&#xD;
      surgeons to visualize tissues in a way previously impossible We conceptualized an iOCT-guided&#xD;
      surgical protocol for the treatment of endothelial cell dysfunction, that refrains from the&#xD;
      current practice of over-pressurizing the eye at the end of surgery.&#xD;
&#xD;
      Objective: The aim of this study is to assess the clinical value of intraoperative OCT (iOCT)&#xD;
      for Descemet Membrane Endothelial Keratoplasty (DMEK) by comparing an iOCT-optimized surgical&#xD;
      protocol with current practice, where the eye is over-pressurized for a set period of time,&#xD;
      in terms of surgical efficiency, clinical outcomes, and adverse events.&#xD;
&#xD;
      Study design: International multicentre non-inferiority randomized clinical trial Study&#xD;
      population: Patients scheduled for posterior lamellar corneal surgery for endothelial cell&#xD;
      dysfunction above the age of 18 years.&#xD;
&#xD;
      Intervention: Both groups will undergo Descemet Membrane Endothelial Keratoplasty. Patients&#xD;
      will be randomized for either the iOCT optimized surgical protocol or current standard&#xD;
      surgical protocol using 8 minutes of overpressure to facilitate graft adherence. Both groups&#xD;
      will be evaluated with iOCT at the end of surgery.&#xD;
&#xD;
      Main study parameters/endpoints:&#xD;
&#xD;
      The main study parameter is the rate of adverse events (particularly graft dislocations).&#xD;
      Secondary parameters/endpoints are surgical time, the recovery of visual acuity and&#xD;
      endothelial graft quality at 3 and 6 months follow-up, and a detailed evaluation of the&#xD;
      extent/duration of surgical tissue manipulations.&#xD;
&#xD;
      Nature and extent of the burden and risks associated with participation, benefit and group&#xD;
      relatedness: The use of iOCT during surgery does not entail additional risk to the patient.&#xD;
      Participants to this study will adhere to the standard of care after corneal transplant&#xD;
      surgery. In addition, they will receive study specific measurements and questionnaires. The&#xD;
      additional measurements and questionnaires will be combined with regular follow up moments.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 13, 2018</start_date>
  <completion_date type="Actual">September 1, 2022</completion_date>
  <primary_completion_date type="Actual">August 1, 2021</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>The design of the study is a prospective, international, multicenter, non-inferiority, randomized controlled interventional clinical trial to compare the outcomes after posterior lamellar surgery with an iOCT optimized surgical protocol, and current practice, where the eye is over-pressurized for a set period of time. These groups will be labelled iOCT optimized protocol (iOCT-p) and current practice protocol (CP-p). Eligible patients will be assigned to either one of the groups. The study will be conducted simultaneously at the University Medical Center Utrecht (UMCU), Maastricht University Medical Center (MUMC) and the University Hospitals Leuven (UZL, Belgium). The inclusion, preoperative and postoperative measurements and questionnaires will take place at the Ophthalmology department of the site were the surgery was conducted. The research activities will be coordinated by the UMCU.</intervention_model_description>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>Single (Participant)</masking>
    <masking_description>The patient will be blinded in the study, to prevent detection bias in filling out the questionnaires</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>rate of the most relevant post-operative surgical complications</measure>
    <time_frame>within 6 weeks post-operatively</time_frame>
    <description>the number of patients that develop adverse events relating to lamellar corneal surgery, specifically graft detachments that necessitate a surgical intervention, early graft failures that lead to intractable corneal edema, or induced iatrogenic acute glaucoma</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Surgical time</measure>
    <time_frame>during surgery</time_frame>
    <description>times are recorded at entry of the OR, start time of the surgery, actual first incision, timepoint for injection of gas, duration of gas, closing time and departure time of the OR. Out of these both skin-to-skin and overall time in surgery can be calculated (i.e. gross/net)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Best-corrected visual acuity</measure>
    <time_frame>3 and 6 months follow-up</time_frame>
    <description>Visual acuity is assessed using an ETDRS (Early Treatment Diabetic Retinopathy Study Chart) visual acuity chart with a spectacle correction. Visual acuity measurement ranges from light perception, hand movements, finger counting, 0.05 till 1.0. (US equivalent 20/20)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Graft endothelial cell densities</measure>
    <time_frame>3 and 6 months follow-up</time_frame>
    <description>The quality of the graft is based on the amount and viability of endothelial cells. These will be measured (number of cells/mm2, variation in size (variation coefficient), hexagonality-coefficient) with in vivo specular microscopy.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Surgical manipulations</measure>
    <time_frame>during surgery</time_frame>
    <description>the recorded videos will be reviewed and scored considering the amount of surgical manipulations, the duration of all steps of the procedure, and the use of iOCT. All according to a study specific standard operating procedure</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">65</enrollment>
  <condition>Fuchs Dystrophy</condition>
  <condition>Endothelial Corneal Dystrophy</condition>
  <condition>Bullous Keratopathy</condition>
  <condition>Vision Disorders</condition>
  <arm_group>
    <arm_group_label>iOCT optimized protocol (iOCT-p)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>In the iOCT optimized protocol (iOCT-p) group, graft apposition will be assessed with special detail for graft orientation, interface fluid, and any peripheral folds as described by Xu et al. Potential tissue manipulations will be therefore based on the iOCT image. Apposition of the graft will be obtained using a complete filling of the anterior chamber with 20% sulphur hexafluoride (SF6) endotamponade for 1-2 minutes, whilst the OCT image is assessed and any graft manipulation can be performed if deemed necessary. After this period, the gas is partly exchanged for BSS (Balanced Salt Solution, Alcon) to achieve a bubble with a diameter of approximately the same size of the graft (i.e. 8.5mm)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>current practice protocol (CP-p)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>In the current practice protocol (CP-p), graft apposition will be obtained using a complete and pressurized (approx. 65mmHg) filling of the anterior chamber with 20% SF6, for 8 minutes. Tissue manipulations, such as corneal swiping, will be performed as deemed necessary by the surgeon, based on the en face view from the conventional microscope image. The intraocular pressure is normalized by exchanging the SF6 gas for BSS, to achieve a gas bubble approximately the size of the graft (i.e 8.5mm). Now, the graft apposition is assessed using iOCT, to ensure all trial patients eventually undergo advanced iOCT imaging. Should this iOCT image reveal improper graft adherence or any other irregularity, the surgeon will perform additional manipulations or interventions as deemed necessary</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>intraoperative optical coherence tomography (iOCT)</intervention_name>
    <description>The OCT technology is fully integrated in a conventional ophthalmic surgical microscope (Zeiss LUMERA 700 platform). The OCT consists of A-scans (length/thickness) and B-scans (X-Y plane) to create the three dimensional image. Alternatively C-scans (3D cube scans) are available. All scans are non-invasive. The surgeon can continue surgery whilst using the iOCT and view a live image projected in the binocular or on the external screen and the video stream can be recorded as well.&#xD;
The iOCT features are controlled using the foot paddle and the images are recorded on device. Investigations will be performed in a standardized matter: iOCT imagery and cube-scans after graft insertion, air injection, and the end of surgery.</description>
    <arm_group_label>current practice protocol (CP-p)</arm_group_label>
    <arm_group_label>iOCT optimized protocol (iOCT-p)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥ 18 years&#xD;
&#xD;
          -  Irreversible corneal decompensation caused by Fuchs corneal endothelial dystrophy or&#xD;
             pseudophakic bullous keratopathy&#xD;
&#xD;
          -  Eligible for posterior lamellar keratoplasty, specifically Descemet Membrane&#xD;
             Endothelial Keratoplasty (DMEK)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any ocular co-morbidity other than cataract, mild dry eye disease, ocular&#xD;
             hypertension, simple primary open angle glaucoma, and mild age-related macular&#xD;
             degeneration&#xD;
&#xD;
          -  Prior corneal transplant surgery&#xD;
&#xD;
          -  Human leukocyte antigen (HLA) matched keratoplasty&#xD;
&#xD;
          -  Any disability that will interfere with performing or understanding the procedures and&#xD;
             questionnaire fulfilment except if it is temporary of nature.&#xD;
&#xD;
          -  Combined phaco-emulsification-DMEK surgery (triple procedure)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>100 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Universiteitsziekenhuis Leuven</name>
      <address>
        <city>Leuven</city>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Maastricht University Hospital</name>
      <address>
        <city>Maastricht</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Medical Center Utrecht</name>
      <address>
        <city>Utrecht</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Belgium</country>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>November 15, 2018</study_first_submitted>
  <study_first_submitted_qc>December 3, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 4, 2018</study_first_posted>
  <last_update_submitted>November 14, 2022</last_update_submitted>
  <last_update_submitted_qc>November 14, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 15, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>UMC Utrecht</investigator_affiliation>
    <investigator_full_name>Robert P.L. Wisse, MD PhD</investigator_full_name>
    <investigator_title>academic staff member</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vision Disorders</mesh_term>
    <mesh_term>Corneal Dystrophies, Hereditary</mesh_term>
    <mesh_term>Fuchs' Endothelial Dystrophy</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</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/NCT03763721
org study id: NL64392.041.17
nct id: NCT03763721
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
Rationale: Intra-operative optical coherence tomography (iOCT) is a new technology that
      incorporates advanced imaging techniques in the ophthalmic operating theatre. This allows
      surgeons to visualize tissues in a way previously impossible We conceptualized an iOCT-guided
      surgical protocol for the treatment of endothelial cell dysfunction, that refrains from the
      current practice of over-pressurizing the eye at the end of surgery.

      Objective: The aim of this study is to assess the clinical value of intraoperative OCT (iOCT)
      for Descemet Membrane Endothelial Keratoplasty (DMEK) by comparing an iOCT-optimized surgical
      protocol with current practice, where the eye is over-pressurized for a set period of time,
      in terms of surgical efficiency, clinical outcomes, and adverse events.

      Study design: International multicentre non-inferiority randomized clinical trial Study
      population: Patients scheduled for posterior lamellar corneal surgery for endothelial cell
      dysfunction above the age of 18 years.

      Intervention: Both groups will undergo Descemet Membrane Endothelial Keratoplasty. Patients
      will be randomized for either the iOCT optimized surgical protocol or current standard
      surgical protocol using 8 minutes of overpressure to facilitate graft adherence. Both groups
      will be evaluated with iOCT at the end of surgery.

      Main study parameters/endpoints:

      The main study parameter is the rate of adverse events (particularly graft dislocations).
      Secondary parameters/endpoints are surgical time, the recovery of visual acuity and
      endothelial graft quality at 3 and 6 months follow-up, and a detailed evaluation of the
      extent/duration of surgical tissue manipulations.

      Nature and extent of the burden and risks associated with participation, benefit and group
      relatedness: The use of iOCT during surgery does not entail additional risk to the patient.
      Participants to this study will adhere to the standard of care after corneal transplant
      surgery. In addition, they will receive study specific measurements and questionnaires. The
      additional measurements and questionnaires will be combined with regular follow up moments.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: The design of the study is a prospective, international, multicenter, non-inferiority, randomized controlled interventional clinical trial to compare the outcomes after posterior lamellar surgery with an iOCT optimized surgical protocol, and current practice, where the eye is over-pressurized for a set period of time. These groups will be labelled iOCT optimized protocol (iOCT-p) and current practice protocol (CP-p). Eligible patients will be assigned to either one of the groups. The study will be conducted simultaneously at the University Medical Center Utrecht (UMCU), Maastricht University Medical Center (MUMC) and the University Hospitals Leuven (UZL, Belgium). The inclusion, preoperative and postoperative measurements and questionnaires will take place at the Ophthalmology department of the site were the surgery was conducted. The research activities will be coordinated by the UMCU.
primary purpose: Diagnostic
masking: Single (Participant)
masking description: The patient will be blinded in the study, to prevent detection bias in filling out the questionnaires
measure: rate of the most relevant post-operative surgical complications
time frame: within 6 weeks post-operatively
description: the number of patients that develop adverse events relating to lamellar corneal surgery, specifically graft detachments that necessitate a surgical intervention, early graft failures that lead to intractable corneal edema, or induced iatrogenic acute glaucoma
measure: Surgical time
time frame: during surgery
description: times are recorded at entry of the OR, start time of the surgery, actual first incision, timepoint for injection of gas, duration of gas, closing time and departure time of the OR. Out of these both skin-to-skin and overall time in surgery can be calculated (i.e. gross/net)
measure: Best-corrected visual acuity
time frame: 3 and 6 months follow-up
description: Visual acuity is assessed using an ETDRS (Early Treatment Diabetic Retinopathy Study Chart) visual acuity chart with a spectacle correction. Visual acuity measurement ranges from light perception, hand movements, finger counting, 0.05 till 1.0. (US equivalent 20/20)
measure: Graft endothelial cell densities
time frame: 3 and 6 months follow-up
description: The quality of the graft is based on the amount and viability of endothelial cells. These will be measured (number of cells/mm2, variation in size (variation coefficient), hexagonality-coefficient) with in vivo specular microscopy.
measure: Surgical manipulations
time frame: during surgery
description: the recorded videos will be reviewed and scored considering the amount of surgical manipulations, the duration of all steps of the procedure, and the use of iOCT. All according to a study specific standard operating procedure
arm group label: iOCT optimized protocol (iOCT-p)
arm group type: Experimental
description: In the iOCT optimized protocol (iOCT-p) group, graft apposition will be assessed with special detail for graft orientation, interface fluid, and any peripheral folds as described by Xu et al. Potential tissue manipulations will be therefore based on the iOCT image. Apposition of the graft will be obtained using a complete filling of the anterior chamber with 20% sulphur hexafluoride (SF6) endotamponade for 1-2 minutes, whilst the OCT image is assessed and any graft manipulation can be performed if deemed necessary. After this period, the gas is partly exchanged for BSS (Balanced Salt Solution, Alcon) to achieve a bubble with a diameter of approximately the same size of the graft (i.e. 8.5mm)
arm group label: current practice protocol (CP-p)
arm group type: Active Comparator
description: In the current practice protocol (CP-p), graft apposition will be obtained using a complete and pressurized (approx. 65mmHg) filling of the anterior chamber with 20% SF6, for 8 minutes. Tissue manipulations, such as corneal swiping, will be performed as deemed necessary by the surgeon, based on the en face view from the conventional microscope image. The intraocular pressure is normalized by exchanging the SF6 gas for BSS, to achieve a gas bubble approximately the size of the graft (i.e 8.5mm). Now, the graft apposition is assessed using iOCT, to ensure all trial patients eventually undergo advanced iOCT imaging. Should this iOCT image reveal improper graft adherence or any other irregularity, the surgeon will perform additional manipulations or interventions as deemed necessary
intervention type: Device
intervention name: intraoperative optical coherence tomography (iOCT)
description: The OCT technology is fully integrated in a conventional ophthalmic surgical microscope (Zeiss LUMERA 700 platform). The OCT consists of A-scans (length/thickness) and B-scans (X-Y plane) to create the three dimensional image. Alternatively C-scans (3D cube scans) are available. All scans are non-invasive. The surgeon can continue surgery whilst using the iOCT and view a live image projected in the binocular or on the external screen and the video stream can be recorded as well.
The iOCT features are controlled using the foot paddle and the images are recorded on device. Investigations will be performed in a standardized matter: iOCT imagery and cube-scans after graft insertion, air injection, and the end of surgery.
arm group label: current practice protocol (CP-p)
arm group label: iOCT optimized protocol (iOCT-p)
criteria: 
gender: All
minimum age: 18 Years
maximum age: 100 Years
healthy volunteers: No
facility: 
facility: 
facility: 
country: Belgium
country: Netherlands
responsible party type: Principal Investigator
investigator affiliation: UMC Utrecht
investigator full name: Robert P.L. Wisse, MD PhD
investigator title: academic staff member
mesh term: Vision Disorders
mesh term: Corneal Dystrophies, Hereditary
mesh term: Fuchs' Endothelial Dystrophy
sharing ipd: No