<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/NCT03274895</url>
  </required_header>
  <id_info>
    <org_study_id>043/SI</org_study_id>
    <nct_id>NCT03274895</nct_id>
  </id_info>
  <brief_title>Polihexanide (PHMB) Eye Drops in Patients Affected by Acanthamoeba Keratitis</brief_title>
  <official_title>Randomized, Active-Controlled, Phase 3 Study to Evaluate Efficacy, Safety and Tolerability of 0.08% PHMB Ophthalmic Solution in Comparison With 0.02% PHMB + 0.1% Propamidine Combination Therapy in Subjects Affected by Acanthamoeba Keratitis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>SIFI SpA</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>SIFI SpA</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Prospective randomized study to evaluate the efficacy, safety and tolerability of 0.08%&#xD;
      polihexanide (PHMB) eye drops in patients affected by acanthamoeba keratitis.&#xD;
&#xD;
      130 subjects were assigned to one of the following 2 treatment groups: Group 1: 0.08%&#xD;
      polihexanide (PHMB) + placebo Group 2: 0.02% polihexanide (PHMB) + 0.1% propamidine&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This was a randomized, assessor-masked, active-controlled, multiple center, parallel-group&#xD;
      phase 3 study to evaluate the efficacy, safety and tolerability of 0.08% polihexanide (PHMB)&#xD;
      ophthalmic solution compared to the conventional 0.02% polihexanide (PHMB) + 0.1% propamidine&#xD;
      in patients affected by acanthamoeba keratitis.&#xD;
&#xD;
      The study was designed as a superiority study with the possibility to test for&#xD;
      non-inferiority if the superiority hypothesis was not met (CPMP/EWP/482/99).The study&#xD;
      consisted of an eligibility screening visit, a treatment period including monthly follow-up&#xD;
      visits until a clinical resolution was obtained (within a maximum of 1 year), followed by 2&#xD;
      post-treatment off-therapy visits (30 and 90 days after treatment discontinuation). 130&#xD;
      subjects with confirmed diagnosis of acanthamoeba keratitis (clinical signs plus positive&#xD;
      confocal microscopy findings) were assigned to one of the following treatment groups in a&#xD;
      ratio of 1:1.&#xD;
&#xD;
      Group 1: 0.08% PHMB + placebo Group 2: 0.02% PHMB + 0.1% propamidine&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 13, 2017</start_date>
  <completion_date type="Actual">March 30, 2022</completion_date>
  <primary_completion_date type="Actual">June 30, 2021</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Clinical Resolution Rate</measure>
    <time_frame>12 months</time_frame>
    <description>Percentage of patients cured 30 days after discontinuing all study therapies, within 12 months of randomization</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time to Cure</measure>
    <time_frame>maximum 12 months</time_frame>
    <description>Time needed to reach a clinical resolution</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Visual Acuity</measure>
    <time_frame>maximum 12 months</time_frame>
    <description>Final visual acuity (best corrected)</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">135</enrollment>
  <condition>Acanthamoeba Keratitis</condition>
  <arm_group>
    <arm_group_label>PHMB 0.08% plus placebo</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>polihexanide (PHMB) 0.08% and placebo were administered in the affected eye until clinical resolution for a maximum of 12 months</description>
  </arm_group>
  <arm_group>
    <arm_group_label>PHMB 0.02% plus propamidine 0.1%</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>polihexanide (PHMB) 0.02% and propamidine 0.1% were administered in the affected eye until clinical resolution for a maximum of 12 months</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>PHMB 0.08%</intervention_name>
    <description>16 drops in a day in the affected eye for 5 days followed by 8 drops in a day for 7 days,6 drops in a day for 7 days and 4 drops in a day up to clinical resolution</description>
    <arm_group_label>PHMB 0.08% plus placebo</arm_group_label>
    <other_name>Polihexanide 0.8 mg/ml</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Propamidine 0.1%</intervention_name>
    <description>16 drops in a day in the affected eye for 5 days followed by 8 drops in a day for 7 days,6 drops in a day for 7 days and 4 drops in a day up to clinical resolution</description>
    <arm_group_label>PHMB 0.02% plus propamidine 0.1%</arm_group_label>
    <other_name>Brolene eye drops</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>placebo</intervention_name>
    <description>16 drops in a day in the affected eye for 5 days followed by 8 drops in a day for 7 days,6 drops in a day for 7 days and 4 drops in a day up to clinical resolution</description>
    <arm_group_label>PHMB 0.08% plus placebo</arm_group_label>
    <other_name>Brolene vehicle</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>PHMB 0.02%</intervention_name>
    <description>16 drops in a day in the affected eye for 5 days followed by 8 drops in a day for 7 days,6 drops in a day for 7 days and 4 drops in a day up to clinical resolution</description>
    <arm_group_label>PHMB 0.02% plus propamidine 0.1%</arm_group_label>
    <other_name>Polihexanide 0.2 mg/ml</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. willing to give informed consent&#xD;
&#xD;
          2. man or woman of any race and ≥12 years of age&#xD;
&#xD;
          3. able to understand and willing to comply with study procedures, restrictions and&#xD;
             requirements&#xD;
&#xD;
          4. Clinical findings consistent with Acanthamoeba keratitis&#xD;
&#xD;
          5. Confocal microscopy findings consistent with Acanthamoeba keratitis&#xD;
&#xD;
          6. The following previous treatments for Acanthamoeba keratitis are eligible:&#xD;
             antibiotics, antiviral and antifungal drugs, antiinflammatory drugs&#xD;
&#xD;
          7. Females of childbearing potential will be included if they are either sexually&#xD;
             inactive or using one highly effective contraceptive&#xD;
&#xD;
          8. Females of childbearing potential agree to remain sexually inactive or to keep the&#xD;
             same birth control method for at least 28 days following the last study drug dose&#xD;
&#xD;
          9. A female of non-childbearing potential must have undergone one sterilization&#xD;
             procedures at least 6 months prior to the first study drug dose&#xD;
&#xD;
         10. A non-vasectomized male subject agrees to use a condom with spermicide or abstain from&#xD;
             sexual intercourse during the study until 90 days beyond the last dose of study drug&#xD;
             and the female partner agrees to comply with inclusion 7 or 8. For a vasectomized male&#xD;
             who has had his vasectomy 6 months or more prior to study start, it is required that&#xD;
             they use a condom during sexual intercourse. A male who has been vasectomized less&#xD;
             than 6 months prior to study start must follow the same restrictions as a&#xD;
             non-vasectomized male.&#xD;
&#xD;
         11. If male, they must agree not to donate sperm from the first study drug dose until 90&#xD;
             days after dosing&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Subject with documented history and/or clinical signs of concomitant presence of an&#xD;
             ocular infection caused by viruses (herpes simplex virus [HSV]) or fungi.&#xD;
&#xD;
          2. Subject treated with drugs having effects on Acanthamoeba cysts prior to study entry,&#xD;
             including biguanides (PHMB, chlorhexidine) and diamidines (propamidine, hexamidine).&#xD;
&#xD;
          3. Subjects requiring systemic immunosuppression for Acanthamoeba associated scleritis.&#xD;
&#xD;
          4. Subjects requiring urgent surgical intervention for advanced Acanthamoeba keratitis in&#xD;
             either eye (e.g., for advanced corneal thinning/melting etc.).&#xD;
&#xD;
          5. Subject with known or suspected allergy to biguanides, diamidines or intolerance to&#xD;
             any other ingredient of the investigational treatments.&#xD;
&#xD;
          6. Subject affected by immunodeficiency diseases or taking systemic immunosuppressive&#xD;
             therapy.&#xD;
&#xD;
          7. Subject with a major systemic disease or other illness that would, in the opinion of&#xD;
             the investigator, compromise subject's safety or interfere with the collection or&#xD;
             interpretation of study results.&#xD;
&#xD;
          8. If female, pregnancy, planned pregnancy, or breast-feeding&#xD;
&#xD;
          9. Subject is participating in another interventional clinical study with an experimental&#xD;
             or unapproved/unlicensed therapy or has participated in another interventional&#xD;
             clinical study within 4 weeks prior to this study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>13 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>John Dart, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Moorfield's Hospital London</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>San Raffaele Hospital</name>
      <address>
        <city>Milano</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>San Giovanni and Paolo Hospital</name>
      <address>
        <city>Venice</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Clinical Center Medical University of Silesia</name>
      <address>
        <city>Katowice</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Moorfields Hospital</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Manchester Royal Eye Hospital</name>
      <address>
        <city>Manchester</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Southampton</name>
      <address>
        <city>Southampton</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
    <country>Poland</country>
    <country>United Kingdom</country>
  </location_countries>
  <reference>
    <citation>Papa V, Rama P, Radford C, Minassian DC, Dart JKG. Acanthamoeba keratitis therapy: time to cure and visual outcome analysis for different antiamoebic therapies in 227 cases. Br J Ophthalmol. 2020 Apr;104(4):575-581. doi: 10.1136/bjophthalmol-2019-314485. Epub 2019 Aug 10.</citation>
    <PMID>31401556</PMID>
  </reference>
  <reference>
    <citation>Papa V, van der Meulen I, Rottey S, Sallet G, Overweel J, Asero N, Minassian DC, Dart JKG. Safety and tolerability of topical polyhexamethylene biguanide: a randomised clinical trial in healthy adult volunteers. Br J Ophthalmol. 2022 Feb;106(2):190-196. doi: 10.1136/bjophthalmol-2020-317848. Epub 2020 Nov 25.</citation>
    <PMID>33239413</PMID>
  </reference>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>September 5, 2017</study_first_submitted>
  <study_first_submitted_qc>September 5, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 7, 2017</study_first_posted>
  <results_first_submitted>September 12, 2022</results_first_submitted>
  <results_first_submitted_qc>August 1, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">August 2, 2023</results_first_posted>
  <last_update_submitted>August 2, 2023</last_update_submitted>
  <last_update_submitted_qc>August 2, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 22, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>polihexanide</keyword>
  <keyword>propamidine</keyword>
  <keyword>confocal microscopy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acanthamoeba Keratitis</mesh_term>
    <mesh_term>Keratitis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Biguanides</mesh_term>
    <mesh_term>Polihexanide</mesh_term>
    <mesh_term>Dibrompropamidine</mesh_term>
    <mesh_term>Propamidine</mesh_term>
  </intervention_browse>
  <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 8, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/95/NCT03274895/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>July 1, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/95/NCT03274895/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Participants were recruited from August 2017 and March 2021. Of the 135 enrolled participants 134 were randomized to treatment</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>PHMB 0.08% Plus Placebo</title>
          <description>16 drops of each solution in a day for 5 days,8 drops each in a day for 7 days,6 drops each in a day for 7 days and 4 drops each in a day up to clinical resolution</description>
        </group>
        <group group_id="P2">
          <title>PHMB 0.02% Plus Propamidine 0.1%</title>
          <description>16 drops of each solution in a day for 5 days,8 drops each in a day for 7 days,6 drops each in a day for 7 days and 4 drops each in a day up to clinical resolution</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="69">3 patients had no confirmation of diagnosis and therefore the overall number of participants analyzed is 66</participants>
                <participants group_id="P2" count="65">4 patients had no confimation of diagnosis and therefore the overall number of participants analyzed is 61</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="56"/>
                <participants group_id="P2" count="54"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="13"/>
                <participants group_id="P2" count="11"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Lack of Efficacy</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="7"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Diagnosis not confirmed</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>PHMB 0.08% Plus Placebo</title>
          <description>Polihexanide (PHMB) 0.08% and placebo were administered in the affected eye until clinical resolution for a maximum of 12 months</description>
        </group>
        <group group_id="B2">
          <title>PHMB 0.02% Plus Propamidine 0.1%</title>
          <description>Polihexanide (PHMB) 0.02% and propamidine 0.1% were administered in the affected eye until clinical resolution for a maximum of 12 months</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="69"/>
            <count group_id="B2" value="65"/>
            <count group_id="B3" value="134"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="69"/>
                    <count group_id="B2" value="65"/>
                    <count group_id="B3" value="134"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="33" lower_limit="25" upper_limit="43"/>
                    <measurement group_id="B2" value="36" lower_limit="26" upper_limit="49"/>
                    <measurement group_id="B3" value="35" lower_limit="25" upper_limit="46"/>
                  </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>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="69"/>
                    <count group_id="B2" value="65"/>
                    <count group_id="B3" value="134"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="41"/>
                    <measurement group_id="B2" value="37"/>
                    <measurement group_id="B3" value="78"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="28"/>
                    <measurement group_id="B2" value="28"/>
                    <measurement group_id="B3" value="56"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race and Ethnicity Not Collected</title>
          <population>Race and Ethnicity were not collected from any participant.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="0"/>
                    <count group_id="B2" value="0"/>
                    <count group_id="B3" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Visual acuity (best corrected)</title>
          <units>LogMAR</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="69"/>
                    <count group_id="B2" value="65"/>
                    <count group_id="B3" value="134"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0.350" lower_limit="0.150" upper_limit="0.70"/>
                    <measurement group_id="B2" value="0.260" lower_limit="0.100" upper_limit="0.480"/>
                    <measurement group_id="B3" value="0.300" lower_limit="0.150" upper_limit="0.700"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Culture positivity for Acanthamoeba</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="69"/>
                    <count group_id="B2" value="65"/>
                    <count group_id="B3" value="134"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="19"/>
                    <measurement group_id="B2" value="17"/>
                    <measurement group_id="B3" value="36"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>PCR positivity for Acanthamoeba</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="69"/>
                    <count group_id="B2" value="65"/>
                    <count group_id="B3" value="134"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="33"/>
                    <measurement group_id="B2" value="25"/>
                    <measurement group_id="B3" value="58"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Clinical Resolution Rate</title>
        <description>Percentage of patients cured 30 days after discontinuing all study therapies, within 12 months of randomization</description>
        <time_frame>12 months</time_frame>
        <population>Intent-to-treat</population>
        <group_list>
          <group group_id="O1">
            <title>PHMB 0.08% Plus Placebo</title>
            <description>Polihexanide (PHMB) 0.08% and placebo were administered in the affected eye until clinical resolution for a maximum of 12 months</description>
          </group>
          <group group_id="O2">
            <title>PHMB 0.02% Plus Propamidine 0.1%</title>
            <description>polihexanide (PHMB) 0.02% and propamidine 0.1% were administered in the affected eye until clinical resolution for a maximum of 12 months</description>
          </group>
        </group_list>
        <measure>
          <title>Clinical Resolution Rate</title>
          <description>Percentage of patients cured 30 days after discontinuing all study therapies, within 12 months of randomization</description>
          <population>Intent-to-treat</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="66"/>
                <count group_id="O2" value="61"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="84.8" lower_limit="73.9" upper_limit="92.5"/>
                    <measurement group_id="O2" value="88.5" lower_limit="77.8" upper_limit="95.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Non-Inferiority</non_inferiority_type>
            <non_inferiority_desc>Non-inferiority margin= 0.20</non_inferiority_desc>
            <param_type>difference in proportion of resolution r</param_type>
            <param_value>-0.036</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.154</ci_lower_limit>
            <ci_upper_limit>0.081</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Time to Cure</title>
        <description>Time needed to reach a clinical resolution</description>
        <time_frame>maximum 12 months</time_frame>
        <population>Intent-to-treat</population>
        <group_list>
          <group group_id="O1">
            <title>PHMB 0.08% Plus Placebo</title>
            <description>Polihexanide (PHMB) 0.08% and placebo were administered in the affected eye until clinical resolution for a maximum of 12 months</description>
          </group>
          <group group_id="O2">
            <title>PHMB 0.02% Plus Propamidine 0.1%</title>
            <description>Polihexanide (PHMB) 0.02% and propamidine 0.1% were administered in the affected eye until clinical resolution for a maximum of 12 months</description>
          </group>
        </group_list>
        <measure>
          <title>Time to Cure</title>
          <description>Time needed to reach a clinical resolution</description>
          <population>Intent-to-treat</population>
          <units>days</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="66"/>
                <count group_id="O2" value="61"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="140" lower_limit="117" upper_limit="150"/>
                    <measurement group_id="O2" value="114" lower_limit="91" upper_limit="127"/>
                  </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>Other</non_inferiority_type>
            <p_value>0.042</p_value>
            <method>Log Rank</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Visual Acuity</title>
        <description>Final visual acuity (best corrected)</description>
        <time_frame>maximum 12 months</time_frame>
        <population>Intent-to-treat</population>
        <group_list>
          <group group_id="O1">
            <title>PHMB 0.08% Plus Placebo</title>
            <description>16 drops of each solution in a day for 5 days,8 drops each in a day for 7 days,6 drops each in a day for 7 days and 4 drops each in a day up to clinical resolution</description>
          </group>
          <group group_id="O2">
            <title>PHMB 0.02% Plus Propamidine 0.1%</title>
            <description>16 drops of each solution in a day for 5 days,8 drops each in a day for 7 days,6 drops each in a day for 7 days and 4 drops each in a day up to clinical resolution</description>
          </group>
        </group_list>
        <measure>
          <title>Visual Acuity</title>
          <description>Final visual acuity (best corrected)</description>
          <population>Intent-to-treat</population>
          <units>LogMAR</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="66"/>
                <count group_id="O2" value="61"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.000" lower_limit="0.000" upper_limit="0.250"/>
                    <measurement group_id="O2" value="0.000" lower_limit="-0.080" upper_limit="0.150"/>
                  </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>Other</non_inferiority_type>
            <p_value>0.577</p_value>
            <method>ANCOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>1 year</time_frame>
      <group_list>
        <group group_id="E1">
          <title>PHMB 0.08% Plus Placebo</title>
          <description>polihexanide (PHMB) 0.08% and placebo were administered in the affected eye until clinical resolution for a maximum of 12 months</description>
        </group>
        <group group_id="E2">
          <title>PHMB 0.02% Plus Propamidine 0.1%</title>
          <description>polihexanide (PHMB) 0.02% and propamidine 0.1% were administered in the affected eye until clinical resolution for a maximum of 12 months</description>
        </group>
      </group_list>
      <serious_events>
        <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="69"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="65"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="65"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>2</frequency_threshold>
        <default_vocab>MedDRA (Unspecified)</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="31" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="29" subjects_at_risk="65"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>eye pain</sub_title>
                <counts group_id="E1" events="11" subjects_affected="9" subjects_at_risk="69"/>
                <counts group_id="E2" events="7" subjects_affected="7" subjects_at_risk="65"/>
              </event>
              <event>
                <sub_title>ocular hyperemia</sub_title>
                <counts group_id="E1" events="9" subjects_affected="8" subjects_at_risk="69"/>
                <counts group_id="E2" events="9" subjects_affected="7" subjects_at_risk="65"/>
              </event>
              <event>
                <sub_title>lacrimation increased</sub_title>
                <counts group_id="E1" events="6" subjects_affected="6" subjects_at_risk="69"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="65"/>
              </event>
              <event>
                <sub_title>conjunctival hyperemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="69"/>
                <counts group_id="E2" events="4" subjects_affected="3" subjects_at_risk="65"/>
              </event>
              <event>
                <sub_title>eye irritation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="69"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="65"/>
              </event>
              <event>
                <sub_title>photophobia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="69"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="65"/>
              </event>
              <event>
                <sub_title>eye inflammation</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="69"/>
                <counts group_id="E2" events="3" subjects_affected="1" subjects_at_risk="65"/>
              </event>
              <event>
                <sub_title>corneal epithelium defect</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="69"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="65"/>
              </event>
              <event>
                <sub_title>corneal infiltrates</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="69"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="65"/>
              </event>
              <event>
                <sub_title>eye pruritus</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="69"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="65"/>
              </event>
              <event>
                <sub_title>eye discharge</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="69"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="65"/>
              </event>
              <event>
                <sub_title>eye swelling</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="69"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="65"/>
              </event>
              <event>
                <sub_title>keratitis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="69"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="65"/>
              </event>
              <event>
                <sub_title>ocular discomfort</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="69"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="65"/>
              </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>
    <point_of_contact>
      <name_or_title>Dr. Jelle Kleijn</name_or_title>
      <organization>SIFI SpA</organization>
      <phone>+31615643708</phone>
      <email>jelle.kleijn@sifigroup.com</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/NCT03274895
org study id: 043/SI
nct id: NCT03274895
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Prospective randomized study to evaluate the efficacy, safety and tolerability of 0.08%
      polihexanide (PHMB) eye drops in patients affected by acanthamoeba keratitis.

      130 subjects were assigned to one of the following 2 treatment groups: Group 1: 0.08%
      polihexanide (PHMB) + placebo Group 2: 0.02% polihexanide (PHMB) + 0.1% propamidine
This was a randomized, assessor-masked, active-controlled, multiple center, parallel-group
      phase 3 study to evaluate the efficacy, safety and tolerability of 0.08% polihexanide (PHMB)
      ophthalmic solution compared to the conventional 0.02% polihexanide (PHMB) + 0.1% propamidine
      in patients affected by acanthamoeba keratitis.

      The study was designed as a superiority study with the possibility to test for
      non-inferiority if the superiority hypothesis was not met (CPMP/EWP/482/99).The study
      consisted of an eligibility screening visit, a treatment period including monthly follow-up
      visits until a clinical resolution was obtained (within a maximum of 1 year), followed by 2
      post-treatment off-therapy visits (30 and 90 days after treatment discontinuation). 130
      subjects with confirmed diagnosis of acanthamoeba keratitis (clinical signs plus positive
      confocal microscopy findings) were assigned to one of the following treatment groups in a
      ratio of 1:1.

      Group 1: 0.08% PHMB + placebo Group 2: 0.02% PHMB + 0.1% propamidine
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Clinical Resolution Rate
time frame: 12 months
description: Percentage of patients cured 30 days after discontinuing all study therapies, within 12 months of randomization
measure: Time to Cure
time frame: maximum 12 months
description: Time needed to reach a clinical resolution
measure: Visual Acuity
time frame: maximum 12 months
description: Final visual acuity (best corrected)
arm group label: PHMB 0.08% plus placebo
arm group type: Experimental
description: polihexanide (PHMB) 0.08% and placebo were administered in the affected eye until clinical resolution for a maximum of 12 months
arm group label: PHMB 0.02% plus propamidine 0.1%
arm group type: Active Comparator
description: polihexanide (PHMB) 0.02% and propamidine 0.1% were administered in the affected eye until clinical resolution for a maximum of 12 months
intervention type: Drug
intervention name: PHMB 0.08%
description: 16 drops in a day in the affected eye for 5 days followed by 8 drops in a day for 7 days,6 drops in a day for 7 days and 4 drops in a day up to clinical resolution
arm group label: PHMB 0.08% plus placebo
other name: Polihexanide 0.8 mg/ml
intervention type: Drug
intervention name: Propamidine 0.1%
description: 16 drops in a day in the affected eye for 5 days followed by 8 drops in a day for 7 days,6 drops in a day for 7 days and 4 drops in a day up to clinical resolution
arm group label: PHMB 0.02% plus propamidine 0.1%
other name: Brolene eye drops
intervention type: Drug
intervention name: placebo
description: 16 drops in a day in the affected eye for 5 days followed by 8 drops in a day for 7 days,6 drops in a day for 7 days and 4 drops in a day up to clinical resolution
arm group label: PHMB 0.08% plus placebo
other name: Brolene vehicle
intervention type: Drug
intervention name: PHMB 0.02%
description: 16 drops in a day in the affected eye for 5 days followed by 8 drops in a day for 7 days,6 drops in a day for 7 days and 4 drops in a day up to clinical resolution
arm group label: PHMB 0.02% plus propamidine 0.1%
other name: Polihexanide 0.2 mg/ml
criteria: 
gender: All
minimum age: 13 Years
maximum age: N/A
healthy volunteers: No
last name: John Dart, MD
role: Principal Investigator
affiliation: Moorfield's Hospital London
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Italy
country: Poland
country: United Kingdom
citation: Papa V, Rama P, Radford C, Minassian DC, Dart JKG. Acanthamoeba keratitis therapy: time to cure and visual outcome analysis for different antiamoebic therapies in 227 cases. Br J Ophthalmol. 2020 Apr;104(4):575-581. doi: 10.1136/bjophthalmol-2019-314485. Epub 2019 Aug 10.
PMID: 31401556
citation: Papa V, van der Meulen I, Rottey S, Sallet G, Overweel J, Asero N, Minassian DC, Dart JKG. Safety and tolerability of topical polyhexamethylene biguanide: a randomised clinical trial in healthy adult volunteers. Br J Ophthalmol. 2022 Feb;106(2):190-196. doi: 10.1136/bjophthalmol-2020-317848. Epub 2020 Nov 25.
PMID: 33239413
responsible party type: Sponsor
mesh term: Acanthamoeba Keratitis
mesh term: Keratitis
mesh term: Biguanides
mesh term: Polihexanide
mesh term: Dibrompropamidine
mesh term: Propamidine
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 