<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/NCT03257813</url>
  </required_header>
  <id_info>
    <org_study_id>SOPH122-0914/III</org_study_id>
    <nct_id>NCT03257813</nct_id>
  </id_info>
  <brief_title>Non-inferiority of PRO-122 Ophthalmic Solution vs KRYTANTEK Ofteno® in Glaucoma or Ocular Hypertension (CONFORTK)</brief_title>
  <acronym>CONFORTK</acronym>
  <official_title>Clinical Study to Evaluate the Non-inferiority of PRO-122 an Ophthlamic Solution Manufactured by Laboratorios Sophia, Previous Treatment With Krytantek Ofteno ®, in Subjects With Primary Open-Angle Glaucoma or Ocular Hypertension.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Laboratorios Sophia S.A de C.V.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Laboratorios Sophia S.A de C.V.</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      Aim: To demonstrate the non-inferiority of the PRO-122 ophthalmic solution manufactured by&#xD;
      Laboratorios Sophia S.A. de C.V. versus Krytantek Ofteno® ophthalmic solution like&#xD;
      hypotensive therapy in subjects with primary open angle glaucoma or ocular hypertension.&#xD;
&#xD;
      Study design: a multicentric, prospective, crossover (2x2), double blind clinical study.&#xD;
      Sample size: one hundred patients with primary open angle glaucoma or ocular hypertension.&#xD;
      Patients in the period 1: In the first sequence 30 patients will be assigned to receive the&#xD;
      ophthalmic solution: Krytantek Ofteno ® (timolol 0.5%%/brimonidine 0.2%/dorzolamide 2%) 1&#xD;
      drop B.I.D. during 30 days and the second sequence 30 patients will be assigned to receive&#xD;
      the ophthalmic solution: PRO-122 1 drop B.I.D. during 30 days in the same period. Washout&#xD;
      period: 20 hours. Patients in the period 2: the pharmacological intervention change to the&#xD;
      opposite therapy for 30 days&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The American Academy of Ophthalmology Glaucoma Panel: The primary open angle glaucoma (POAG)&#xD;
      is a progressive, chronic optic neuropathy in adults in which intraocular pressure (IOP) and&#xD;
      other currently unknown factors contribute to damage and in which, in the absence of other&#xD;
      identifiable causes, there is a characteristic acquired atrophy of the optic nerve and loss&#xD;
      of retinal ganglion cells and their axons. This condition is associated with an anterior&#xD;
      chamber angle that is open by gonioscopic appearance.&#xD;
&#xD;
      This is a multicentric, crossover, double blind and prospective clinical study. The&#xD;
      investigators will include patients with confirmed diagnosis of primary open-angle glaucoma&#xD;
      or ocular hypertension, with target intraocular pressure (TIOP) within a range at which a&#xD;
      patient is likely to remain stable or at which worsening of glaucoma will be slow enough that&#xD;
      the risk of additional intervention is not justified.&#xD;
&#xD;
      Patients will be randomly divided into 2 groups, one of them treated with a known formulation&#xD;
      of timolol 0.5%/brimonidine 0.2%/dorzolamide 2% (Krytantek Ofteno®, Laboratorios Sophia,&#xD;
      Mexico) and the other one treated with PRO-122 ophthalmic solution. Patients will receive 1&#xD;
      drop B.I.D. into the lower conjunctival sac of either formulations and were examined at days:&#xD;
      1, 15, 30, 45 and 61 after initiation of treatment. A phone call security at day 75 will be&#xD;
      performed.&#xD;
&#xD;
      Primary efficacy outcome: To evaluate the efficacy of PRO-122 versus Krytantek Ofteno®&#xD;
      instilled onto the ocular surface in subjects with primary open angle glaucoma (POAG) or&#xD;
      ocular hypertension (HTO), to control and maintenance of the target intraocular pressure&#xD;
      (TIOP).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 1, 2016</start_date>
  <completion_date type="Actual">June 18, 2017</completion_date>
  <primary_completion_date type="Actual">March 1, 2017</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <intervention_model_description>60 subjects with diagnosis of open angle primary glaucoma with mild, moderate or severe damage and / or with intraocular hypertension users of Krytantek Ofteno® at least two previous months and are under control Of the corresponding IOP target.&#xD;
a study group A or B will be randomly assigned, in group A, therapy with Krytantek Ofteno® will be continued for 30 days, in which the subject will be evaluated again and switched from therapy to solution PRO-122 which will be used for 30 days until the 60th day, date of the final visit.&#xD;
In the case of those assigned to group B on day 1, the change to PRO-122 solution will be made for 30 continuous days until the date of revision on day 30, the day on which treatment with Krytantek Ofteno® will be restored to continue until the Day 60 for the final evaluation.&#xD;
The selected subjects will be observed for 60 days.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
    <masking_description>Masking will be carried out using identical boxes in the primary package in both groups.&#xD;
Blinding for the research subject and the investigator will be carried out by using labels containing the assignation number, which will replace the original labels in the case of the comparator. Due to the nature of the primary containers of the research products, single-dose vials and multidose bottle, it is not possible to use identical labels.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Intraocular Pressure (IOP)</measure>
    <time_frame>Change from Baseline intraocular pressure at day 30 and 60.</time_frame>
    <description>Intraocular pressure, Unit: Millimeters of mercury (mmHg) type of variable: Continuous, Measurement method: Goldman applanation tonometry. Normal intraocular pressure 11-21 mmHg.&#xD;
The change between the IOP of both groups was compared (sequence 1 versus sequence 2) of the data obtained at the end of each period (day 30 and day 60).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Visual Acuity (VA)</measure>
    <time_frame>Visual Acuity at Baseline (day 1) crossover visit (day 30) and final visit (day 60)</time_frame>
    <description>The VA will be evaluated basally, without refractive correction with the Snellen chart. A Snellen chart is placed at a standard distance: 20 ft. At this distance, the symbols on the line representing &quot;normal&quot; acuity subtend. This line, designated 20/20 is the smallest line that a person with normal acuity can read at a distance of 20fs. the scale consists of 11 lines of letters of different size, the size of the letter gives a fractional value according to the visual acuity of the patient, the value is inversely proportional to the visual acuity, if the denominator is greater the visual acuity will be less.&#xD;
Line 1: 20/200 Line 2: 20/100, Line 3: 20/70, line 4: 20/50, line 5: 20/40, Line 6: 20/30, line 7: 20/25, Line 8: 20/20, line 9: 20/15, line 10: 20/13, line 11: 20/10. the differences between groups in the basal, cross over and final visit will be evaluated.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Adverse Events</measure>
    <time_frame>75 days, includes the security call</time_frame>
    <description>The presence of adverse events by percentage between groups will be evaluated. the scale is present or absent.</description>
  </other_outcome>
  <other_outcome>
    <measure>Conjunctival Hyperemia</measure>
    <time_frame>Baseline (day 1) crossover visit (day 30) and final visit (day 60)</time_frame>
    <description>the conjunctival hyperemia will be evaluated by the presence or absence of it and the percentage of affected by group will be reported.</description>
  </other_outcome>
  <other_outcome>
    <measure>Chemosis</measure>
    <time_frame>Baseline (day 1) crossover visit (day 30) and final visit (day 60)</time_frame>
    <description>Chemosis: qualitative ordinal variable, will be evaluated by the presence or absence of it and the percentage of affected by group will be reported.</description>
  </other_outcome>
  <other_outcome>
    <measure>Eye Burning</measure>
    <time_frame>Baseline (day 1) crossover visit (day 30) and final visit (day 60)</time_frame>
    <description>Eye ocular burning will be evaluated by the presence or absence of it and the number of affected by group will be reported.</description>
  </other_outcome>
  <other_outcome>
    <measure>Number of Eyes With Tearing</measure>
    <time_frame>Baseline (day 1) crossover visit (day 30) and final visit (day 60)</time_frame>
    <description>Tearing will be evaluated by the presence or absence of it and the number of affected by group will be reported</description>
  </other_outcome>
  <other_outcome>
    <measure>Number of Eyes With Foreign Body Sensation</measure>
    <time_frame>Baseline (day 1) crossover visit (day 30) and final visit (day 60)</time_frame>
    <description>Foreign body sensation will be evaluated by the presence or absence of it and the number of affected by group will be reported.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">60</enrollment>
  <condition>Primary Open Angle Glaucoma</condition>
  <condition>Ocular Hypertension</condition>
  <arm_group>
    <arm_group_label>Group A</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>In group A, therapy with Krytantek Ofteno® will be continued for 30 days, in which the subject will be retested and switched to a PRO-122 solution which will be used for 30 days until the 60th day, The final visit.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group B</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>In group B, therapy with Krytantek Ofteno® will be suspended and changes for PRO-122 for 30 days, in which the subject will be retested and later switched to Krytantek Ofteno® solution which will be used for 30 days until the 60th day, The final visit.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>PRO-122</intervention_name>
    <description>1 drop every 12 hours for 30 days of alternating treatment with 30 days</description>
    <arm_group_label>Group A</arm_group_label>
    <arm_group_label>Group B</arm_group_label>
    <other_name>timolol, dorzolamide, brimonidine</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Krytantek Ofteno®</intervention_name>
    <description>1 drop every 12 hours for 30 days of alternating treatment with 30 days</description>
    <arm_group_label>Group A</arm_group_label>
    <arm_group_label>Group B</arm_group_label>
    <other_name>timolol, dorzolamide, brimonidine</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  18 years of age or older&#xD;
&#xD;
          -  male or female.&#xD;
&#xD;
          -  obtained in the external consultation.&#xD;
&#xD;
          -  With diagnosis primary of open-angle glaucoma and / or hypertension classified as&#xD;
             mild, moderate or severe glaucomatous damage, users of Krytantek Ofteno® at least two&#xD;
             months prior to inclusion and under control of the target IOP.&#xD;
&#xD;
          -  informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        General Criteria&#xD;
&#xD;
          1. Subjects with topical or systemic medication that interferes decisively in the results&#xD;
             of the study. (Such as topical immunomodulators, lacrimal point tamponade,&#xD;
             corticosteroids, ocular hypotensives other than those listed above, artificial tears&#xD;
             with preservative).&#xD;
&#xD;
          2. Subjects (female) with an active sex life who are not using a contraceptive method.&#xD;
&#xD;
          3. Female Subjects in pregnancy or breastfeeding.&#xD;
&#xD;
          4. Female subjects with positive urine pregnancy test.&#xD;
&#xD;
          5. Positive drug addiction (verbal interrogation).&#xD;
&#xD;
          6. Subjects who have participated in any clinical research study in the last 40 days.&#xD;
&#xD;
          7. Legally or mentally disabled subjects to give informed consent for their participation&#xD;
             in this study.&#xD;
&#xD;
          8. Subjects who can not comply with the appointments or with all the requirements of the&#xD;
             protocol.&#xD;
&#xD;
        Ophthalmologic criteria&#xD;
&#xD;
          1. Subject with only one eye with vision.&#xD;
&#xD;
          2. Subjects with visual capacity 20/200 or worse.&#xD;
&#xD;
          3. Subjects with a narrow-angle history without treatment, with or without total or&#xD;
             partial closure of the angle in either eye.&#xD;
&#xD;
          4. Subjects with corneal abnormalities that prevent applanation tonometry.&#xD;
&#xD;
          5. Subjects with ocular surgery or ocular trauma 6 months prior to inclusion.&#xD;
&#xD;
          6. Any ocular laser surgery 3 months prior.&#xD;
&#xD;
          7. Any uncontrolled or progressive retinal disease.&#xD;
&#xD;
          8. Inflammatory diseases of any kind.&#xD;
&#xD;
          9. Contact lens wearers.&#xD;
&#xD;
         10. Subjects with a history of hypersensitivity to any of the ingredients of the research&#xD;
             product or its analogues.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <verification_date>November 2019</verification_date>
  <study_first_submitted>August 1, 2017</study_first_submitted>
  <study_first_submitted_qc>August 18, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 22, 2017</study_first_posted>
  <results_first_submitted>February 1, 2018</results_first_submitted>
  <results_first_submitted_qc>November 20, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">December 9, 2019</results_first_posted>
  <last_update_submitted>November 20, 2019</last_update_submitted>
  <last_update_submitted_qc>November 20, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">December 9, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>timolol</keyword>
  <keyword>dorzolamide</keyword>
  <keyword>brimonidine</keyword>
  <keyword>Glaucoma</keyword>
  <keyword>Ocular hypertension</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glaucoma</mesh_term>
    <mesh_term>Glaucoma, Open-Angle</mesh_term>
    <mesh_term>Ocular Hypertension</mesh_term>
    <mesh_term>Hypertension</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Timolol</mesh_term>
    <mesh_term>Brimonidine Tartrate</mesh_term>
    <mesh_term>Dorzolamide</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Confidentiality Policy</ipd_description>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>March 1, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/13/NCT03257813/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Group A</title>
          <description>In group A, therapy with Krytantek Ofteno® will be continued for 30 days, in which the subject will be retested and switched to a PRO-122 solution which will be used for 30 days until the 60th day, The final visit.&#xD;
PRO-122: 1 drop every 12 hours for 30 days of alternating treatment with 30 days&#xD;
Krytantek Ofteno®: 1 drop every 12 hours for 30 days of alternating treatment with 30 days</description>
        </group>
        <group group_id="P2">
          <title>Group B</title>
          <description>In group B, therapy with Krytantek Ofteno® will be suspended and changes for PRO-122 for 30 days, in which the subject will be retested and later switched to Krytantek Ofteno® solution which will be used for 30 days until the 60th day, The final visit.&#xD;
PRO-122: 1 drop every 12 hours for 30 days of alternating treatment with 30 days&#xD;
Krytantek Ofteno®: 1 drop every 12 hours for 30 days of alternating treatment with 30 days</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="30"/>
                <participants group_id="P2" count="30"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="24"/>
                <participants group_id="P2" count="27"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Group A</title>
          <description>In group A, therapy with Krytantek Ofteno® will be continued for 30 days, in which the subject will be retested and switched to a PRO-122 solution which will be used for 30 days until the 60th day, The final visit.&#xD;
PRO-122: 1 drop every 12 hours for 30 days of alternating treatment with 30 days&#xD;
Krytantek Ofteno®: 1 drop every 12 hours for 30 days of alternating treatment with 30 days</description>
        </group>
        <group group_id="B2">
          <title>Group B</title>
          <description>In group B, therapy with Krytantek Ofteno® will be suspended and changes for PRO-122 for 30 days, in which the subject will be retested and later switched to Krytantek Ofteno® solution which will be used for 30 days until the 60th day, The final visit.&#xD;
PRO-122: 1 drop every 12 hours for 30 days of alternating treatment with 30 days&#xD;
Krytantek Ofteno®: 1 drop every 12 hours for 30 days of alternating treatment with 30 days</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="30"/>
            <count group_id="B2" value="30"/>
            <count group_id="B3" value="60"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="68.43" spread="8.86"/>
                    <measurement group_id="B2" value="64.37" spread="12.84"/>
                    <measurement group_id="B3" value="66.44" spread="11.17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="24"/>
                    <measurement group_id="B2" value="21"/>
                    <measurement group_id="B3" value="45"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>hispanic</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="30"/>
                    <measurement group_id="B2" value="30"/>
                    <measurement group_id="B3" value="60"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Intraocular Pressure (IOP)</title>
        <description>Intraocular pressure, Unit: Millimeters of mercury (mmHg) type of variable: Continuous, Measurement method: Goldman applanation tonometry. Normal intraocular pressure 11-21 mmHg.&#xD;
The change between the IOP of both groups was compared (sequence 1 versus sequence 2) of the data obtained at the end of each period (day 30 and day 60).</description>
        <time_frame>Change from Baseline intraocular pressure at day 30 and 60.</time_frame>
        <population>the statistical analysis was carried out taking into account each eye as a case number, therefore, each research subject could provide 2 cases.</population>
        <group_list>
          <group group_id="O1">
            <title>Sequence A</title>
            <description>First Period: PRO-122: 1 drop every 12 hours for 30 days of alternating treatment with 30 days&#xD;
Second Period: Krytantek Ofteno®: 1 drop every 12 hours for 30 days of alternating treatment with 30 days</description>
          </group>
          <group group_id="O2">
            <title>Sequence B</title>
            <description>First Period: Krytantek Ofteno®: 1 drop every 12 hours for 30 days of alternating treatment with 30 days&#xD;
Second Period: PRO-122: 1 drop every 12 hours for 30 days of alternating treatment with 30 days</description>
          </group>
        </group_list>
        <measure>
          <title>Intraocular Pressure (IOP)</title>
          <description>Intraocular pressure, Unit: Millimeters of mercury (mmHg) type of variable: Continuous, Measurement method: Goldman applanation tonometry. Normal intraocular pressure 11-21 mmHg.&#xD;
The change between the IOP of both groups was compared (sequence 1 versus sequence 2) of the data obtained at the end of each period (day 30 and day 60).</description>
          <population>the statistical analysis was carried out taking into account each eye as a case number, therefore, each research subject could provide 2 cases.</population>
          <units>mmHg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <units_analyzed>eyes</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="30"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>eyes</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="48"/>
                <count group_id="O2" value="54"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>basal visit (day 1)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13.60" spread="2.9"/>
                    <measurement group_id="O2" value="12.13" spread="1.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Crossover visit (day 30)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13.19" spread="3.2"/>
                    <measurement group_id="O2" value="11.80" spread="2.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Final visit (day 60)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12.60" spread="3.0"/>
                    <measurement group_id="O2" value="11.24" spread="1.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>it will be considered not inferior if they keep the IOP goal with differences of no more than 1.5 mmHg</non_inferiority_desc>
            <p_value>0.013</p_value>
            <p_value_desc>Baseline</p_value_desc>
            <method>t-test, 2 sided</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>it will be considered not inferior if they keep the IOP goal with differences of no more than 1.5 mmHg</non_inferiority_desc>
            <p_value>0.001</p_value>
            <p_value_desc>CrossOver</p_value_desc>
            <method>t-test, 2 sided</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>it will be considered not inferior if they keep the IOP goal with differences of no more than 1.5 mmHg</non_inferiority_desc>
            <p_value>0.050</p_value>
            <p_value_desc>Final Visit</p_value_desc>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Visual Acuity (VA)</title>
        <description>The VA will be evaluated basally, without refractive correction with the Snellen chart. A Snellen chart is placed at a standard distance: 20 ft. At this distance, the symbols on the line representing &quot;normal&quot; acuity subtend. This line, designated 20/20 is the smallest line that a person with normal acuity can read at a distance of 20fs. the scale consists of 11 lines of letters of different size, the size of the letter gives a fractional value according to the visual acuity of the patient, the value is inversely proportional to the visual acuity, if the denominator is greater the visual acuity will be less.&#xD;
Line 1: 20/200 Line 2: 20/100, Line 3: 20/70, line 4: 20/50, line 5: 20/40, Line 6: 20/30, line 7: 20/25, Line 8: 20/20, line 9: 20/15, line 10: 20/13, line 11: 20/10. the differences between groups in the basal, cross over and final visit will be evaluated.</description>
        <time_frame>Visual Acuity at Baseline (day 1) crossover visit (day 30) and final visit (day 60)</time_frame>
        <population>the statistical analysis was carried out taking into account each eye as a case number, therefore, each research subject could provide 2 cases.</population>
        <group_list>
          <group group_id="O1">
            <title>Sequence A</title>
            <description>First Period: PRO-122: 1 drop every 12 hours for 30 days of alternating treatment with 30 days&#xD;
Second Period: Krytantek Ofteno®: 1 drop every 12 hours for 30 days of alternating treatment with 30 days</description>
          </group>
          <group group_id="O2">
            <title>Sequence B</title>
            <description>First Period: Krytantek Ofteno®: 1 drop every 12 hours for 30 days of alternating treatment with 30 days&#xD;
Second Period: _1 drop every 12 hours for 30 days of alternating treatment with 30 days</description>
          </group>
        </group_list>
        <measure>
          <title>Visual Acuity (VA)</title>
          <description>The VA will be evaluated basally, without refractive correction with the Snellen chart. A Snellen chart is placed at a standard distance: 20 ft. At this distance, the symbols on the line representing &quot;normal&quot; acuity subtend. This line, designated 20/20 is the smallest line that a person with normal acuity can read at a distance of 20fs. the scale consists of 11 lines of letters of different size, the size of the letter gives a fractional value according to the visual acuity of the patient, the value is inversely proportional to the visual acuity, if the denominator is greater the visual acuity will be less.&#xD;
Line 1: 20/200 Line 2: 20/100, Line 3: 20/70, line 4: 20/50, line 5: 20/40, Line 6: 20/30, line 7: 20/25, Line 8: 20/20, line 9: 20/15, line 10: 20/13, line 11: 20/10. the differences between groups in the basal, cross over and final visit will be evaluated.</description>
          <population>the statistical analysis was carried out taking into account each eye as a case number, therefore, each research subject could provide 2 cases.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <units_analyzed>eyes</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="30"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>eyes</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="48"/>
                <count group_id="O2" value="54"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>basal visit (day 1)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="38.31" spread="3.577"/>
                    <measurement group_id="O2" value="39.48" spread="3.742"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Crossover visit (day 30)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="36.85" spread="3.806"/>
                    <measurement group_id="O2" value="40.43" spread="3.753"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Final visit (day 60)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="38.98" spread="3.717"/>
                    <measurement group_id="O2" value="35.50" spread="3.402"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>to be considered as not inferior to the group, the differences between both should not be greater than 2 points on the snellen scale</non_inferiority_desc>
            <p_value>0.823</p_value>
            <p_value_desc>Baseline</p_value_desc>
            <method>t-test, 2 sided</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>to be considered as not inferior to the group, the differences between both should not be greater than 2 points on the snellen scale</non_inferiority_desc>
            <p_value>0.507</p_value>
            <p_value_desc>CrossOver</p_value_desc>
            <method>t-test, 2 sided</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>to be considered as not inferior to the group, the differences between both should not be greater than 2 points on the snellen scale</non_inferiority_desc>
            <p_value>0.495</p_value>
            <p_value_desc>Final Visit</p_value_desc>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Adverse Events</title>
        <description>The presence of adverse events by percentage between groups will be evaluated. the scale is present or absent.</description>
        <time_frame>75 days, includes the security call</time_frame>
        <population>the statistical analysis was carried out taking into account each eye as a case number, therefore, each research subject could provide 2 cases. statistical analysis by intention to treat (ITT)</population>
        <group_list>
          <group group_id="O1">
            <title>PRO-122</title>
            <description>all subjects who received at least one application of PRO-122 in both sequences</description>
          </group>
          <group group_id="O2">
            <title>Krytantek Ofteno</title>
            <description>all subjects who received at least one application of Krytantek Ofteno in both sequences</description>
          </group>
        </group_list>
        <measure>
          <title>Adverse Events</title>
          <description>The presence of adverse events by percentage between groups will be evaluated. the scale is present or absent.</description>
          <population>the statistical analysis was carried out taking into account each eye as a case number, therefore, each research subject could provide 2 cases. statistical analysis by intention to treat (ITT)</population>
          <units>percentage of adverse events</units>
          <param>Number</param>
          <units_analyzed>eyes</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="60"/>
                <count group_id="O2" value="60"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>eyes</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="120"/>
                <count group_id="O2" value="120"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>mild</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="55.6"/>
                    <measurement group_id="O2" value="18.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>moderate</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="44.4"/>
                    <measurement group_id="O2" value="72.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>severe</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="9.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>to be considered as not inferior to the group, the differences between both should not be greater than 20% of the frequency.</non_inferiority_desc>
            <p_value>0.085</p_value>
            <method>Chi-squared</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Conjunctival Hyperemia</title>
        <description>the conjunctival hyperemia will be evaluated by the presence or absence of it and the percentage of affected by group will be reported.</description>
        <time_frame>Baseline (day 1) crossover visit (day 30) and final visit (day 60)</time_frame>
        <population>the statistical analysis was carried out taking into account each eye as a case number, therefore, each research subject could provide 2 cases.</population>
        <group_list>
          <group group_id="O1">
            <title>Sequence A</title>
            <description>First Period: PRO-122: 1 drop every 12 hours for 30 days of alternating treatment with 30 days&#xD;
Second Period: Krytantek Ofteno®: 1 drop every 12 hours for 30 days of alternating treatment with 30 days</description>
          </group>
          <group group_id="O2">
            <title>Sequence B</title>
            <description>First Period: Krytantek Ofteno®: 1 drop every 12 hours for 30 days of alternating treatment with 30 days&#xD;
Second Period: _1 drop every 12 hours for 30 days of alternating treatment with 30 days</description>
          </group>
        </group_list>
        <measure>
          <title>Conjunctival Hyperemia</title>
          <description>the conjunctival hyperemia will be evaluated by the presence or absence of it and the percentage of affected by group will be reported.</description>
          <population>the statistical analysis was carried out taking into account each eye as a case number, therefore, each research subject could provide 2 cases.</population>
          <units>percentage of eyes</units>
          <param>Number</param>
          <units_analyzed>eyes</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="30"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>eyes</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="49"/>
                <count group_id="O2" value="60"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>basal visit (day 1)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="39.6"/>
                    <measurement group_id="O2" value="11.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Crossover visit (day 30)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="37.5"/>
                    <measurement group_id="O2" value="25.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Final visit (day 60)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="20.8"/>
                    <measurement group_id="O2" value="13.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>to be considered as not inferior to the group, the differences between both should not be greater than 20% of the frequency.</non_inferiority_desc>
            <p_value>0.001</p_value>
            <p_value_desc>Baseline</p_value_desc>
            <method>Fisher Exact</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>to be considered as not inferior to the group, the differences between both should not be greater than 20% of the frequency.</non_inferiority_desc>
            <p_value>0.148</p_value>
            <p_value_desc>CrossOver</p_value_desc>
            <method>Fisher Exact</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>to be considered as not inferior to the group, the differences between both should not be greater than 20% of the frequency.</non_inferiority_desc>
            <p_value>0.212</p_value>
            <p_value_desc>Final Visit</p_value_desc>
            <method>Fisher Exact</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Chemosis</title>
        <description>Chemosis: qualitative ordinal variable, will be evaluated by the presence or absence of it and the percentage of affected by group will be reported.</description>
        <time_frame>Baseline (day 1) crossover visit (day 30) and final visit (day 60)</time_frame>
        <population>the statistical analysis was carried out taking into account each eye as a case number, therefore, each research subject could provide 2 cases.</population>
        <group_list>
          <group group_id="O1">
            <title>Sequence A</title>
            <description>First Period: PRO-122: 1 drop every 12 hours for 30 days of alternating treatment with 30 days&#xD;
Second Period: Krytantek Ofteno®: 1 drop every 12 hours for 30 days of alternating treatment with 30 days</description>
          </group>
          <group group_id="O2">
            <title>Sequence B</title>
            <description>First Period: Krytantek Ofteno®: 1 drop every 12 hours for 30 days of alternating treatment with 30 days&#xD;
Second Period: _1 drop every 12 hours for 30 days of alternating treatment with 30 days</description>
          </group>
        </group_list>
        <measure>
          <title>Chemosis</title>
          <description>Chemosis: qualitative ordinal variable, will be evaluated by the presence or absence of it and the percentage of affected by group will be reported.</description>
          <population>the statistical analysis was carried out taking into account each eye as a case number, therefore, each research subject could provide 2 cases.</population>
          <units>percentage of chemosis</units>
          <param>Number</param>
          <units_analyzed>eyes</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="30"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>eyes</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="49"/>
                <count group_id="O2" value="50"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>basal visit (day 1)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="3.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Crossover visit (day 30)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="3.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Final visit (day 60)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>to be considered as not inferior to the group, the differences between both should not be greater than 20% of the frequency.</non_inferiority_desc>
            <p_value>0.497</p_value>
            <p_value_desc>Baseline</p_value_desc>
            <method>Chi-squared, Corrected</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>to be considered as not inferior to the group, the differences between both should not be greater than 20% of the frequency.</non_inferiority_desc>
            <p_value>0.497</p_value>
            <p_value_desc>CrossOver</p_value_desc>
            <method>Chi-squared, Corrected</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>to be considered as not inferior to the group, the differences between both should not be greater than 20% of the frequency.</non_inferiority_desc>
            <p_value>0</p_value>
            <p_value_desc>Final Visit&#xD;
No statistic will be calculated because Final Chemosis is a constant</p_value_desc>
            <method>Chi-squared, Corrected</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Eye Burning</title>
        <description>Eye ocular burning will be evaluated by the presence or absence of it and the number of affected by group will be reported.</description>
        <time_frame>Baseline (day 1) crossover visit (day 30) and final visit (day 60)</time_frame>
        <population>the statistical analysis was carried out taking into account each eye as a case number, therefore, each research subject could provide 2 cases.</population>
        <group_list>
          <group group_id="O1">
            <title>Sequence A</title>
            <description>First Period: PRO-122: 1 drop every 12 hours for 30 days of alternating treatment with 30 days&#xD;
Second Period: Krytantek Ofteno®: 1 drop every 12 hours for 30 days of alternating treatment with 30 days</description>
          </group>
          <group group_id="O2">
            <title>Sequence B</title>
            <description>First Period: Krytantek Ofteno®: 1 drop every 12 hours for 30 days of alternating treatment with 30 days&#xD;
Second Period: _1 drop every 12 hours for 30 days of alternating treatment with 30 days</description>
          </group>
        </group_list>
        <measure>
          <title>Eye Burning</title>
          <description>Eye ocular burning will be evaluated by the presence or absence of it and the number of affected by group will be reported.</description>
          <population>the statistical analysis was carried out taking into account each eye as a case number, therefore, each research subject could provide 2 cases.</population>
          <units>number of eye burning</units>
          <param>Number</param>
          <units_analyzed>eyes</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="30"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>eyes</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="49"/>
                <count group_id="O2" value="50"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>basal visit (day 1)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="16"/>
                    <measurement group_id="O2" value="18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Crossover visit (day 30)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12"/>
                    <measurement group_id="O2" value="18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Final visit (day 60)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14"/>
                    <measurement group_id="O2" value="19"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>to be considered as not inferior to the group, the differences between both should not be greater than 20% of the frequency.</non_inferiority_desc>
            <p_value>1.000</p_value>
            <p_value_desc>baseline</p_value_desc>
            <method>Chi-squared</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>to be considered as not inferior to the group, the differences between both should not be greater than 20% of the frequency.</non_inferiority_desc>
            <p_value>0.391</p_value>
            <p_value_desc>Cross Over</p_value_desc>
            <method>Chi-squared</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>to be considered as not inferior to the group, the differences between both should not be greater than 20% of the frequency.</non_inferiority_desc>
            <p_value>0.534</p_value>
            <p_value_desc>Final Visit</p_value_desc>
            <method>Chi-squared</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Number of Eyes With Tearing</title>
        <description>Tearing will be evaluated by the presence or absence of it and the number of affected by group will be reported</description>
        <time_frame>Baseline (day 1) crossover visit (day 30) and final visit (day 60)</time_frame>
        <population>the statistical analysis was carried out taking into account each eye as a case number, therefore, each research subject could provide 2 cases.</population>
        <group_list>
          <group group_id="O1">
            <title>Sequence A</title>
            <description>First Period: PRO-122: 1 drop every 12 hours for 30 days of alternating treatment with 30 days&#xD;
Second Period: Krytantek Ofteno®: 1 drop every 12 hours for 30 days of alternating treatment with 30 days</description>
          </group>
          <group group_id="O2">
            <title>Sequence B</title>
            <description>First Period: Krytantek Ofteno®: 1 drop every 12 hours for 30 days of alternating treatment with 30 days&#xD;
Second Period: _1 drop every 12 hours for 30 days of alternating treatment with 30 days</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Eyes With Tearing</title>
          <description>Tearing will be evaluated by the presence or absence of it and the number of affected by group will be reported</description>
          <population>the statistical analysis was carried out taking into account each eye as a case number, therefore, each research subject could provide 2 cases.</population>
          <units>eyes</units>
          <param>Number</param>
          <units_analyzed>eyes</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="30"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>eyes</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="49"/>
                <count group_id="O2" value="50"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>basal visit (day 1)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Crossover visit (day 30)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8"/>
                    <measurement group_id="O2" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Final visit (day 60)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7"/>
                    <measurement group_id="O2" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>to be considered as not inferior to the group, the differences between both should not be greater than 20% of the frequency.</non_inferiority_desc>
            <p_value>0.023</p_value>
            <p_value_desc>Baseline</p_value_desc>
            <method>Chi-squared, Corrected</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>to be considered as not inferior to the group, the differences between both should not be greater than 20% of the frequency.</non_inferiority_desc>
            <p_value>1.000</p_value>
            <p_value_desc>CrossOver</p_value_desc>
            <method>Chi-squared</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>to be considered as not inferior to the group, the differences between both should not be greater than 20% of the frequency.</non_inferiority_desc>
            <p_value>0.793</p_value>
            <p_value_desc>Final Visit</p_value_desc>
            <method>Chi-squared</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Number of Eyes With Foreign Body Sensation</title>
        <description>Foreign body sensation will be evaluated by the presence or absence of it and the number of affected by group will be reported.</description>
        <time_frame>Baseline (day 1) crossover visit (day 30) and final visit (day 60)</time_frame>
        <population>the statistical analysis was carried out taking into account each eye as a case number, therefore, each research subject could provide 2 cases.</population>
        <group_list>
          <group group_id="O1">
            <title>Sequence A</title>
            <description>First Period: PRO-122: 1 drop every 12 hours for 30 days of alternating treatment with 30 days&#xD;
Second Period: Krytantek Ofteno®: 1 drop every 12 hours for 30 days of alternating treatment with 30 days</description>
          </group>
          <group group_id="O2">
            <title>Sequence B</title>
            <description>First Period: Krytantek Ofteno®: 1 drop every 12 hours for 30 days of alternating treatment with 30 days&#xD;
Second Period: _1 drop every 12 hours for 30 days of alternating treatment with 30 days</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Eyes With Foreign Body Sensation</title>
          <description>Foreign body sensation will be evaluated by the presence or absence of it and the number of affected by group will be reported.</description>
          <population>the statistical analysis was carried out taking into account each eye as a case number, therefore, each research subject could provide 2 cases.</population>
          <units>eyes</units>
          <param>Number</param>
          <units_analyzed>eyes</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="30"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>eyes</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="49"/>
                <count group_id="O2" value="50"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>basal visit (day 1)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14"/>
                    <measurement group_id="O2" value="14"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Crossover visit (day 30)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14"/>
                    <measurement group_id="O2" value="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Final visit (day 60)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                    <measurement group_id="O2" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>to be considered as not inferior to the group, the differences between both should not be greater than 20% of the frequency.</non_inferiority_desc>
            <p_value>0.825</p_value>
            <p_value_desc>Baseline</p_value_desc>
            <method>Chi-squared</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>to be considered as not inferior to the group, the differences between both should not be greater than 20% of the frequency.</non_inferiority_desc>
            <p_value>1.000</p_value>
            <p_value_desc>CrossOver</p_value_desc>
            <method>Chi-squared</method>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>to be considered as not inferior to the group, the differences between both should not be greater than 20% of the frequency.</non_inferiority_desc>
            <p_value>0.765</p_value>
            <method>Chi-squared</method>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>2 months</time_frame>
      <desc>The study's e-CRF was designed to collect adverse events for each research product separately. The sequence or crossing of the products under investigation was not considered for the report of adverse events because it can be detected at what time the event occurs and directly link it to the product that was being administered at the same time.</desc>
      <group_list>
        <group group_id="E1">
          <title>PRO-122</title>
          <description>All adverse events that occurred with the product under investigation PRO-122 were collected regardless of the sequence in which they participated.&#xD;
The 30 participants of both sequences received at least one dose of PRO-122, therefore 60 subjects exposed in this group are considered.</description>
        </group>
        <group group_id="E2">
          <title>Krytantek Ofteno®</title>
          <description>All adverse events that occurred with the product under investigation Krytantek Ofteno® were collected regardless of the sequence in which they participated.&#xD;
The 30 participants of both sequences received at least one dose of Krytantek Ofteno®, therefore 60 subjects exposed in this group are considered.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (Unspecified)</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="60"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="60"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>acute gastritis</sub_title>
                <description>presented with acute abdominal pain, was hospitalized with a presumptive diagnosis of appendicitis; appendicitis is ruled out and the diagnosis of acute gastritis is given, receiving treatment and resolved without sequelae.</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="60"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="12" subjects_at_risk="60"/>
                <counts group_id="E2" subjects_affected="08" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>sinus bradycardia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="60"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>vertigo</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="60"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>allergic Blepharokeratoconjunctivitis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="60"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>bacterial conjunctivitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="60"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Dotted Keratopathy</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="60"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>pharyngitis tonsillitis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="60"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>stomach flu</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="60"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>intestinal amebiasis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="60"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>peptic acid disease</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="60"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>headache</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="60"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>Meniere syndrome exacerbated</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="60"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>maxillary traumatism</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="60"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>ankle pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="60"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>low back pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="60"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>rhinopharyngitis</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="60"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>atopic dermatitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="60"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="60"/>
              </event>
              <event>
                <sub_title>atopic dermatitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="60"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="60"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. Ricardo Llamas (clinical safety pharmacologist)</name_or_title>
      <organization>Laboratorios Sophia</organization>
      <phone>3001 4200 ext 1059</phone>
      <email>ricardo.llamas@sophia.com.mx</email>
    </point_of_contact>
  </clinical_results>
</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/NCT03257813
org study id: SOPH122-0914/III
nct id: NCT03257813
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Aim: To demonstrate the non-inferiority of the PRO-122 ophthalmic solution manufactured by
      Laboratorios Sophia S.A. de C.V. versus Krytantek Ofteno® ophthalmic solution like
      hypotensive therapy in subjects with primary open angle glaucoma or ocular hypertension.

      Study design: a multicentric, prospective, crossover (2x2), double blind clinical study.
      Sample size: one hundred patients with primary open angle glaucoma or ocular hypertension.
      Patients in the period 1: In the first sequence 30 patients will be assigned to receive the
      ophthalmic solution: Krytantek Ofteno ® (timolol 0.5%%/brimonidine 0.2%/dorzolamide 2%) 1
      drop B.I.D. during 30 days and the second sequence 30 patients will be assigned to receive
      the ophthalmic solution: PRO-122 1 drop B.I.D. during 30 days in the same period. Washout
      period: 20 hours. Patients in the period 2: the pharmacological intervention change to the
      opposite therapy for 30 days
The American Academy of Ophthalmology Glaucoma Panel: The primary open angle glaucoma (POAG)
      is a progressive, chronic optic neuropathy in adults in which intraocular pressure (IOP) and
      other currently unknown factors contribute to damage and in which, in the absence of other
      identifiable causes, there is a characteristic acquired atrophy of the optic nerve and loss
      of retinal ganglion cells and their axons. This condition is associated with an anterior
      chamber angle that is open by gonioscopic appearance.

      This is a multicentric, crossover, double blind and prospective clinical study. The
      investigators will include patients with confirmed diagnosis of primary open-angle glaucoma
      or ocular hypertension, with target intraocular pressure (TIOP) within a range at which a
      patient is likely to remain stable or at which worsening of glaucoma will be slow enough that
      the risk of additional intervention is not justified.

      Patients will be randomly divided into 2 groups, one of them treated with a known formulation
      of timolol 0.5%/brimonidine 0.2%/dorzolamide 2% (Krytantek Ofteno®, Laboratorios Sophia,
      Mexico) and the other one treated with PRO-122 ophthalmic solution. Patients will receive 1
      drop B.I.D. into the lower conjunctival sac of either formulations and were examined at days:
      1, 15, 30, 45 and 61 after initiation of treatment. A phone call security at day 75 will be
      performed.

      Primary efficacy outcome: To evaluate the efficacy of PRO-122 versus Krytantek Ofteno®
      instilled onto the ocular surface in subjects with primary open angle glaucoma (POAG) or
      ocular hypertension (HTO), to control and maintenance of the target intraocular pressure
      (TIOP).
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: 60 subjects with diagnosis of open angle primary glaucoma with mild, moderate or severe damage and / or with intraocular hypertension users of Krytantek Ofteno® at least two previous months and are under control Of the corresponding IOP target.
a study group A or B will be randomly assigned, in group A, therapy with Krytantek Ofteno® will be continued for 30 days, in which the subject will be evaluated again and switched from therapy to solution PRO-122 which will be used for 30 days until the 60th day, date of the final visit.
In the case of those assigned to group B on day 1, the change to PRO-122 solution will be made for 30 continuous days until the date of revision on day 30, the day on which treatment with Krytantek Ofteno® will be restored to continue until the Day 60 for the final evaluation.
The selected subjects will be observed for 60 days.
primary purpose: Treatment
masking: Double (Participant, Investigator)
masking description: Masking will be carried out using identical boxes in the primary package in both groups.
Blinding for the research subject and the investigator will be carried out by using labels containing the assignation number, which will replace the original labels in the case of the comparator. Due to the nature of the primary containers of the research products, single-dose vials and multidose bottle, it is not possible to use identical labels.
measure: Intraocular Pressure (IOP)
time frame: Change from Baseline intraocular pressure at day 30 and 60.
description: Intraocular pressure, Unit: Millimeters of mercury (mmHg) type of variable: Continuous, Measurement method: Goldman applanation tonometry. Normal intraocular pressure 11-21 mmHg.
The change between the IOP of both groups was compared (sequence 1 versus sequence 2) of the data obtained at the end of each period (day 30 and day 60).
measure: Visual Acuity (VA)
time frame: Visual Acuity at Baseline (day 1) crossover visit (day 30) and final visit (day 60)
description: The VA will be evaluated basally, without refractive correction with the Snellen chart. A Snellen chart is placed at a standard distance: 20 ft. At this distance, the symbols on the line representing "normal" acuity subtend. This line, designated 20/20 is the smallest line that a person with normal acuity can read at a distance of 20fs. the scale consists of 11 lines of letters of different size, the size of the letter gives a fractional value according to the visual acuity of the patient, the value is inversely proportional to the visual acuity, if the denominator is greater the visual acuity will be less.
Line 1: 20/200 Line 2: 20/100, Line 3: 20/70, line 4: 20/50, line 5: 20/40, Line 6: 20/30, line 7: 20/25, Line 8: 20/20, line 9: 20/15, line 10: 20/13, line 11: 20/10. the differences between groups in the basal, cross over and final visit will be evaluated.
measure: Adverse Events
time frame: 75 days, includes the security call
description: The presence of adverse events by percentage between groups will be evaluated. the scale is present or absent.
measure: Conjunctival Hyperemia
time frame: Baseline (day 1) crossover visit (day 30) and final visit (day 60)
description: the conjunctival hyperemia will be evaluated by the presence or absence of it and the percentage of affected by group will be reported.
measure: Chemosis
time frame: Baseline (day 1) crossover visit (day 30) and final visit (day 60)
description: Chemosis: qualitative ordinal variable, will be evaluated by the presence or absence of it and the percentage of affected by group will be reported.
measure: Eye Burning
time frame: Baseline (day 1) crossover visit (day 30) and final visit (day 60)
description: Eye ocular burning will be evaluated by the presence or absence of it and the number of affected by group will be reported.
measure: Number of Eyes With Tearing
time frame: Baseline (day 1) crossover visit (day 30) and final visit (day 60)
description: Tearing will be evaluated by the presence or absence of it and the number of affected by group will be reported
measure: Number of Eyes With Foreign Body Sensation
time frame: Baseline (day 1) crossover visit (day 30) and final visit (day 60)
description: Foreign body sensation will be evaluated by the presence or absence of it and the number of affected by group will be reported.
arm group label: Group A
arm group type: Other
description: In group A, therapy with Krytantek Ofteno® will be continued for 30 days, in which the subject will be retested and switched to a PRO-122 solution which will be used for 30 days until the 60th day, The final visit.
arm group label: Group B
arm group type: Other
description: In group B, therapy with Krytantek Ofteno® will be suspended and changes for PRO-122 for 30 days, in which the subject will be retested and later switched to Krytantek Ofteno® solution which will be used for 30 days until the 60th day, The final visit.
intervention type: Drug
intervention name: PRO-122
description: 1 drop every 12 hours for 30 days of alternating treatment with 30 days
arm group label: Group A
arm group label: Group B
other name: timolol, dorzolamide, brimonidine
intervention type: Drug
intervention name: Krytantek Ofteno®
description: 1 drop every 12 hours for 30 days of alternating treatment with 30 days
arm group label: Group A
arm group label: Group B
other name: timolol, dorzolamide, brimonidine
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
responsible party type: Sponsor
mesh term: Glaucoma
mesh term: Glaucoma, Open-Angle
mesh term: Ocular Hypertension
mesh term: Hypertension
mesh term: Timolol
mesh term: Brimonidine Tartrate
mesh term: Dorzolamide
sharing ipd: No
ipd description: Confidentiality Policy
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 