<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/NCT02976727</url>
  </required_header>
  <id_info>
    <org_study_id>DAUderma-07</org_study_id>
    <nct_id>NCT02976727</nct_id>
  </id_info>
  <brief_title>Efficacy of Topical Calcipotriol-assisted AFL-PDT in Actinic Keratosis</brief_title>
  <official_title>Efficacy of Topical Calcipotriol-assisted Ablative Fractional Laser Photodynamic Therapy for the Treatment of Actinic Keratosis: 12-month Follow-up Results of a Prospective, Randomised, Comparative Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Dong-A University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Dong-A University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Vitamin D(Vit D) is a pro-differentiation agent that enhances the accumulation of&#xD;
      protoporphyrin IX (PpIX) after MAL(methyl-aminolevulinate) incubation in actinic keratosis&#xD;
      and may have significant benefit for the treatment of actinic keratosis by ablative&#xD;
      fractional laser-primed photodynamic therapy (AFL-PDT).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Photodynamic therapy (PDT) with methyl-aminolevulinate (MAL) is effective in the treatment of&#xD;
      actinic keratosis (AK). Many strategies have been studied to improve the production of&#xD;
      protoporphyrin IX (PpIX), to improve efficacy of PDT. Pre-treatment of the skin with&#xD;
      fractional laser resurfacing is a novel alternative technique to improve the efficacy of PDT&#xD;
      for AK. The investigators' previous studies showed that ablative fractional laser primed PDT&#xD;
      (AFL-PDT) offered higher efficacy than conventional MAL-PDT in the treatment of AK. But,&#xD;
      reduced response rates are also observed in thicker skin lesions, which may be due to&#xD;
      insufficient PpIX accumulation within the target tissue.&#xD;
&#xD;
      Cellular differentiation leads to increased synthesis of PpIX from MAL and consecutively,&#xD;
      differentiation therapy enhances photosensitization effect. Topical calcipotriol is a&#xD;
      well-known pro-differentiation hormone and was demonstrated to influence the effect of PDT on&#xD;
      keratinocytes.&#xD;
&#xD;
      The aim of this study was to evaluate efficacy of topical vitamin D in AFL-PDT for AK&#xD;
      treatment. Consequently, the investigator compared efficacy, recurrence rate, cosmetic&#xD;
      outcome and safety between VitD - AFL-PDT and conventional AFL-PDT.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>May 2014</start_date>
  <completion_date type="Actual">August 2015</completion_date>
  <primary_completion_date type="Actual">August 2015</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>Factorial Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Differences of short-term complete response rates between VitD-AFL-PDT and AFL-PDT</measure>
    <time_frame>Short-term complete response rates were evaluated at 3 months after treatment</time_frame>
    <description>Lesion responses were classified as either a complete response (complete disappearance of the lesion) or a noncomplete response (incomplete disappearance)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Differences of long-term complete response rates between VitD-AFL-PDT and AFL-PDT</measure>
    <time_frame>Long-term complete response rates were evaluated at 12 months</time_frame>
    <description>In all cases of complete response, the patients were reviewed at 12 months to check for recurrence. Recurrence was assessed by inspection, dermoscopy, photography, palpation, and histologic findings. For the histopathologic evaluation of treatment response, at the 12-month follow-up visit, a 3-mm punch biopsy of the treated AK lesion was performed in all cases of clinically incomplete response.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Difference of the recurrence rates between VitD-AFL-PDT and AFL-PDT</measure>
    <time_frame>Recurrence rates were evaluated respectively at 12 months after treatment.</time_frame>
    <description>In all cases of complete response, the patients were reviewed at 12 months to check for recurrence. Recurrence was assessed by inspection, dermoscopy, photography, palpation, and histologic findings. For the histopathologic evaluation of treatment response, at the 12-month follow-up visit, a 3-mm punch biopsy of the treated AK lesion was performed in all cases of clinically incomplete response.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Differences of cosmetic outcomes between VitD-AFL-PDT and AFL-PDT</measure>
    <time_frame>The overall cosmetic outcome was assessed 12 months after treatment</time_frame>
    <description>Cosmetic outcomes were graded as excellent (slight redness or pigmentation change), good (moderate redness or pigmentation change), fair (slight-to-moderate scarring, atrophy, or induration), or poor (extensive scarring, atrophy, or induration)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Difference of adverse events (erythema, post-inflammatory hyperpigmentation, edema, itching, oozing, bleeding) rates between VitD-AFL-PDT and AFL-PDT</measure>
    <time_frame>Within 12 months after each treatment</time_frame>
    <description>Adverse events reported by the patient were noted at each follow-up visit, including severity, duration and need for additional therapy. All events due to PDT were described as phototoxic reactions (i.e., erythema, post-inflammatory hyperpigmentation, oedema, itching, oozing, bleeding and so forth).</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Differences of the fluorescence intensity between VitD-AFL-PDT and AFL-PDT</measure>
    <time_frame>After 3 hours of application with MAL, fluorescence intensity imaging was assessed 10 minutes before illumination.</time_frame>
    <description>After 3 hours of application with MAL, Fluorescence imaging analysis was performed on treatment area with ultraviolet examination light (model 31602,356 nm; Burton Medical Products Crop.) at 10 cm height above the base of each lesion. The red fluorescence was separated and extracted by ImageJ program and then used to measure the amount of 633 nm fluorescence of protoporphyrin IX.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">48</enrollment>
  <condition>Actinic Dermatosis</condition>
  <arm_group>
    <arm_group_label>GroupA (Vit-D pretreated AFL-PDT group )</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Group A was treated with topical VitD-assisted AFL-PDT</description>
  </arm_group>
  <arm_group>
    <arm_group_label>GroupB (Conventional AFL PDT group )</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Group B was treated with conventional AFL-PDT</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Topical Vitamin D (Calcipotriol) application</intervention_name>
    <description>Calcipotriol ointment 50 mcg/g (Daivonex, Leo Pharma, Denmark) was applied twice for daily on treatment area for 15 consecutive days.</description>
    <arm_group_label>GroupA (Vit-D pretreated AFL-PDT group )</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo cream application</intervention_name>
    <description>placebo cream (indistinguishable from calcipotriol cream by visual and physical appearance and sense of smell) was applied twice for daily on treatment area for 15 consecutive days.</description>
    <arm_group_label>GroupB (Conventional AFL PDT group )</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>lidocaine/prilocaine (5%) application</intervention_name>
    <description>For AFL pre-treatment, lidocaine/prilocaine (5%) cream (EMLA; Astra Pharmaceuticals, LP, Westborough, MA, USA) was applied to the treatment area under occlusion for 30 min</description>
    <arm_group_label>GroupA (Vit-D pretreated AFL-PDT group )</arm_group_label>
    <arm_group_label>GroupB (Conventional AFL PDT group )</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>2940-nm Er:YAG AFL pretreatment</intervention_name>
    <description>After the anaesthetic cream was removed, AFL therapy was performed using a 2940-nm Er:YAG AFL (Joule; Sciton Inc., Palo Alto, CA, USA) at 300-550 µm ablation depth, level 1 coagulation, 22% treatment density and a single pulse</description>
    <arm_group_label>GroupA (Vit-D pretreated AFL-PDT group )</arm_group_label>
    <arm_group_label>GroupB (Conventional AFL PDT group )</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>MAL application</intervention_name>
    <description>Immediately after AFL treatment, an approximately 1- mm-thick layer of MAL (Metvix, PhotoCure ASA, Oslo, Norway) was applied to the lesion and on 5 mm of surrounding normal tissue. Incubation time is 3 hours</description>
    <arm_group_label>GroupA (Vit-D pretreated AFL-PDT group )</arm_group_label>
    <arm_group_label>GroupB (Conventional AFL PDT group )</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Measurements of the fluorescence intensity</intervention_name>
    <description>After 3 hours of application with MAL, saline wash was performed and fluorescence imaging analysis was performed with ultraviolet examination light (model 31602,356 nm; Burton Medical Products Crop.) at 10 cm height above the base of each lesion. The red fluorescence (610 nm-700 nm) was separated and extracted by ImageJ program and then used to measure the amount of 633 nm fluorescence of protoporphyrin IX.</description>
    <arm_group_label>GroupA (Vit-D pretreated AFL-PDT group )</arm_group_label>
    <arm_group_label>GroupB (Conventional AFL PDT group )</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>irradiation with red light-emitting diode lamp</intervention_name>
    <description>After incubation for 3 hours, the dressing and cream were removed, and the area was cleansed with saline. The area was irradiated with a red light-emitting diode lamp (Aktilite CL 128; PhotoCure ASA, Oslo, Norway) with peak emission at 632 nm, placed 5 cm away from the skin surface, and a total light dose of 37 J/cm-2. All patients wore protective goggles during illumination.</description>
    <arm_group_label>GroupA (Vit-D pretreated AFL-PDT group )</arm_group_label>
    <arm_group_label>GroupB (Conventional AFL PDT group )</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Korean patients aged ≥ 18 years who had biopsy-confirmed Actinic keratosis lesions&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  calcium metabolic disorder patients&#xD;
&#xD;
          -  photosensitivity disorder patients&#xD;
&#xD;
          -  lactating or pregnant women&#xD;
&#xD;
          -  patients with porphyria or a known allergy to any of the constituents of the MAL cream&#xD;
             and lidocaine&#xD;
&#xD;
          -  patients with systemic disease, history of malignant melanoma, tendency of melasma&#xD;
             development or keloid formation, any AK treatment of the area in the previous 4 weeks,&#xD;
             or any conditions associated with a risk of poor protocol compliance; and patients on&#xD;
             immunosuppressive treatment&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>65 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Dong-A University</name>
      <address>
        <city>Busan, Seo-gu, Korea, Republic of, 602-715</city>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Korea, Republic of</country>
  </location_countries>
  <verification_date>November 2016</verification_date>
  <study_first_submitted>November 5, 2016</study_first_submitted>
  <study_first_submitted_qc>November 28, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 29, 2016</study_first_posted>
  <last_update_submitted>November 28, 2016</last_update_submitted>
  <last_update_submitted_qc>November 28, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">November 29, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Dong-A University</investigator_affiliation>
    <investigator_full_name>Song Ki-Hoon</investigator_full_name>
    <investigator_title>Assistant professor and chairman, Department of dermatology Dong-A University, College of medicine</investigator_title>
  </responsible_party>
  <keyword>Vitamin D</keyword>
  <keyword>Calcipotriol</keyword>
  <keyword>Ablative fractional laser</keyword>
  <keyword>Actinic keratosis</keyword>
  <keyword>Photodynamic therapy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Keratosis, Actinic</mesh_term>
    <mesh_term>Keratosis</mesh_term>
    <mesh_term>Skin Diseases</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vitamin D</mesh_term>
    <mesh_term>Lidocaine</mesh_term>
    <mesh_term>Prilocaine</mesh_term>
    <mesh_term>Lidocaine, Prilocaine Drug Combination</mesh_term>
    <mesh_term>Calcipotriene</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02976727
org study id: DAUderma-07
nct id: NCT02976727
lead sponsor: 
has dmc: No
Vitamin D(Vit D) is a pro-differentiation agent that enhances the accumulation of
      protoporphyrin IX (PpIX) after MAL(methyl-aminolevulinate) incubation in actinic keratosis
      and may have significant benefit for the treatment of actinic keratosis by ablative
      fractional laser-primed photodynamic therapy (AFL-PDT).
Photodynamic therapy (PDT) with methyl-aminolevulinate (MAL) is effective in the treatment of
      actinic keratosis (AK). Many strategies have been studied to improve the production of
      protoporphyrin IX (PpIX), to improve efficacy of PDT. Pre-treatment of the skin with
      fractional laser resurfacing is a novel alternative technique to improve the efficacy of PDT
      for AK. The investigators' previous studies showed that ablative fractional laser primed PDT
      (AFL-PDT) offered higher efficacy than conventional MAL-PDT in the treatment of AK. But,
      reduced response rates are also observed in thicker skin lesions, which may be due to
      insufficient PpIX accumulation within the target tissue.

      Cellular differentiation leads to increased synthesis of PpIX from MAL and consecutively,
      differentiation therapy enhances photosensitization effect. Topical calcipotriol is a
      well-known pro-differentiation hormone and was demonstrated to influence the effect of PDT on
      keratinocytes.

      The aim of this study was to evaluate efficacy of topical vitamin D in AFL-PDT for AK
      treatment. Consequently, the investigator compared efficacy, recurrence rate, cosmetic
      outcome and safety between VitD - AFL-PDT and conventional AFL-PDT.
allocation: Randomized
intervention model: Factorial Assignment
primary purpose: Treatment
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Differences of short-term complete response rates between VitD-AFL-PDT and AFL-PDT
time frame: Short-term complete response rates were evaluated at 3 months after treatment
description: Lesion responses were classified as either a complete response (complete disappearance of the lesion) or a noncomplete response (incomplete disappearance)
measure: Differences of long-term complete response rates between VitD-AFL-PDT and AFL-PDT
time frame: Long-term complete response rates were evaluated at 12 months
description: In all cases of complete response, the patients were reviewed at 12 months to check for recurrence. Recurrence was assessed by inspection, dermoscopy, photography, palpation, and histologic findings. For the histopathologic evaluation of treatment response, at the 12-month follow-up visit, a 3-mm punch biopsy of the treated AK lesion was performed in all cases of clinically incomplete response.
measure: Difference of the recurrence rates between VitD-AFL-PDT and AFL-PDT
time frame: Recurrence rates were evaluated respectively at 12 months after treatment.
description: In all cases of complete response, the patients were reviewed at 12 months to check for recurrence. Recurrence was assessed by inspection, dermoscopy, photography, palpation, and histologic findings. For the histopathologic evaluation of treatment response, at the 12-month follow-up visit, a 3-mm punch biopsy of the treated AK lesion was performed in all cases of clinically incomplete response.
measure: Differences of cosmetic outcomes between VitD-AFL-PDT and AFL-PDT
time frame: The overall cosmetic outcome was assessed 12 months after treatment
description: Cosmetic outcomes were graded as excellent (slight redness or pigmentation change), good (moderate redness or pigmentation change), fair (slight-to-moderate scarring, atrophy, or induration), or poor (extensive scarring, atrophy, or induration)
measure: Difference of adverse events (erythema, post-inflammatory hyperpigmentation, edema, itching, oozing, bleeding) rates between VitD-AFL-PDT and AFL-PDT
time frame: Within 12 months after each treatment
description: Adverse events reported by the patient were noted at each follow-up visit, including severity, duration and need for additional therapy. All events due to PDT were described as phototoxic reactions (i.e., erythema, post-inflammatory hyperpigmentation, oedema, itching, oozing, bleeding and so forth).
measure: Differences of the fluorescence intensity between VitD-AFL-PDT and AFL-PDT
time frame: After 3 hours of application with MAL, fluorescence intensity imaging was assessed 10 minutes before illumination.
description: After 3 hours of application with MAL, Fluorescence imaging analysis was performed on treatment area with ultraviolet examination light (model 31602,356 nm; Burton Medical Products Crop.) at 10 cm height above the base of each lesion. The red fluorescence was separated and extracted by ImageJ program and then used to measure the amount of 633 nm fluorescence of protoporphyrin IX.
arm group label: GroupA (Vit-D pretreated AFL-PDT group )
arm group type: Experimental
description: Group A was treated with topical VitD-assisted AFL-PDT
arm group label: GroupB (Conventional AFL PDT group )
arm group type: Active Comparator
description: Group B was treated with conventional AFL-PDT
intervention type: Drug
intervention name: Topical Vitamin D (Calcipotriol) application
description: Calcipotriol ointment 50 mcg/g (Daivonex, Leo Pharma, Denmark) was applied twice for daily on treatment area for 15 consecutive days.
arm group label: GroupA (Vit-D pretreated AFL-PDT group )
intervention type: Drug
intervention name: Placebo cream application
description: placebo cream (indistinguishable from calcipotriol cream by visual and physical appearance and sense of smell) was applied twice for daily on treatment area for 15 consecutive days.
arm group label: GroupB (Conventional AFL PDT group )
intervention type: Drug
intervention name: lidocaine/prilocaine (5%) application
description: For AFL pre-treatment, lidocaine/prilocaine (5%) cream (EMLA; Astra Pharmaceuticals, LP, Westborough, MA, USA) was applied to the treatment area under occlusion for 30 min
arm group label: GroupA (Vit-D pretreated AFL-PDT group )
arm group label: GroupB (Conventional AFL PDT group )
intervention type: Device
intervention name: 2940-nm Er:YAG AFL pretreatment
description: After the anaesthetic cream was removed, AFL therapy was performed using a 2940-nm Er:YAG AFL (Joule; Sciton Inc., Palo Alto, CA, USA) at 300-550 µm ablation depth, level 1 coagulation, 22% treatment density and a single pulse
arm group label: GroupA (Vit-D pretreated AFL-PDT group )
arm group label: GroupB (Conventional AFL PDT group )
intervention type: Drug
intervention name: MAL application
description: Immediately after AFL treatment, an approximately 1- mm-thick layer of MAL (Metvix, PhotoCure ASA, Oslo, Norway) was applied to the lesion and on 5 mm of surrounding normal tissue. Incubation time is 3 hours
arm group label: GroupA (Vit-D pretreated AFL-PDT group )
arm group label: GroupB (Conventional AFL PDT group )
intervention type: Other
intervention name: Measurements of the fluorescence intensity
description: After 3 hours of application with MAL, saline wash was performed and fluorescence imaging analysis was performed with ultraviolet examination light (model 31602,356 nm; Burton Medical Products Crop.) at 10 cm height above the base of each lesion. The red fluorescence (610 nm-700 nm) was separated and extracted by ImageJ program and then used to measure the amount of 633 nm fluorescence of protoporphyrin IX.
arm group label: GroupA (Vit-D pretreated AFL-PDT group )
arm group label: GroupB (Conventional AFL PDT group )
intervention type: Device
intervention name: irradiation with red light-emitting diode lamp
description: After incubation for 3 hours, the dressing and cream were removed, and the area was cleansed with saline. The area was irradiated with a red light-emitting diode lamp (Aktilite CL 128; PhotoCure ASA, Oslo, Norway) with peak emission at 632 nm, placed 5 cm away from the skin surface, and a total light dose of 37 J/cm-2. All patients wore protective goggles during illumination.
arm group label: GroupA (Vit-D pretreated AFL-PDT group )
arm group label: GroupB (Conventional AFL PDT group )
criteria: 
gender: All
minimum age: 65 Years
maximum age: 85 Years
healthy volunteers: Accepts Healthy Volunteers
facility: 
country: Korea, Republic of
responsible party type: Principal Investigator
investigator affiliation: Dong-A University
investigator full name: Song Ki-Hoon
investigator title: Assistant professor and chairman, Department of dermatology Dong-A University, College of medicine
mesh term: Keratosis, Actinic
mesh term: Keratosis
mesh term: Skin Diseases
mesh term: Vitamin D
mesh term: Lidocaine
mesh term: Prilocaine
mesh term: Lidocaine, Prilocaine Drug Combination
mesh term: Calcipotriene
sharing ipd: No