<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/NCT04427956</url>
  </required_header>
  <id_info>
    <org_study_id>DNR2015/373</org_study_id>
    <nct_id>NCT04427956</nct_id>
  </id_info>
  <brief_title>Corneal Crosslinking Treatment Study</brief_title>
  <official_title>Prospective Randomised Corneal Crosslinking Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Region Skane</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Region Skane</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Three different protocols for inducing corneal crosslinks in subjets with progressive&#xD;
      keratoconus will be evaluated in this randomised clinical study.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Riboflavin does not penetrate the intact corneal epithelium. Corneal cross linking (CXL) is&#xD;
      typically performed using the so-called &quot;Dresden protocol&quot;. The Dresden protocol states 30&#xD;
      minutes of UVA-radiation (3mW/cm2) but a 10 minute irradiation protocol (9mW/cm2) is&#xD;
      frequently used. Both of the protocols involve mechanical removal of the epithelium over the&#xD;
      central 8 mm of the corneal surface. The first days after treatment therefore involves some&#xD;
      degree of pain, often intense, and the presence of a healing epithelial defect may be&#xD;
      associated with development of infiltrates in the cornea. A number of approaches have been&#xD;
      evaluated in order to promote riboflavin penetration through the intact epithelium, of which&#xD;
      iontophoresis appears most promising. Keratoconic corneas are thin at the cone location and&#xD;
      sometimes it is difficult to maintain the safety margin of 400 microns during corneal&#xD;
      crosslinking. Instead of using isotonic standard riboflavin, a swelling effect of the cornea&#xD;
      can be obtained by using hypotonic riboflavin. However, the latter has been indicated as less&#xD;
      effective in the process of inducing cross links.&#xD;
&#xD;
      Eighty-one of 81 patients of various degrees of keratoconus will be randomised to one of the&#xD;
      following groups: 1) CXL (UVA 9mW/cm2) using isotonic riboflavin, or 2) CXL (UVA 9mW/cm2)&#xD;
      using hypotonic riboflavin or 3) Iontophoresis with Ricrolin with following CXL (UVA&#xD;
      9mW/cm2).&#xD;
&#xD;
      Hypothesis:&#xD;
&#xD;
      i) CXL with hypotonic riboflavin or CXL with Ricrolin administered by iontophoresis or CXL&#xD;
      with isotonic riboflavin is non-inferior compared to standard CXL with isotonic riboflavin.&#xD;
&#xD;
      ii) The morphological structure post-CXL in the three different groups will be similar&#xD;
      without any significant differences.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">May 23, 2017</start_date>
  <completion_date type="Anticipated">December 2024</completion_date>
  <primary_completion_date type="Anticipated">December 2023</primary_completion_date>
  <phase>Phase 4</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>Prospective randomized interventional clinical trial</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Postoperative change in visual acuity</measure>
    <time_frame>Patients will be evaluated 1, 6, 12 and 24 months after treatment.</time_frame>
    <description>Uncorrected visual acuity (UCVA) and best spectacle corrected visual acuity (BSCVA)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Postoperative change in Kmax</measure>
    <time_frame>Patients will be evaluated 1, 6, 12 and 24 months after treatment.</time_frame>
    <description>Maximum corneal steepness</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Postoperative change in astigmatism</measure>
    <time_frame>Patients will be evaluated 1, 6, 12 and 24 months after treatment.</time_frame>
    <description>Corneal astigmatism</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>postoperative change in corneal nerve cell density</measure>
    <time_frame>Confocal microscopy will be performed at 6 and 12 months.</time_frame>
    <description>Corneal nerve cell density will be evaluated using confocal microscopy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Postoperative change in Keratocyte cell density</measure>
    <time_frame>Confocal microscopy will be performed at 6 and 12 months.</time_frame>
    <description>Keratocyte cell density will be evaluated using confocal microscopy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Postoperative change in endothelial cell count</measure>
    <time_frame>Confocal microscopy will be performed at 6 and 12 months.</time_frame>
    <description>Endothelial cell count will be evaluated using confocal microscopy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Postoperative change in demarcation lines</measure>
    <time_frame>Confocal microscopy will be performed at 6 and 12 months.</time_frame>
    <description>Identification of the demarcation lines with confocal microscopy will help establishing how deep was the effect of the CXL treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Postoperative change in the corneal thickness during CXL treatment</measure>
    <time_frame>Corneal pachymetry will be evaluated before and then every 5 minutes during 30 minutes under CXL treatment.</time_frame>
    <description>Corneal pachymetry is the process of measuring the thickness of the cornea</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">81</enrollment>
  <condition>Progressive Keratoconus</condition>
  <arm_group>
    <arm_group_label>Isotonic riboflavin</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>CXL (UVA 9mW/cm2) treatment using isotonic riboflavin</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Hypotonic riboflavin</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>CXL (UVA 9mW/cm2) using hypotonic riboflavin</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Iontophoresis</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Iontophoresis with Ricrolin with following CXL (UVA 9mW/cm2).</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Corneal crosslinking: CXL (UVA 9mW/cm2)</intervention_name>
    <description>CXL treatment with UVA-radiation (9mW/cm2) with a 10 minute irradiation protocol.</description>
    <arm_group_label>Hypotonic riboflavin</arm_group_label>
    <arm_group_label>Iontophoresis</arm_group_label>
    <arm_group_label>Isotonic riboflavin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Isotonic riboflavin</intervention_name>
    <description>CXL protocol with isotonic riboflavin</description>
    <arm_group_label>Isotonic riboflavin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Hypotonic riboflavin</intervention_name>
    <description>CXL protocol with hypotonic riboflavin</description>
    <arm_group_label>Hypotonic riboflavin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Iontophoresis</intervention_name>
    <description>CXL protocol with iontophoresis and ricrolin</description>
    <arm_group_label>Iontophoresis</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Progress in keratoconic eye. We define progress as an increase in Kmax of 1.0 diopter&#xD;
             in 1 year or 0.5 diopter in 6 months. This increase in Kmax will be accepted as&#xD;
             progression if concomitant changes tomographic parameters.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Concurrent ocular infection or corneal disease other than keratoconus.&#xD;
&#xD;
          -  Pregnancy.&#xD;
&#xD;
          -  Treatment with Isotretinoin.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ingemar Gustafsson, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Region Skåne</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Ingemar Gustafsson, M.D Ph.D</last_name>
    <phone>004640332548</phone>
    <email>ingemar.gustafsson@med.lu.se</email>
  </overall_contact>
  <location>
    <facility>
      <name>Skåne University Hospital</name>
      <address>
        <city>Lund</city>
        <state>Skåne</state>
        <zip>22242</zip>
        <country>Sweden</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ingemar Gustafsson, MD, PhD</last_name>
      <phone>004640332548</phone>
      <email>ingemar.gustafsson@med.lu.se</email>
    </contact>
  </location>
  <location_countries>
    <country>Sweden</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>June 3, 2020</study_first_submitted>
  <study_first_submitted_qc>June 9, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 11, 2020</study_first_posted>
  <last_update_submitted>May 24, 2023</last_update_submitted>
  <last_update_submitted_qc>May 24, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 26, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>corneal crosslinking</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Keratoconus</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Riboflavin</mesh_term>
  </intervention_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/NCT04427956
org study id: DNR2015/373
nct id: NCT04427956
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
Three different protocols for inducing corneal crosslinks in subjets with progressive
      keratoconus will be evaluated in this randomised clinical study.
Riboflavin does not penetrate the intact corneal epithelium. Corneal cross linking (CXL) is
      typically performed using the so-called "Dresden protocol". The Dresden protocol states 30
      minutes of UVA-radiation (3mW/cm2) but a 10 minute irradiation protocol (9mW/cm2) is
      frequently used. Both of the protocols involve mechanical removal of the epithelium over the
      central 8 mm of the corneal surface. The first days after treatment therefore involves some
      degree of pain, often intense, and the presence of a healing epithelial defect may be
      associated with development of infiltrates in the cornea. A number of approaches have been
      evaluated in order to promote riboflavin penetration through the intact epithelium, of which
      iontophoresis appears most promising. Keratoconic corneas are thin at the cone location and
      sometimes it is difficult to maintain the safety margin of 400 microns during corneal
      crosslinking. Instead of using isotonic standard riboflavin, a swelling effect of the cornea
      can be obtained by using hypotonic riboflavin. However, the latter has been indicated as less
      effective in the process of inducing cross links.

      Eighty-one of 81 patients of various degrees of keratoconus will be randomised to one of the
      following groups: 1) CXL (UVA 9mW/cm2) using isotonic riboflavin, or 2) CXL (UVA 9mW/cm2)
      using hypotonic riboflavin or 3) Iontophoresis with Ricrolin with following CXL (UVA
      9mW/cm2).

      Hypothesis:

      i) CXL with hypotonic riboflavin or CXL with Ricrolin administered by iontophoresis or CXL
      with isotonic riboflavin is non-inferior compared to standard CXL with isotonic riboflavin.

      ii) The morphological structure post-CXL in the three different groups will be similar
      without any significant differences.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Prospective randomized interventional clinical trial
primary purpose: Treatment
masking: None (Open Label)
measure: Postoperative change in visual acuity
time frame: Patients will be evaluated 1, 6, 12 and 24 months after treatment.
description: Uncorrected visual acuity (UCVA) and best spectacle corrected visual acuity (BSCVA)
measure: Postoperative change in Kmax
time frame: Patients will be evaluated 1, 6, 12 and 24 months after treatment.
description: Maximum corneal steepness
measure: Postoperative change in astigmatism
time frame: Patients will be evaluated 1, 6, 12 and 24 months after treatment.
description: Corneal astigmatism
measure: postoperative change in corneal nerve cell density
time frame: Confocal microscopy will be performed at 6 and 12 months.
description: Corneal nerve cell density will be evaluated using confocal microscopy
measure: Postoperative change in Keratocyte cell density
time frame: Confocal microscopy will be performed at 6 and 12 months.
description: Keratocyte cell density will be evaluated using confocal microscopy
measure: Postoperative change in endothelial cell count
time frame: Confocal microscopy will be performed at 6 and 12 months.
description: Endothelial cell count will be evaluated using confocal microscopy
measure: Postoperative change in demarcation lines
time frame: Confocal microscopy will be performed at 6 and 12 months.
description: Identification of the demarcation lines with confocal microscopy will help establishing how deep was the effect of the CXL treatment.
measure: Postoperative change in the corneal thickness during CXL treatment
time frame: Corneal pachymetry will be evaluated before and then every 5 minutes during 30 minutes under CXL treatment.
description: Corneal pachymetry is the process of measuring the thickness of the cornea
arm group label: Isotonic riboflavin
arm group type: Active Comparator
description: CXL (UVA 9mW/cm2) treatment using isotonic riboflavin
arm group label: Hypotonic riboflavin
arm group type: Active Comparator
description: CXL (UVA 9mW/cm2) using hypotonic riboflavin
arm group label: Iontophoresis
arm group type: Active Comparator
description: Iontophoresis with Ricrolin with following CXL (UVA 9mW/cm2).
intervention type: Procedure
intervention name: Corneal crosslinking: CXL (UVA 9mW/cm2)
description: CXL treatment with UVA-radiation (9mW/cm2) with a 10 minute irradiation protocol.
arm group label: Hypotonic riboflavin
arm group label: Iontophoresis
arm group label: Isotonic riboflavin
intervention type: Drug
intervention name: Isotonic riboflavin
description: CXL protocol with isotonic riboflavin
arm group label: Isotonic riboflavin
intervention type: Drug
intervention name: Hypotonic riboflavin
description: CXL protocol with hypotonic riboflavin
arm group label: Hypotonic riboflavin
intervention type: Procedure
intervention name: Iontophoresis
description: CXL protocol with iontophoresis and ricrolin
arm group label: Iontophoresis
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Ingemar Gustafsson, MD
role: Principal Investigator
affiliation: Region Skåne
last name: Ingemar Gustafsson, M.D Ph.D
phone: 004640332548
email: ingemar.gustafsson@med.lu.se
facility: 
status: Recruiting
contact: 
country: Sweden
responsible party type: Sponsor
mesh term: Keratoconus
mesh term: Riboflavin
sharing ipd: No