<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/NCT04505787</url>
  </required_header>
  <id_info>
    <org_study_id>1378fbp19ct</org_study_id>
    <secondary_id>2019-003918-14</secondary_id>
    <secondary_id>TK-254R-0101</secondary_id>
    <nct_id>NCT04505787</nct_id>
  </id_info>
  <brief_title>S-flurbiprofen Bioavailability Trial to Compare a Newly Developed Patch vs. a Marketed Tablet</brief_title>
  <official_title>Characterisation of Relative Bioavailability of a Newly Developed S-flurbiprofen Containing Patch Formulation in Comparison With a Marketed Oral Flurbiprofen Containing Tablet Formulation - a Multiple Dose, Randomised, 2-period Crossover...</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>SocraTec R&amp;D GmbH</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Teikoku Seiyaku Co., Ltd.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>SocraMetrics GmbH</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>SocraTec R&amp;D GmbH</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>
      Teikoku Seiyaku Co., Ltd. (Japan) is developing a new Esflurbiprofen Hydrogel Patch (EFHP), a&#xD;
      transdermal product containing 165 mg of the S-enantiomer of flurbiprofen (S-flurbiprofen) as&#xD;
      its active pharmaceutical ingredient.&#xD;
&#xD;
      The present clinical trial will be conducted to characterise maximum observed systemic&#xD;
      exposure of the newly developed EFHP (Test) vs. &quot;Froben 100 mg&quot; (Reference, containing 100 mg&#xD;
      racemic flurbiprofen in a 1:1 ratio). Characterisation will be performed under steady state&#xD;
      conditions in order to bridge the available safety information on the basis of the comparison&#xD;
      of maximum observed systemic exposure by means of AUC0-24h,ss,P vs. AUC0-24,ss,T and&#xD;
      Cmax,ss,P vs. Cmax,ss,T of S-flurbiprofen.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This single centre, open-label, randomised (order of treatments), balanced, multiple dose&#xD;
      trial will be performed in a 2-period, 2-sequence-crossover design.&#xD;
&#xD;
      The Test Product (patch) will be applied once daily over 14 consecutive days, whereby each&#xD;
      patch will remain applied for 24 h. Blood sampling will be performed after the 1st patch&#xD;
      application over 24 h in order to characterise the single dose application and after the 14th&#xD;
      patch application over 72 h in order to characterise pharmacokinetic parameters after&#xD;
      multiple dosing including elimination phase. In between through values will be taken in the&#xD;
      morning of specified study days to characterise steady-state built-up phase.&#xD;
&#xD;
      The Reference product will be administered after a light meal as single oral doses of 100 mg&#xD;
      flurbiprofen three times daily (i.e. every 8 h) over 4 days. Blood sampling will be performed&#xD;
      after the 10th tablet administration over 72 h in order to characterise pharmacokinetic&#xD;
      parameters after multiple dosing including elimination phase. In between through values will&#xD;
      be taken in the morning of study days 1 to 4 to characterise steady-state built-up phase.&#xD;
&#xD;
      The clinical trial will be performed as a cross-over investigation with intra-individual&#xD;
      comparison, thus reducing variability of the pharmacokinetic parameters, which is supposed to&#xD;
      be higher between subjects than within an individual subject.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 24, 2020</start_date>
  <completion_date type="Actual">September 24, 2020</completion_date>
  <primary_completion_date type="Actual">September 9, 2020</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Assessment of non-superiority of Test in comparison to Reference under steady-state conditions determined by use of AUC0-24,ss,P vs. AUC0-24,ss,T of S-flurbiprofen</measure>
    <time_frame>24 hours</time_frame>
    <description>AUC0-24,ss,P = area under the plasma concentration vs. time curve from dosing time to the end of the dosing interval (profiling day after 14th patch application), calculated by means of the linear up/log down method (linear trapezoidal rule for increases in concentration/logarithmic trapezoidal rule for decreases in concentrations AUC0-24,ss,T = area under the plasma concentration vs. time profile over 24 h at profiling day from dosing time of 10th administration to 8 h after 12th administration, calculated by means of the linear up/log down method (linear trapezoidal rule for increases in concentration/logarithmic trapezoidal rule for decreases in concentrations</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Assessment of non-superiority of Test in comparison to Reference under steady-state conditions determined by use of Cmax,ss,P vs. Cmax,ss,T of S flurbiprofen</measure>
    <time_frame>24 hours</time_frame>
    <description>Cmax,ss,P = maximum concentration in plasma within the dosing interval (profiling day after 14th patch application), obtained directly from measured values Cmax,ss,T = maximum concentration over 24 h at profiling day from dosing time of 10th administration to 8 h after 12th administration, obtained directly from measured values</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Skin irritation properties for Esflurbiprofen hydrogel patch by frequency of scores</measure>
    <time_frame>16 days</time_frame>
    <description>frequency of scores for local tolerability and skin irritation per time point according to &quot;Assessing the Irritation and Sensitization Potential of Transdermal and Topical Delivery Systems for ANDAs&quot;, Guidance for Industry, DRAFT. 2018 October</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patch adhesion properties for Esflurbiprofen hydrogel patch by percentage of adhered patch area</measure>
    <time_frame>15 days</time_frame>
    <description>documentation of the percentage of area that remains adhered and scoring (i.e. percentage of adhered area and scores will be matched/combined) per time point according to &quot;Assessing Adhesion With Transdermal and Topical Delivery Systems for ANDAs&quot;, Guidance for Industry, DRAFT. 2018 October</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse Events</measure>
    <time_frame>28 days</time_frame>
    <description>Descriptive characterisation with regard to frequency and intensity, relationship to the IMP, action taken, outcome, and seriousness as well as period and treatment</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">26</enrollment>
  <condition>Comparative Bioavailability</condition>
  <arm_group>
    <arm_group_label>Esflurbiprofen hydrogel patch</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>&quot;Esflurbiprofen hydrogel patch 165 mg&quot; (EFHP) (Teikoku Seiyaku Co.), transdermal patch containing 165 mg S-flurbiprofen, once daily consecutive application over 14 days; each patch to be applied for 24 h, application site: outer ankle (same site and position for all applied patches)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Froben</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>&quot;Froben 100 mg comprimidos revestidos&quot; (Abbott Laboratórios, Lda., Portugal), immediate release tablets containing 100 mg flurbiprofen, oral multiple dose administration of 1 tablet three times daily (TID) over 4 consecutive days after a light meal</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Esflurbiprofen hydrogel patch 165 mg (EFHP)</intervention_name>
    <description>patch application with PK blood sampling</description>
    <arm_group_label>Esflurbiprofen hydrogel patch</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Froben 100 mg comprimidos revestidos</intervention_name>
    <description>tablet administration with PK blood sampling</description>
    <arm_group_label>Froben</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. age: 18 to 64 years (inclusive)&#xD;
&#xD;
          2. body-mass index (BMI): &gt;= 18.5 kg/m² and &lt;= 30.0 kg/m²&#xD;
&#xD;
          3. good state of health&#xD;
&#xD;
          4. non-smoker or ex-smoker for at least 3 months&#xD;
&#xD;
          5. written informed consent, after having been informed about benefits and potential&#xD;
             risks of the clinical trial, as well as details of the insurance taken out to cover&#xD;
             the subjects participating in the clinical trial&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Safety concerns&#xD;
&#xD;
          1. existing cardiac and/or haematological diseases or pathological findings, which might&#xD;
             interfere with the safety or tolerability of the active ingredient&#xD;
&#xD;
          2. existing or history of hypertension and/or heart failure&#xD;
&#xD;
          3. existing hepatic and/or renal diseases or pathological findings, which might interfere&#xD;
             with the safety or tolerability, and/or pharmacokinetics of the active ingredient&#xD;
&#xD;
          4. existing gastrointestinal diseases or pathological findings, which might interfere&#xD;
             with the safety, tolerability, absorption and/or pharmacokinetics of the active&#xD;
             ingredient&#xD;
&#xD;
          5. history of gastrointestinal bleeding or perforation related to previous NSAID therapy&#xD;
&#xD;
          6. active, or history of, ulcerative colitis, Crohn's disease, peptic ulceration or&#xD;
             gastrointestinal haemorrhage&#xD;
&#xD;
          7. existing metabolic, endocrine and/or immunologic diseases or pathological findings,&#xD;
             which might interfere with the safety or tolerability, and/or pharmacokinetics of the&#xD;
             active ingredient&#xD;
&#xD;
          8. diabetes mellitus&#xD;
&#xD;
          9. hyperlipidaemia (LDL &gt; 160 mg/dL; HDL &lt; 35 mg/dL; triglycerides &gt; 200 mg/dL;&#xD;
             cholesterol &gt; 240 mg/dL)&#xD;
&#xD;
         10. history of relevant CNS and/or psychiatric disorders and/or currently treated CNS&#xD;
             and/or psychiatric disorders&#xD;
&#xD;
         11. presence or history of acute or chronic diseases of the skin (e.g. atopy,&#xD;
             neurodermatitis, contact allergy, eczema, psoriasis, vitiligo, melanoma, squamous cell&#xD;
             carcinoma), any dermatological condition or skin sensitivity which might interfere&#xD;
             with the safety, tolerability, absorption and/or pharmacokinetics of the active&#xD;
             ingredient&#xD;
&#xD;
         12. existing or history of bronchial asthma&#xD;
&#xD;
         13. known allergic reactions (e.g. bronchospasm, rhinitis, angioedema, or urticaria) to&#xD;
             the active ingredients used, to acetylsalicylic acid or other NSAIDs, or to&#xD;
             constituents of the pharmaceutical preparations&#xD;
&#xD;
         14. history of severe allergies or multiple drug allergies unless it is judged as not&#xD;
             relevant for the clinical trial by the investigator&#xD;
&#xD;
         15. fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase&#xD;
             insufficiency&#xD;
&#xD;
         16. galactose intolerance or Lapp lactase deficiency&#xD;
&#xD;
         17. systolic blood pressure &lt; 90 or &gt; 139 mmHg&#xD;
&#xD;
         18. diastolic blood pressure &lt; 60 or &gt; 89 mmHg&#xD;
&#xD;
         19. heart rate &lt; 50 bpm or &gt; 90 bpm&#xD;
&#xD;
         20. QTc interval &gt; 450 ms for men and &gt; 470 ms for women&#xD;
&#xD;
         21. laboratory values out of normal range unless the deviation from normal is judged as&#xD;
             not relevant for the clinical trial by the investigator&#xD;
&#xD;
         22. ASAT &gt; 20% ULN, ALAT &gt; 10% ULN, bilirubin &gt; 20% ULN (except in case of existing Morbus&#xD;
             Gilbert-Meulengracht deduced from anamnesis/medical history) and creatinine &gt; 0.1&#xD;
             mg/dL ULN (limit of &gt; 0.1 mg/dL correspondents to of &gt; 9 µmol/l ULN).&#xD;
&#xD;
         23. positive anti-HIV-test (if positive to be verified by western blot), HBs-AG-test or&#xD;
             anti-HCV-test&#xD;
&#xD;
         24. symptoms of, or diagnosis of COVID-19 within the last 14 days prior to individual&#xD;
             enrolment of the subject&#xD;
&#xD;
         25. contact to persons in risk regions as defined by the Robert Koch Institute within the&#xD;
             last 14 days prior to individual enrolment of the subject&#xD;
&#xD;
         26. direct contact to persons with symptoms of, or diagnosis of COVID-19 within the last&#xD;
             14 days prior to individual enrolment of the subject Lack of suitability for the&#xD;
             clinical trial&#xD;
&#xD;
         27. skin abnormality (e.g. tattoo (including tattoo that was removed), scar, sunburn or&#xD;
             obvious difference in skin colour), open sores, or excessive hair at the application&#xD;
             site&#xD;
&#xD;
         28. acute or chronic diseases which may interfere with the pharmacokinetics of the IMP&#xD;
&#xD;
         29. history of or current drug or alcohol dependence&#xD;
&#xD;
         30. positive alcohol or drug test at screening examination&#xD;
&#xD;
         31. regular intake of alcoholic food or beverages of &gt;= 24 g pure ethanol for male or &gt;=&#xD;
             12 g pure ethanol for female per day&#xD;
&#xD;
         32. subjects who are on a diet which could affect the pharmacokinetics of the active&#xD;
             ingredient&#xD;
&#xD;
         33. regular intake of caffeine containing food or beverages of &gt;= 500 mg caffeine per day&#xD;
&#xD;
         34. blood donation or other blood loss of more than 400 ml within the last 2 months prior&#xD;
             to individual enrolment of the subject&#xD;
&#xD;
         35. administration of any investigational medicinal product during the last 2 months prior&#xD;
             to individual enrolment of the subject&#xD;
&#xD;
         36. regular treatment with any systemically available medication (except hormonal&#xD;
             contraceptives and hormonal replacement therapy, e.g. estrogens, L-thyroxine)&#xD;
&#xD;
         37. subjects, who report a frequent occurrence of migraine attacks&#xD;
&#xD;
             For female subjects with childbearing potential only:&#xD;
&#xD;
         38. positive pregnancy test at screening examination&#xD;
&#xD;
         39. pregnant or lactating women&#xD;
&#xD;
         40. female subjects who do not agree to apply highly effective contraceptive methods&#xD;
             Administrative reasons&#xD;
&#xD;
         41. subjects suspected or known not to follow instructions&#xD;
&#xD;
         42. subjects who are unable to understand the written and verbal instructions, in&#xD;
             particular regarding the risks and inconveniences they will be exposed to during their&#xD;
             participation in the clinical trial&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>64 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Frank Donath, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>SocraTec R&amp;D GmbH Clinical Pharmacology Unit</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>SocraTec R&amp;D GmbH, Clinical Pharmacology Unit</name>
      <address>
        <city>Erfurt</city>
        <state>Thuringia</state>
        <zip>99084</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <verification_date>October 2020</verification_date>
  <study_first_submitted>July 13, 2020</study_first_submitted>
  <study_first_submitted_qc>August 6, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 10, 2020</study_first_posted>
  <last_update_submitted>October 20, 2020</last_update_submitted>
  <last_update_submitted_qc>October 20, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">October 22, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Bioavailability</keyword>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04505787
org study id: 1378fbp19ct
secondary id: 2019-003918-14
secondary id: TK-254R-0101
nct id: NCT04505787
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
Teikoku Seiyaku Co., Ltd. (Japan) is developing a new Esflurbiprofen Hydrogel Patch (EFHP), a
      transdermal product containing 165 mg of the S-enantiomer of flurbiprofen (S-flurbiprofen) as
      its active pharmaceutical ingredient.

      The present clinical trial will be conducted to characterise maximum observed systemic
      exposure of the newly developed EFHP (Test) vs. "Froben 100 mg" (Reference, containing 100 mg
      racemic flurbiprofen in a 1:1 ratio). Characterisation will be performed under steady state
      conditions in order to bridge the available safety information on the basis of the comparison
      of maximum observed systemic exposure by means of AUC0-24h,ss,P vs. AUC0-24,ss,T and
      Cmax,ss,P vs. Cmax,ss,T of S-flurbiprofen.
This single centre, open-label, randomised (order of treatments), balanced, multiple dose
      trial will be performed in a 2-period, 2-sequence-crossover design.

      The Test Product (patch) will be applied once daily over 14 consecutive days, whereby each
      patch will remain applied for 24 h. Blood sampling will be performed after the 1st patch
      application over 24 h in order to characterise the single dose application and after the 14th
      patch application over 72 h in order to characterise pharmacokinetic parameters after
      multiple dosing including elimination phase. In between through values will be taken in the
      morning of specified study days to characterise steady-state built-up phase.

      The Reference product will be administered after a light meal as single oral doses of 100 mg
      flurbiprofen three times daily (i.e. every 8 h) over 4 days. Blood sampling will be performed
      after the 10th tablet administration over 72 h in order to characterise pharmacokinetic
      parameters after multiple dosing including elimination phase. In between through values will
      be taken in the morning of study days 1 to 4 to characterise steady-state built-up phase.

      The clinical trial will be performed as a cross-over investigation with intra-individual
      comparison, thus reducing variability of the pharmacokinetic parameters, which is supposed to
      be higher between subjects than within an individual subject.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Other
masking: None (Open Label)
measure: Assessment of non-superiority of Test in comparison to Reference under steady-state conditions determined by use of AUC0-24,ss,P vs. AUC0-24,ss,T of S-flurbiprofen
time frame: 24 hours
description: AUC0-24,ss,P = area under the plasma concentration vs. time curve from dosing time to the end of the dosing interval (profiling day after 14th patch application), calculated by means of the linear up/log down method (linear trapezoidal rule for increases in concentration/logarithmic trapezoidal rule for decreases in concentrations AUC0-24,ss,T = area under the plasma concentration vs. time profile over 24 h at profiling day from dosing time of 10th administration to 8 h after 12th administration, calculated by means of the linear up/log down method (linear trapezoidal rule for increases in concentration/logarithmic trapezoidal rule for decreases in concentrations
measure: Assessment of non-superiority of Test in comparison to Reference under steady-state conditions determined by use of Cmax,ss,P vs. Cmax,ss,T of S flurbiprofen
time frame: 24 hours
description: Cmax,ss,P = maximum concentration in plasma within the dosing interval (profiling day after 14th patch application), obtained directly from measured values Cmax,ss,T = maximum concentration over 24 h at profiling day from dosing time of 10th administration to 8 h after 12th administration, obtained directly from measured values
measure: Skin irritation properties for Esflurbiprofen hydrogel patch by frequency of scores
time frame: 16 days
description: frequency of scores for local tolerability and skin irritation per time point according to "Assessing the Irritation and Sensitization Potential of Transdermal and Topical Delivery Systems for ANDAs", Guidance for Industry, DRAFT. 2018 October
measure: Patch adhesion properties for Esflurbiprofen hydrogel patch by percentage of adhered patch area
time frame: 15 days
description: documentation of the percentage of area that remains adhered and scoring (i.e. percentage of adhered area and scores will be matched/combined) per time point according to "Assessing Adhesion With Transdermal and Topical Delivery Systems for ANDAs", Guidance for Industry, DRAFT. 2018 October
measure: Adverse Events
time frame: 28 days
description: Descriptive characterisation with regard to frequency and intensity, relationship to the IMP, action taken, outcome, and seriousness as well as period and treatment
arm group label: Esflurbiprofen hydrogel patch
arm group type: Experimental
description: "Esflurbiprofen hydrogel patch 165 mg" (EFHP) (Teikoku Seiyaku Co.), transdermal patch containing 165 mg S-flurbiprofen, once daily consecutive application over 14 days; each patch to be applied for 24 h, application site: outer ankle (same site and position for all applied patches)
arm group label: Froben
arm group type: Active Comparator
description: "Froben 100 mg comprimidos revestidos" (Abbott Laboratórios, Lda., Portugal), immediate release tablets containing 100 mg flurbiprofen, oral multiple dose administration of 1 tablet three times daily (TID) over 4 consecutive days after a light meal
intervention type: Drug
intervention name: Esflurbiprofen hydrogel patch 165 mg (EFHP)
description: patch application with PK blood sampling
arm group label: Esflurbiprofen hydrogel patch
intervention type: Drug
intervention name: Froben 100 mg comprimidos revestidos
description: tablet administration with PK blood sampling
arm group label: Froben
criteria: 
gender: All
minimum age: 18 Years
maximum age: 64 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Frank Donath, MD
role: Principal Investigator
affiliation: SocraTec R&D GmbH Clinical Pharmacology Unit
facility: 
country: Germany
responsible party type: Sponsor
sharing ipd: Yes