<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/NCT03019627</url>
  </required_header>
  <id_info>
    <org_study_id>NGF0216</org_study_id>
    <nct_id>NCT03019627</nct_id>
  </id_info>
  <brief_title>An 8-week Study to Evaluate Safety and Efficacy of NGF Eye Drops Solution Versus Vehicle in Patients With Dry Eye</brief_title>
  <official_title>An 8-week, Phase II, Single-center, Randomized, Double-masked, Vehicle-controlled, Parallel-group Study With 4 Weeks of Follow-up to Evaluate Safety and Efficacy of rhNGF Eye Drops Solution vs Vehicle in Patients With Dry Eye</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Dompé Farmaceutici S.p.A</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Dompé Farmaceutici S.p.A</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The primary objective of this study was to assess the efficacy and safety of rhNGF when&#xD;
      administered as eye drops to patients with dry eye&#xD;
&#xD;
      The secondary objectives of this study were:&#xD;
&#xD;
        -  To assess change from baseline in Symptom Assessment In Dry Eye (SANDE) scores (without&#xD;
           imputation), corneal and conjunctival staining according to National Eye Institute (NEI)&#xD;
           scale, and in Tear Film Break-up Time (TFBUT) and Schirmer test I, following 4 and 8&#xD;
           weeks of treatment.&#xD;
&#xD;
        -  To assess change in levels of inflammatory biomarker matrix metallopeptidase 9 (MMP-9)&#xD;
           in tears following 8 weeks of treatment.&#xD;
&#xD;
        -  To assess the incidence and frequency of treatment-emergent adverse events (TEAEs)&#xD;
           following 8 weeks of treatment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The proposed phase II study is a single-center, randomized, double-masked, parallel-arm,&#xD;
      vehicle-controlled trial, designed to evaluate the safety and efficacy of Recombinant Human&#xD;
      Nerve Growth Factor (rhNGF) eye drops at 20 μg/ml concentration administered six times daily&#xD;
      for 8 weeks in patients with dry eye. After confirmation of inclusion and exclusion criteria&#xD;
      all eligible patients will be randomized at 2:1 ratio to rhNGF or vehicle control treatment&#xD;
      with 8 weeks of study treatments administration with 4 weeks Follow-up.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 20, 2017</start_date>
  <completion_date type="Actual">August 31, 2017</completion_date>
  <primary_completion_date type="Actual">August 31, 2017</primary_completion_date>
  <phase>Phase 2</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
    <masking_description>The identity of the treatments was concealed from the patient, Investigator, site staff, and Dompé's clinical research personnel until the study was unmasked for the final statistical analysis (after data base lock) except in case of specific events that required unmasking of the patient.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Symptom Assessment in Dry Eye (SANDE) Scores</measure>
    <time_frame>week 8</time_frame>
    <description>Change from baseline with Last Observation Carried Forward (LOCF) imputation. LOCF is a method of imputing missing data in longitudinal studies and tests for difference in mean rates of change in controlled repeated measurements designs with dropouts.&#xD;
The SANDE score is calculated by taking the square root of the product of the frequency of symptoms score and the severity of symptoms score. The SANDE scale ranges from 0 to 100 with 100 being the maximal amount of dry eye symptoms and 0 being the minimal amount of dry eye symptoms.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>SANDE Scores</measure>
    <time_frame>Week 4, week 8, week 12</time_frame>
    <description>Change from baseline with Last Observation Carried Forward (LOCF) imputation. LOCF is a method of imputing missing data in longitudinal studies and tests for difference in mean rates of change in controlled repeated measurements designs with dropouts.&#xD;
The SANDE score is calculated by taking the square root of the product of the frequency of symptoms score and the severity of symptoms score. The SANDE scale ranges from 0 to 100 with 100 being the maximal amount of dry eye symptoms and 0 being the minimal amount of dry eye symptoms.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cornea Vital Staining</measure>
    <time_frame>week 4, week 8, week 12</time_frame>
    <description>Changes from baseline on National Eye Institute (NEI) scale. The NEI/Industry Workshop guidelines were used for grading the scale of corneal and conjunctival damage. The cornea was divided into five sectors (central, superior, inferior, nasal and temporal), each of which was scored on a scale of 0-3, with a maximal total corneal staining score of 15.&#xD;
Both nasally and temporally, the conjunctiva was divided into a superior paralimbal area, an inferior paralimbal area, and a peripheral area with a grading scale of 0-3 and with a maximal total score of 9 for the nasal and temporal conjunctiva (overall the total score ranged from 0-18).&#xD;
Briefly, grade 0 reflected normal/healthy situation, whereas grade 3 reflected a severe damage in the considered sector.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Conjunctival Vital Staining</measure>
    <time_frame>week 4, week 8, week 12</time_frame>
    <description>Changes from baseline on National Eye Institute (NEI) scale. The NEI/Industry Workshop guidelines were used for grading the scale of corneal and conjunctival damage. The cornea was divided into five sectors (central, superior, inferior, nasal and temporal), each of which was scored on a scale of 0-3, with a maximal total corneal staining score of 15.&#xD;
Both nasally and temporally, the conjunctiva was divided into a superior paralimbal area, an inferior paralimbal area, and a peripheral area with a grading scale of 0-3 and with a maximal total score of 9 for the nasal and temporal conjunctiva (overall the total score ranged from 0-18).&#xD;
Briefly, grade 0 reflected normal/healthy situation, whereas grade 3 reflected a severe damage in the considered sector.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Tear Film Break-up Time (TFBUT)</measure>
    <time_frame>week 4, week 8, week 12</time_frame>
    <description>TFBUT was measured by determining the time to tear break-up. The TFBUT was performed after instillation of 5 μL of 2% preservative-free sodium fluorescein solution into the inferior conjunctival cul-de-sac of each eye. The patient was instructed to blink several times to thoroughly mix the fluorescein with the tear film.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Wetting Distance</measure>
    <time_frame>week 8</time_frame>
    <description>The Schirmer test without anesthesia was performed to measure aqueous tear secretion prior to the instillation of any dilating or eye drops</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">150</enrollment>
  <condition>Dry Eye</condition>
  <arm_group>
    <arm_group_label>rhNGF 20μg/mL</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Recombinant Human Nerve Growth Factor (rhNGF) at 20 μg/mL eye drops six times daily</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Vehicle</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>vehicle eye drops six times daily</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>NGF</intervention_name>
    <description>Eye Drop 20 μg/mL</description>
    <arm_group_label>rhNGF 20μg/mL</arm_group_label>
    <other_name>cenegermin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Vehicle</intervention_name>
    <description>Vehicle Eye Drop</description>
    <arm_group_label>Vehicle</arm_group_label>
    <other_name>Placebo</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patients (male or female) must be ≥ 18 years of age.&#xD;
&#xD;
          2. Patients must be diagnosed with any type of dry eye (e.g. Meibomian Gland Dysfunction,&#xD;
             Blepharitis, Keratoconjunctivitis sicca etc) at least 3 months before enrollment.&#xD;
&#xD;
          3. Patients must present dry eye pathology characterized by the following clinical&#xD;
             features:&#xD;
&#xD;
               1. Corneal and/or conjunctival staining with fluorescein and lissamine green using&#xD;
                  National Eye Institute (NEI) grading system &gt; 3&#xD;
&#xD;
               2. Mean Symptom Assessment in Dry Eye (SANDE) questionnaire ≥30&#xD;
&#xD;
               3. Schirmer test without anesthesia &lt; 10 mm/5 minutes and/or tear film break-up time&#xD;
                  (TFBUT) &lt; 10 seconds in the study eye&#xD;
&#xD;
          4. The same eye (study eye) must fulfill all the above criteria.&#xD;
&#xD;
          5. Patients must have best corrected distance visual acuity (BCDVA) score of ≥ 0.1&#xD;
             decimal units in both eyes at the time of study enrollment.&#xD;
&#xD;
          6. Female patients must have negative pregnancy test if at childbirth potential.&#xD;
&#xD;
          7. Only patients who satisfy all requirements for informed consent may be included in the&#xD;
             study. Written Informed Consent must be obtained before the initiation of any study&#xD;
             specific procedures.&#xD;
&#xD;
          8. Patients must have the ability and willingness to comply with study procedures.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Best corrected distance visual acuity (BCDVA) score of &lt; 0.1 decimal units in either&#xD;
             eye.&#xD;
&#xD;
          2. Evidence of an active ocular infection in either eye.&#xD;
&#xD;
          3. Presence or history of any ocular disorder or condition, including ocular surgery,&#xD;
             trauma, or disease that could possibly interfere with the interpretation of study&#xD;
             results in the opinion of the Investigator.&#xD;
&#xD;
          4. Intraocular inflammation defined as Tyndall score &gt;0.&#xD;
&#xD;
          5. Active or recent diagnosis of malignancy (i.e., currently under chemo/radiotherapy).&#xD;
&#xD;
          6. Systemic disease not stabilized within 1 month before baseline visit (e.g.,&#xD;
             uncontrolled diabetes; thyroid malfunction) or judged by the Investigator to be&#xD;
             incompatible with the study (e.g., current systemic infections) or with a condition&#xD;
             incompatible with the frequent assessment required by the study.&#xD;
&#xD;
          7. Patients who have had a serious adverse reaction or significant hypersensitivity to&#xD;
             any drug or chemically related compounds, or had a clinically significant allergy to&#xD;
             drugs, foods, amide local anesthetics, or other materials, including commercial&#xD;
             artificial tears containing carboxymethylcellulose (CMC) (in the opinion of the&#xD;
             Investigator).&#xD;
&#xD;
          8. Use of topical cyclosporine, topical corticosteroids, or any other topical medication&#xD;
             for the treatment of dry eye in either eye until the day of study enrollment.&#xD;
&#xD;
          9. Contact lenses or punctal plug use during the study (previous use not an exclusion&#xD;
             criteria, but must be discontinued at the baseline visit.&#xD;
&#xD;
         10. An anticipated need of additional systemic treatments for dry eye during the study&#xD;
             (all prior treatment must be continued for the entire duration of the study).&#xD;
&#xD;
         11. Females of childbearing potential (those who are not surgically sterilized or&#xD;
             postmenopausal for at least 1 year) are excluded from participation in the study if&#xD;
             they meet any one of the following conditions:&#xD;
&#xD;
               1. are currently pregnant or,&#xD;
&#xD;
               2. have a positive result at the urine pregnancy test (Baseline/Day 0) or,&#xD;
&#xD;
               3. intend to become pregnant during the study treatment period or,&#xD;
&#xD;
               4. are breast-feeding or,&#xD;
&#xD;
               5. are not willing to use highly effective birth control measures, such as: hormonal&#xD;
                  contraceptives - oral, implanted, transdermal, or injected - and/or mechanical&#xD;
                  barrier methods - spermicide in conjunction with a barrier such as a condom or&#xD;
                  diaphragm or a intrauterine device (IUD) - during the entire course of and 30&#xD;
                  days after the study treatment periods.&#xD;
&#xD;
         12. History of drug addiction or alcohol abuse.&#xD;
&#xD;
         13. Any prior ocular surgery (including refractive palpebral and cataract surgery) if&#xD;
             within 90 days before the screening visit.&#xD;
&#xD;
         14. Participation in a clinical trial with a new active substance during the past 30 days.&#xD;
&#xD;
         15. Participation in another clinical trial study at the same time as the present study.&#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>Giacomina Massaro Giordano, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Penn Dry Eye and Oc. Surf. Center, Univ. of Pennsylvania, Scheie Eye Institute</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Penn Dry Eye and Ocular Surface Center, University of Pennsylvania</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2018</verification_date>
  <study_first_submitted>January 11, 2017</study_first_submitted>
  <study_first_submitted_qc>January 11, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 12, 2017</study_first_posted>
  <results_first_submitted>October 19, 2018</results_first_submitted>
  <results_first_submitted_qc>January 16, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">February 8, 2019</results_first_posted>
  <last_update_submitted>January 16, 2019</last_update_submitted>
  <last_update_submitted_qc>January 16, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">February 8, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dry Eye Syndromes</mesh_term>
    <mesh_term>Keratoconjunctivitis Sicca</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>October 27, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/27/NCT03019627/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>October 5, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/27/NCT03019627/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>After confirmation of inclusion and exclusion criteria all eligible patients were randomized at 2:1 ratio to rhNGF or vehicle control treatment with 8 weeks of study treatments administration with 4 weeks Follow-up. rhNGF and vehicle were administered as eye drops at 20 μg/mL concentration, six times daily for 8 weeks in patients with dry eye</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>rhNGF 20μg/mL</title>
          <description>Recombinant Human Nerve Growth Factor (rhNGF) at 20 μg/mL eye drops six times daily&#xD;
NGF: Eye Drop 20 μg/mL</description>
        </group>
        <group group_id="P2">
          <title>Vehicle</title>
          <description>vehicle eye drops six times daily&#xD;
Vehicle: Vehicle Eye Drop</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="100"/>
                <participants group_id="P2" count="50"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="85"/>
                <participants group_id="P2" count="42"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="15"/>
                <participants group_id="P2" count="8"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Unrelated to adverse event</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>not compliance</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Other</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Enrolled set = All patients who were randomized comprised the Enrolled Set. Data from this set was used to summarize demographic, baseline, and background characteristics.</population>
      <group_list>
        <group group_id="B1">
          <title>rhNGF 20μg/mL</title>
          <description>Recombinant Human Nerve Growth Factor (rhNGF) at 20 μg/mL eye drops six times daily&#xD;
NGF: Eye Drop 20 μg/mL</description>
        </group>
        <group group_id="B2">
          <title>Vehicle</title>
          <description>vehicle eye drops six times daily&#xD;
Vehicle: Vehicle Eye Drop</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="100"/>
            <count group_id="B2" value="50"/>
            <count group_id="B3" value="150"/>
          </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="57.5" spread="11.89"/>
                    <measurement group_id="B2" value="57.7" spread="10.33"/>
                    <measurement group_id="B3" value="57.5" spread="11.36"/>
                  </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="85"/>
                    <measurement group_id="B2" value="46"/>
                    <measurement group_id="B3" value="131"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="19"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="99"/>
                    <measurement group_id="B2" value="48"/>
                    <measurement group_id="B3" value="147"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="100"/>
                    <measurement group_id="B2" value="50"/>
                    <measurement group_id="B3" value="150"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Number of baseline participants</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="100"/>
                    <measurement group_id="B2" value="50"/>
                    <measurement group_id="B3" value="150"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Symptom Assessment in Dry Eye (SANDE) Scores</title>
        <description>Change from baseline with Last Observation Carried Forward (LOCF) imputation. LOCF is a method of imputing missing data in longitudinal studies and tests for difference in mean rates of change in controlled repeated measurements designs with dropouts.&#xD;
The SANDE score is calculated by taking the square root of the product of the frequency of symptoms score and the severity of symptoms score. The SANDE scale ranges from 0 to 100 with 100 being the maximal amount of dry eye symptoms and 0 being the minimal amount of dry eye symptoms.</description>
        <time_frame>week 8</time_frame>
        <population>Full analysis set population</population>
        <group_list>
          <group group_id="O1">
            <title>rhNGF 20μg/mL</title>
            <description>Recombinant Human Nerve Growth Factor (rhNGF) at 20 μg/mL eye drops six times daily&#xD;
NGF: Eye Drop 20 μg/mL</description>
          </group>
          <group group_id="O2">
            <title>Vehicle</title>
            <description>vehicle eye drops six times daily&#xD;
Vehicle: Vehicle Eye Drop</description>
          </group>
        </group_list>
        <measure>
          <title>Symptom Assessment in Dry Eye (SANDE) Scores</title>
          <description>Change from baseline with Last Observation Carried Forward (LOCF) imputation. LOCF is a method of imputing missing data in longitudinal studies and tests for difference in mean rates of change in controlled repeated measurements designs with dropouts.&#xD;
The SANDE score is calculated by taking the square root of the product of the frequency of symptoms score and the severity of symptoms score. The SANDE scale ranges from 0 to 100 with 100 being the maximal amount of dry eye symptoms and 0 being the minimal amount of dry eye symptoms.</description>
          <population>Full analysis set population</population>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="97"/>
                <count group_id="O2" value="48"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Frequency</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="96"/>
                    <count group_id="O2" value="48"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-38.8" spread="28.97"/>
                    <measurement group_id="O2" value="-34.0" spread="26.67"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Severity</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="97"/>
                    <count group_id="O2" value="48"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-32.2" spread="31.04"/>
                    <measurement group_id="O2" value="-31.07" spread="28.32"/>
                  </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>
            <groups_desc>Frequency statistical analysis</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>=0.428</p_value>
            <method>ANCOVA</method>
            <param_type>difference in least square means</param_type>
            <param_value>-3.83</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-13.34</ci_lower_limit>
            <ci_upper_limit>5.68</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Severity statistical analysis</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>=0.974</p_value>
            <method>ANCOVA</method>
            <param_type>difference in least square means</param_type>
            <param_value>0.16</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-9.45</ci_lower_limit>
            <ci_upper_limit>9.76</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>SANDE Scores</title>
        <description>Change from baseline with Last Observation Carried Forward (LOCF) imputation. LOCF is a method of imputing missing data in longitudinal studies and tests for difference in mean rates of change in controlled repeated measurements designs with dropouts.&#xD;
The SANDE score is calculated by taking the square root of the product of the frequency of symptoms score and the severity of symptoms score. The SANDE scale ranges from 0 to 100 with 100 being the maximal amount of dry eye symptoms and 0 being the minimal amount of dry eye symptoms.</description>
        <time_frame>Week 4, week 8, week 12</time_frame>
        <population>Full analysis set population</population>
        <group_list>
          <group group_id="O1">
            <title>rhNGF 20μg/mL</title>
            <description>Recombinant Human Nerve Growth Factor (rhNGF) at 20 μg/mL eye drops six times daily&#xD;
NGF: Eye Drop 20 μg/mL</description>
          </group>
          <group group_id="O2">
            <title>Vehicle</title>
            <description>vehicle eye drops six times daily&#xD;
Vehicle: Vehicle Eye Drop</description>
          </group>
        </group_list>
        <measure>
          <title>SANDE Scores</title>
          <description>Change from baseline with Last Observation Carried Forward (LOCF) imputation. LOCF is a method of imputing missing data in longitudinal studies and tests for difference in mean rates of change in controlled repeated measurements designs with dropouts.&#xD;
The SANDE score is calculated by taking the square root of the product of the frequency of symptoms score and the severity of symptoms score. The SANDE scale ranges from 0 to 100 with 100 being the maximal amount of dry eye symptoms and 0 being the minimal amount of dry eye symptoms.</description>
          <population>Full analysis set population</population>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="97"/>
                <count group_id="O2" value="48"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Frequency - week 4</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="94"/>
                    <count group_id="O2" value="47"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-22.1" spread="24.08"/>
                    <measurement group_id="O2" value="-20.4" spread="20.66"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Frequency - week 8</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="86"/>
                    <count group_id="O2" value="42"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-39.6" spread="28.55"/>
                    <measurement group_id="O2" value="-34.6" spread="27.60"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Frequency - week 12</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="88"/>
                    <count group_id="O2" value="42"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-44.8" spread="28.69"/>
                    <measurement group_id="O2" value="-28.2" spread="28.94"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Severity - week 4</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="94"/>
                    <count group_id="O2" value="47"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-19.9" spread="25.20"/>
                    <measurement group_id="O2" value="-22.2" spread="24.31"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Severity - week 8</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="86"/>
                    <count group_id="O2" value="42"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-32.6" spread="30.64"/>
                    <measurement group_id="O2" value="-33.1" spread="28.30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Severity - week 12</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="88"/>
                    <count group_id="O2" value="42"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-38.8" spread="29.20"/>
                    <measurement group_id="O2" value="-24.3" spread="28.43"/>
                  </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>
            <groups_desc>frequency statistical analysis - week 4</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>=0.783</p_value>
            <method>ANCOVA</method>
            <param_type>Difference in least square means</param_type>
            <param_value>-1.12</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-9.14</ci_lower_limit>
            <ci_upper_limit>6.91</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Frequency statistical analysis - week 8</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>=0.461</p_value>
            <method>ANCOVA</method>
            <param_type>difference in least square means</param_type>
            <param_value>-3.82</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-14.1</ci_lower_limit>
            <ci_upper_limit>6.41</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Frequency statistical analysis - week 12</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>=0.004</p_value>
            <method>ANCOVA</method>
            <param_type>difference in least square means</param_type>
            <param_value>-15.3</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-25.6</ci_lower_limit>
            <ci_upper_limit>-4.97</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Severity statistical analysis - week 4</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>=0.544</p_value>
            <method>ANCOVA</method>
            <param_type>difference in least square means</param_type>
            <param_value>2.55</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-5.72</ci_lower_limit>
            <ci_upper_limit>10.82</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Severity statistical analysis - week 8</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>=0.837</p_value>
            <method>ANCOVA</method>
            <param_type>difference in least square means</param_type>
            <param_value>1.06</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-9.12</ci_lower_limit>
            <ci_upper_limit>11.24</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Severity statistical analysis - week 12</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>=0.007</p_value>
            <method>ANCOVA</method>
            <param_type>difference in least square means</param_type>
            <param_value>-13.8</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-23.7</ci_lower_limit>
            <ci_upper_limit>3.88</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Cornea Vital Staining</title>
        <description>Changes from baseline on National Eye Institute (NEI) scale. The NEI/Industry Workshop guidelines were used for grading the scale of corneal and conjunctival damage. The cornea was divided into five sectors (central, superior, inferior, nasal and temporal), each of which was scored on a scale of 0-3, with a maximal total corneal staining score of 15.&#xD;
Both nasally and temporally, the conjunctiva was divided into a superior paralimbal area, an inferior paralimbal area, and a peripheral area with a grading scale of 0-3 and with a maximal total score of 9 for the nasal and temporal conjunctiva (overall the total score ranged from 0-18).&#xD;
Briefly, grade 0 reflected normal/healthy situation, whereas grade 3 reflected a severe damage in the considered sector.</description>
        <time_frame>week 4, week 8, week 12</time_frame>
        <population>Full analysis set population</population>
        <group_list>
          <group group_id="O1">
            <title>rhNGF 20μg/mL</title>
            <description>Recombinant Human Nerve Growth Factor (rhNGF) at 20 μg/mL eye drops six times daily&#xD;
NGF: Eye Drop 20 μg/mL</description>
          </group>
          <group group_id="O2">
            <title>Vehicle</title>
            <description>vehicle eye drops six times daily&#xD;
Vehicle: Vehicle Eye Drop</description>
          </group>
        </group_list>
        <measure>
          <title>Cornea Vital Staining</title>
          <description>Changes from baseline on National Eye Institute (NEI) scale. The NEI/Industry Workshop guidelines were used for grading the scale of corneal and conjunctival damage. The cornea was divided into five sectors (central, superior, inferior, nasal and temporal), each of which was scored on a scale of 0-3, with a maximal total corneal staining score of 15.&#xD;
Both nasally and temporally, the conjunctiva was divided into a superior paralimbal area, an inferior paralimbal area, and a peripheral area with a grading scale of 0-3 and with a maximal total score of 9 for the nasal and temporal conjunctiva (overall the total score ranged from 0-18).&#xD;
Briefly, grade 0 reflected normal/healthy situation, whereas grade 3 reflected a severe damage in the considered sector.</description>
          <population>Full analysis set population</population>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="97"/>
                <count group_id="O2" value="48"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>week 4</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="94"/>
                    <count group_id="O2" value="47"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-3.5" spread="2.32"/>
                    <measurement group_id="O2" value="-3.0" spread="2.27"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>week 8</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="86"/>
                    <count group_id="O2" value="41"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-4.2" spread="2.92"/>
                    <measurement group_id="O2" value="-4.4" spread="2.70"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>week 12</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="88"/>
                    <count group_id="O2" value="42"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-4.4" spread="2.80"/>
                    <measurement group_id="O2" value="-5.1" spread="2.93"/>
                  </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>
            <groups_desc>week 4</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>=0.046</p_value>
            <method>ANCOVA</method>
            <param_type>Difference in least square means</param_type>
            <param_value>-0.70</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-1.38</ci_lower_limit>
            <ci_upper_limit>-0.01</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>week 8</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>=0.425</p_value>
            <method>ANCOVA</method>
            <param_type>Difference in least square means</param_type>
            <param_value>-0.30</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-1.05</ci_lower_limit>
            <ci_upper_limit>0.44</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>week 12</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>=0.788</p_value>
            <method>ANCOVA</method>
            <param_type>Difference in least square means</param_type>
            <param_value>-0.09</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.76</ci_lower_limit>
            <ci_upper_limit>0.58</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Conjunctival Vital Staining</title>
        <description>Changes from baseline on National Eye Institute (NEI) scale. The NEI/Industry Workshop guidelines were used for grading the scale of corneal and conjunctival damage. The cornea was divided into five sectors (central, superior, inferior, nasal and temporal), each of which was scored on a scale of 0-3, with a maximal total corneal staining score of 15.&#xD;
Both nasally and temporally, the conjunctiva was divided into a superior paralimbal area, an inferior paralimbal area, and a peripheral area with a grading scale of 0-3 and with a maximal total score of 9 for the nasal and temporal conjunctiva (overall the total score ranged from 0-18).&#xD;
Briefly, grade 0 reflected normal/healthy situation, whereas grade 3 reflected a severe damage in the considered sector.</description>
        <time_frame>week 4, week 8, week 12</time_frame>
        <population>Full analysis set population</population>
        <group_list>
          <group group_id="O1">
            <title>rhNGF 20μg/mL</title>
            <description>Recombinant Human Nerve Growth Factor (rhNGF) at 20 μg/mL eye drops six times daily&#xD;
NGF: Eye Drop 20 μg/mL</description>
          </group>
          <group group_id="O2">
            <title>Vehicle</title>
            <description>vehicle eye drops six times daily&#xD;
Vehicle: Vehicle Eye Drop</description>
          </group>
        </group_list>
        <measure>
          <title>Conjunctival Vital Staining</title>
          <description>Changes from baseline on National Eye Institute (NEI) scale. The NEI/Industry Workshop guidelines were used for grading the scale of corneal and conjunctival damage. The cornea was divided into five sectors (central, superior, inferior, nasal and temporal), each of which was scored on a scale of 0-3, with a maximal total corneal staining score of 15.&#xD;
Both nasally and temporally, the conjunctiva was divided into a superior paralimbal area, an inferior paralimbal area, and a peripheral area with a grading scale of 0-3 and with a maximal total score of 9 for the nasal and temporal conjunctiva (overall the total score ranged from 0-18).&#xD;
Briefly, grade 0 reflected normal/healthy situation, whereas grade 3 reflected a severe damage in the considered sector.</description>
          <population>Full analysis set population</population>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="97"/>
                <count group_id="O2" value="48"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>week 4</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="94"/>
                    <count group_id="O2" value="47"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-4.7" spread="3.94"/>
                    <measurement group_id="O2" value="-4.1" spread="3.45"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>week 8</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="86"/>
                    <count group_id="O2" value="42"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-6.7" spread="4.16"/>
                    <measurement group_id="O2" value="-5.9" spread="4.07"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>week 12</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="88"/>
                    <count group_id="O2" value="42"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-7.2" spread="4.23"/>
                    <measurement group_id="O2" value="-7.0" spread="3.90"/>
                  </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>
            <groups_desc>week 4</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>=0.265</p_value>
            <method>ANCOVA</method>
            <param_type>Difference in least square means</param_type>
            <param_value>-0.71</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-1.95</ci_lower_limit>
            <ci_upper_limit>0.54</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>week 8</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>=0.026</p_value>
            <method>ANCOVA</method>
            <param_type>Difference in least square means</param_type>
            <param_value>-1.38</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-2.59</ci_lower_limit>
            <ci_upper_limit>-0.17</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>week 12</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>=0.361</p_value>
            <method>ANCOVA</method>
            <param_type>Difference in least square means</param_type>
            <param_value>-0.60</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-1.90</ci_lower_limit>
            <ci_upper_limit>0.70</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Tear Film Break-up Time (TFBUT)</title>
        <description>TFBUT was measured by determining the time to tear break-up. The TFBUT was performed after instillation of 5 μL of 2% preservative-free sodium fluorescein solution into the inferior conjunctival cul-de-sac of each eye. The patient was instructed to blink several times to thoroughly mix the fluorescein with the tear film.</description>
        <time_frame>week 4, week 8, week 12</time_frame>
        <population>Full analysis set population</population>
        <group_list>
          <group group_id="O1">
            <title>rhNGF 20μg/mL</title>
            <description>Recombinant Human Nerve Growth Factor (rhNGF) at 20 μg/mL eye drops six times daily&#xD;
NGF: Eye Drop 20 μg/mL</description>
          </group>
          <group group_id="O2">
            <title>Vehicle</title>
            <description>vehicle eye drops six times daily&#xD;
Vehicle: Vehicle Eye Drop</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Tear Film Break-up Time (TFBUT)</title>
          <description>TFBUT was measured by determining the time to tear break-up. The TFBUT was performed after instillation of 5 μL of 2% preservative-free sodium fluorescein solution into the inferior conjunctival cul-de-sac of each eye. The patient was instructed to blink several times to thoroughly mix the fluorescein with the tear film.</description>
          <population>Full analysis set population</population>
          <units>seconds</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="97"/>
                <count group_id="O2" value="48"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>week 4</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="94"/>
                    <count group_id="O2" value="47"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.4" spread="1.68"/>
                    <measurement group_id="O2" value="0.8" spread="1.57"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>week 8</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="86"/>
                    <count group_id="O2" value="42"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.5" spread="1.74"/>
                    <measurement group_id="O2" value="0.7" spread="1.89"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>week 12</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="88"/>
                    <count group_id="O2" value="42"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.5" spread="2.34"/>
                    <measurement group_id="O2" value="0.9" spread="1.42"/>
                  </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>
            <groups_desc>week 4</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>=0.323</p_value>
            <method>ANCOVA</method>
            <param_type>Difference in least square means</param_type>
            <param_value>-0.25</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.76</ci_lower_limit>
            <ci_upper_limit>0.25</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>week 8</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>=0.908</p_value>
            <method>ANCOVA</method>
            <param_type>Difference in least square means</param_type>
            <param_value>0.03</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.55</ci_lower_limit>
            <ci_upper_limit>0.62</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>week 12</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>=0.702</p_value>
            <method>ANCOVA</method>
            <param_type>Difference in least square means</param_type>
            <param_value>-0.12</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.76</ci_lower_limit>
            <ci_upper_limit>0.52</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Wetting Distance</title>
        <description>The Schirmer test without anesthesia was performed to measure aqueous tear secretion prior to the instillation of any dilating or eye drops</description>
        <time_frame>week 8</time_frame>
        <population>Full analysis set population</population>
        <group_list>
          <group group_id="O1">
            <title>rhNGF 20μg/mL</title>
            <description>Recombinant Human Nerve Growth Factor (rhNGF) at 20 μg/mL eye drops six times daily&#xD;
NGF: Eye Drop 20 μg/mL</description>
          </group>
          <group group_id="O2">
            <title>Vehicle</title>
            <description>vehicle eye drops six times daily&#xD;
Vehicle: Vehicle Eye Drop</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Wetting Distance</title>
          <description>The Schirmer test without anesthesia was performed to measure aqueous tear secretion prior to the instillation of any dilating or eye drops</description>
          <population>Full analysis set population</population>
          <units>millimeters</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="85"/>
                <count group_id="O2" value="42"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.4" spread="11.41"/>
                    <measurement group_id="O2" value="-3.1" spread="8.66"/>
                  </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>Superiority</non_inferiority_type>
            <p_value>=0.003</p_value>
            <method>ANCOVA</method>
            <param_type>Difference in least square means</param_type>
            <param_value>5.75</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>2.02</ci_lower_limit>
            <ci_upper_limit>9.48</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse events were collected at each time point of the study (ie. Baseline visit, Week 4, Week 8 and ETV or early termination</time_frame>
      <group_list>
        <group group_id="E1">
          <title>rhNGF 20μg/mL</title>
          <description>Recombinant Human Nerve Growth Factor (rhNGF) at 20 μg/mL eye drops six times daily&#xD;
NGF: Eye Drop 20 μg/mL</description>
        </group>
        <group group_id="E2">
          <title>Vehicle</title>
          <description>vehicle eye drops six times daily&#xD;
Vehicle: Vehicle Eye Drop</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA 20.0</default_vocab>
        <default_assessment>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="100"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="100"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Diverticulitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Paraesthesia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Chronic obstructive pulmonary disease</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>1</frequency_threshold>
        <default_vocab>MedDRA 20.0</default_vocab>
        <default_assessment>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="97" subjects_at_risk="100"/>
                <counts group_id="E2" subjects_affected="38" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Palpitations</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Ear pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Vertigo</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Ocular discomfort</sub_title>
                <counts group_id="E1" events="87" subjects_affected="69" subjects_at_risk="100"/>
                <counts group_id="E2" events="17" subjects_affected="10" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Eye pain</sub_title>
                <counts group_id="E1" events="67" subjects_affected="42" subjects_at_risk="100"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Eye irritation</sub_title>
                <counts group_id="E1" events="19" subjects_affected="15" subjects_at_risk="100"/>
                <counts group_id="E2" events="11" subjects_affected="10" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Vision blurred</sub_title>
                <counts group_id="E1" events="14" subjects_affected="13" subjects_at_risk="100"/>
                <counts group_id="E2" events="6" subjects_affected="4" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Photophobia</sub_title>
                <counts group_id="E1" events="14" subjects_affected="12" subjects_at_risk="100"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Eye pruritus</sub_title>
                <counts group_id="E1" events="8" subjects_affected="8" subjects_at_risk="100"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Eye discharge</sub_title>
                <counts group_id="E1" events="13" subjects_affected="9" subjects_at_risk="100"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Eyelid disorder</sub_title>
                <counts group_id="E1" events="8" subjects_affected="8" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Eyelid oedema</sub_title>
                <counts group_id="E1" events="6" subjects_affected="4" subjects_at_risk="100"/>
                <counts group_id="E2" events="3" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Dry eye</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Eyelid pain</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Lacrimation increased</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="100"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Ocular hyperaemia</sub_title>
                <counts group_id="E1" events="8" subjects_affected="3" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Blepharospasm</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="100"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Eye swelling</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Eyelid margin crusting</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="100"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Foreign body sensation in eyes</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Abnormal sensation in eye</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Eyelid pruritus</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Asthenopia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Conjunctival haemorrhage</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Diplopia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Eye allergy</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Scleral haemorrhage</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>visual impairment</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Vitreous floaters</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Eye paraesthesia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Conjunctival deposit</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Conjunctivitis allergic</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Corneal oedema</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Eye inflammation</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Eyelid irritation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Eyelid sensory disorder</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Lacrimation decreased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Photopsia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Scleral discolouration</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>abdominal discomfort</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Abdominal pain upper</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Diverticulum</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Glossodynia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Salivary gland calculus</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Stomatitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Sensation of foreign body</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Generalized oedema</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Humidity intolerance</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Oedema peripheral</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Temperature intolerance</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Seasonal allergy</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Hypersensivity</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Graft versus host disease</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Multiple allergies</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Viral upper respiratory tract infection</sub_title>
                <counts group_id="E1" events="10" subjects_affected="8" subjects_at_risk="100"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Sinusitis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="100"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Bronchitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="100"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Acute sinusitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Cellulitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Conjunctivitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Conjunctivitis viral</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Diverticulitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Ear infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Fungal infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Herpes simplex</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Herpes virus infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Influenza</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Ophthalmic herpes simplex</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Pertussis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Pharyngitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Pyelonephritis acute</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Vaginal infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Foreign body in eye</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Superficial injury of eye</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Contusion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Eye burns</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Eye contusion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Eye injury</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Intraocular pressure test</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Glucose tolerance impaired</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Iron deficiency</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="100"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Bursitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Intervertebral disc disorder</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Joint stiffness</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Muscle spasms</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Myofascial pain syndrome</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>plantar fasciitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Rotator cuff syndrome</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Tendonitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="14" subjects_affected="12" subjects_at_risk="100"/>
                <counts group_id="E2" events="11" subjects_affected="5" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Migrane</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Burning sensation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Paraesthesia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Autonomic failure syndrome</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Cervical Myelopathy</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Dysarthria</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Hypoaesthesia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Neuralgia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Polyneuropathy idiopathic progressive</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Sciatica</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Sinus headache</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Panic attack</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Lupus nephritis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nasal discomfort</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Oropharyngeal pain</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Sinus congestion</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Asthma</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Asthma exercise induced</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Chronic obstructive pulmonary disease</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Dry throat</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Haemoptysis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Nasal dryness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Nasal inflammation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Urticaria</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="8" subjects_affected="3" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Madarosis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Acne</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Erythema</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Skin discolouration</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Skin irritation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Dental implantation</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Endodontic procedure</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Eye laser surgery</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Haemorrhoid operation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Tooth extraction</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Vena cava filter removal</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="100"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="50"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Raynaud's phenomenon</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </event>
              <event>
                <sub_title>Vein disorder</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="100"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="50"/>
              </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>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>LImitations and caveats are not specified.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Valeria Motta, PhD</name_or_title>
      <organization>Dompé</organization>
      <phone>02583831</phone>
      <email>info@dompe.it</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/NCT03019627
org study id: NGF0216
nct id: NCT03019627
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
The primary objective of this study was to assess the efficacy and safety of rhNGF when
      administered as eye drops to patients with dry eye

      The secondary objectives of this study were:

        -  To assess change from baseline in Symptom Assessment In Dry Eye (SANDE) scores (without
           imputation), corneal and conjunctival staining according to National Eye Institute (NEI)
           scale, and in Tear Film Break-up Time (TFBUT) and Schirmer test I, following 4 and 8
           weeks of treatment.

        -  To assess change in levels of inflammatory biomarker matrix metallopeptidase 9 (MMP-9)
           in tears following 8 weeks of treatment.

        -  To assess the incidence and frequency of treatment-emergent adverse events (TEAEs)
           following 8 weeks of treatment.
The proposed phase II study is a single-center, randomized, double-masked, parallel-arm,
      vehicle-controlled trial, designed to evaluate the safety and efficacy of Recombinant Human
      Nerve Growth Factor (rhNGF) eye drops at 20 μg/ml concentration administered six times daily
      for 8 weeks in patients with dry eye. After confirmation of inclusion and exclusion criteria
      all eligible patients will be randomized at 2:1 ratio to rhNGF or vehicle control treatment
      with 8 weeks of study treatments administration with 4 weeks Follow-up.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
masking description: The identity of the treatments was concealed from the patient, Investigator, site staff, and Dompé's clinical research personnel until the study was unmasked for the final statistical analysis (after data base lock) except in case of specific events that required unmasking of the patient.
measure: Symptom Assessment in Dry Eye (SANDE) Scores
time frame: week 8
description: Change from baseline with Last Observation Carried Forward (LOCF) imputation. LOCF is a method of imputing missing data in longitudinal studies and tests for difference in mean rates of change in controlled repeated measurements designs with dropouts.
The SANDE score is calculated by taking the square root of the product of the frequency of symptoms score and the severity of symptoms score. The SANDE scale ranges from 0 to 100 with 100 being the maximal amount of dry eye symptoms and 0 being the minimal amount of dry eye symptoms.
measure: SANDE Scores
time frame: Week 4, week 8, week 12
description: Change from baseline with Last Observation Carried Forward (LOCF) imputation. LOCF is a method of imputing missing data in longitudinal studies and tests for difference in mean rates of change in controlled repeated measurements designs with dropouts.
The SANDE score is calculated by taking the square root of the product of the frequency of symptoms score and the severity of symptoms score. The SANDE scale ranges from 0 to 100 with 100 being the maximal amount of dry eye symptoms and 0 being the minimal amount of dry eye symptoms.
measure: Cornea Vital Staining
time frame: week 4, week 8, week 12
description: Changes from baseline on National Eye Institute (NEI) scale. The NEI/Industry Workshop guidelines were used for grading the scale of corneal and conjunctival damage. The cornea was divided into five sectors (central, superior, inferior, nasal and temporal), each of which was scored on a scale of 0-3, with a maximal total corneal staining score of 15.
Both nasally and temporally, the conjunctiva was divided into a superior paralimbal area, an inferior paralimbal area, and a peripheral area with a grading scale of 0-3 and with a maximal total score of 9 for the nasal and temporal conjunctiva (overall the total score ranged from 0-18).
Briefly, grade 0 reflected normal/healthy situation, whereas grade 3 reflected a severe damage in the considered sector.
measure: Conjunctival Vital Staining
time frame: week 4, week 8, week 12
description: Changes from baseline on National Eye Institute (NEI) scale. The NEI/Industry Workshop guidelines were used for grading the scale of corneal and conjunctival damage. The cornea was divided into five sectors (central, superior, inferior, nasal and temporal), each of which was scored on a scale of 0-3, with a maximal total corneal staining score of 15.
Both nasally and temporally, the conjunctiva was divided into a superior paralimbal area, an inferior paralimbal area, and a peripheral area with a grading scale of 0-3 and with a maximal total score of 9 for the nasal and temporal conjunctiva (overall the total score ranged from 0-18).
Briefly, grade 0 reflected normal/healthy situation, whereas grade 3 reflected a severe damage in the considered sector.
measure: Change in Tear Film Break-up Time (TFBUT)
time frame: week 4, week 8, week 12
description: TFBUT was measured by determining the time to tear break-up. The TFBUT was performed after instillation of 5 μL of 2% preservative-free sodium fluorescein solution into the inferior conjunctival cul-de-sac of each eye. The patient was instructed to blink several times to thoroughly mix the fluorescein with the tear film.
measure: Change From Baseline in Wetting Distance
time frame: week 8
description: The Schirmer test without anesthesia was performed to measure aqueous tear secretion prior to the instillation of any dilating or eye drops
arm group label: rhNGF 20μg/mL
arm group type: Experimental
description: Recombinant Human Nerve Growth Factor (rhNGF) at 20 μg/mL eye drops six times daily
arm group label: Vehicle
arm group type: Placebo Comparator
description: vehicle eye drops six times daily
intervention type: Drug
intervention name: NGF
description: Eye Drop 20 μg/mL
arm group label: rhNGF 20μg/mL
other name: cenegermin
intervention type: Other
intervention name: Vehicle
description: Vehicle Eye Drop
arm group label: Vehicle
other name: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Giacomina Massaro Giordano, MD
role: Principal Investigator
affiliation: Penn Dry Eye and Oc. Surf. Center, Univ. of Pennsylvania, Scheie Eye Institute
facility: 
country: United States
responsible party type: Sponsor
mesh term: Dry Eye Syndromes
mesh term: Keratoconjunctivitis Sicca
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: LImitations and caveats are not specified.
point of contact: 