<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/NCT01682811</url>
  </required_header>
  <id_info>
    <org_study_id>PRO 14555</org_study_id>
    <nct_id>NCT01682811</nct_id>
  </id_info>
  <brief_title>Phase I Photodynamic Therapy (PDT) for Benign Dermal Neurofibromas (NF1)</brief_title>
  <official_title>Photodynamic Therapy for Benign Dermal Neurofibromas Using Levulan Kerastick For Topical Solution, Plus Illumination With Red Light</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Harry T Whelan, MD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Medical College of Wisconsin</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      GENERAL OBJECTIVE The general objective is to assess the safety and efficacy of photodynamic&#xD;
      therapy (PDT) in the treatment of neurofibromatosis 1 (NF1) tumors in the skin.&#xD;
&#xD;
      SPECIFIC OBJECTIVE This is a light dose escalation pilot study to determine the safety and&#xD;
      efficacy of PDT using 5-aminolevulinic acid (ALA) and 633 nm light in the treatment of benign&#xD;
      dermal neurofibromas.&#xD;
&#xD;
      Specifically, the primary goal of the current study is to determine the maximum tolerable&#xD;
      light doses that can be administered to subjects undergoing topical photoillumination&#xD;
      photodynamic therapy with standard application of Levulan Kerastick (ALA) for Topical&#xD;
      Solution.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      STUDY DESIGN This protocol is a Phase I light dose escalation pilot study to determine the&#xD;
      safety and, secondarily, the efficacy of PDT using Levulan and 633 nm light in the treatment&#xD;
      of benign dermal neurofibromas. This protocol represents the first two parts of a planned&#xD;
      three part study including both pediatric and adult subjects. Part 1 will consist of studying&#xD;
      the penetration and uptake of the PS in neurofibromas that are scheduled for excision. These&#xD;
      tumors will be excised for therapeutic reasons unrelated to this study, and so this study&#xD;
      will place no further burden on the subject other than a 3-24 hr incubation of the Levulan on&#xD;
      the tumor prior to excision. The primary hypothesis to be tested is whether Levulan will&#xD;
      accumulate, and be converted to PpIX, by the tumor tissue more than by the surrounding normal&#xD;
      tissue. Secondary hypotheses are that tumors incubated with Levulan will show greater&#xD;
      fluorescence than untreated tumors and tumors incubated with vehicle only (placebo&#xD;
      application).&#xD;
&#xD;
      As the Institutional Review Boards involved generally desire pilot data on adult populations&#xD;
      first, we will with then proceed with the adult clinical trial portion of this protocol as&#xD;
      part 2. Part 2 will use the optimum incubation time, if one has been identified in part 1,&#xD;
      and add a dose escalation study of the amount of red light used to activate the Levulan. Part&#xD;
      3, with pediatric subjects, will commence at a future date, pending review of the initial&#xD;
      adult study results.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 12, 2012</start_date>
  <completion_date type="Actual">July 7, 2016</completion_date>
  <primary_completion_date type="Actual">October 23, 2015</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Part 1: Photosensitizer Uptake and Conversion to Protoporphyrin IX</measure>
    <time_frame>24 hours</time_frame>
    <description>The average fluorescence value for PpIX positive tumor areas in excised, sectioned tumors, as determined by fluorescence microscopy. PpIX signals were detected with excitation at 405 nm and emission with a 600 nm long pass filter. PpIX positive areas were determined to be those exhibiting fluorescence above background levels.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part 2: Maximum Tolerated Dose (MTD) of 633 nm Red Light</measure>
    <time_frame>48 hours</time_frame>
    <description>MTD was determined by testing increasing doses up to 200 J/cm^2 on dose escalation cohorts 1 to 3 with 3 to 6 participants each. MTD reflects the highest dose of red light that did not cause a Dose-Limiting Toxicity (DLT) in &gt; 33% of participants. DLT was defined as pain during irradiation requiring cessation of the light treatment, or any serious cutaneous adverse events.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Part 1: Optimal Occlusion Time</measure>
    <time_frame>24 hours</time_frame>
    <description>An optimal occlusion time may be apparent from the results of the three time points. If no optimal occlusion time is seen, any occlusion time from 3-24 hours may be chosen for part 2. This secondary outcome measure is not critical to continuing the study, but may be useful in guiding treatment protocols</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 2: Efficacy - Lesion Area Growth Rate</measure>
    <time_frame>12 weeks</time_frame>
    <description>Average lesion growth rates observed in ALA-treated lesions compared to vehicle-treated lesions within the same subjects.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 2: Cosmetic Improvement</measure>
    <time_frame>1 year</time_frame>
    <description>Potential cosmetic improvement using subject satisfaction scale.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part 2: Pain Reduction</measure>
    <time_frame>1 year</time_frame>
    <description>Potential pain reduction, as measured by standard visual analog 1-10 scale.</description>
  </secondary_outcome>
  <number_of_arms>7</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Neurofibromatoses</condition>
  <arm_group>
    <arm_group_label>Part 1 Levulan injection</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>5-aminolevulinic acid uptake by control lesions after Levulan vehicle (placebo) injection and 3 hr incubation, and by Levulan treated lesions after 3 or 24 hr incubation.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 1 Levulan painting</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>5-aminolevulinic acid uptake by control lesions after Levulan vehicle (placebo) surface application and 3 hr incubation, and by Levulan treated lesions and 3 or 24 hr incubation.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 1 Levulan painted twice</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>5-aminolevulinic acid uptake by control lesions after Levulan vehicle (placebo) surface application twice or by Levulan treated lesions twice and 24 hr incubation.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 1 Levulan painted twice with microneedling</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>5-aminolevulinic acid uptake by control lesions after Levulan vehicle (placebo) surface application twice or by Levulan treated lesions twice and 24 hr incubation. All lesions prepared with microneedling.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 2 Dose level 1 50 J/cm^2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 1 - 50 J/cm^2 633 nm red light to Levulan vehicle (placebo) treated control lesions or Levulan treated lesions and 24 hr incubation. Follow-ups on day 2 for punch biopsies, 14-28 days for evaluation of cutaneous adverse events, and every 3 months up to one year for lesion measurements.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 2 Dose level 2 100 J/cm^2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 2 - 100 J/cm^2 633 nm red light to Levulan vehicle (placebo) treated control lesions or Levulan treated lesions and 24 hr incubation. Follow-ups on day 2 for punch biopsies, 14-28 days for evaluation of cutaneous adverse events, and every 3 months up to one year for lesion measurements.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 2 Dose level 3 200 J/cm^2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 3 - 200 J/cm^2 633 nm red light to Levulan vehicle (placebo) treated control lesions or Levulan treated lesions and 24 hr incubation. Follow-ups on day 2 for punch biopsies, 14-28 days for evaluation of cutaneous adverse events, and every 3 months up to one year for lesion measurements.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Part 1 Levulan injection</intervention_name>
    <description>Control or treatment lesions will be injected with Levulan vehicle only or active drug and incubated under occlusion for 3 or 24 hrs. A minimum of three lesions per group on the same subject will be treated. Lesions will then be excised in the normal manner, sectioned vertically, and checked for Protoporphyrin IX using fluorescence microscopy.</description>
    <arm_group_label>Part 1 Levulan injection</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Part 1 Levulan surface application</intervention_name>
    <description>Control or treatment lesions will be painted with Levulan vehicle only or active drug, allowed to dry, and incubated under occlusion for 3 or 24 hrs. A minimum of three lesions per group on the same subject will be treated. Lesions will then be excised in the normal manner, sectioned vertically, and checked for Protoporphyrin IX using fluorescence microscopy.</description>
    <arm_group_label>Part 1 Levulan painting</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Part 1 Levulan surface application twice</intervention_name>
    <description>Control or treatment lesions will be painted twice with Levulan vehicle only or active drug, allowed to dry between and after applications, and incubated under occlusion for 3 hrs. A minimum of three tumors per group on the same subject will be treated. Lesions will then be excised in the normal manner, sectioned vertically, and checked for Protoporphyrin IX using fluorescence microscopy.</description>
    <arm_group_label>Part 1 Levulan painted twice</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Part 1 Levulan surface application twice with microneedling</intervention_name>
    <description>Control or treatment lesions will be prepared with microneedling, painted twice with Levulan vehicle only or active drug, allowed to dry between and after applications, and incubated under occlusion for 24 hrs. A minimum of three tumors per group on the same subject will be treated. Lesions will then be excised in the normal manner, sectioned vertically, and checked for Protoporphyrin IX using fluorescence microscopy.</description>
    <arm_group_label>Part 1 Levulan painted twice with microneedling</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 1</intervention_name>
    <description>2-6 adult subjects with 3-8 lesions per (Levulan or control) group per subject. Controls will consist of lesions treated with vehicle only and light illumination, and will be paired with treatment lesions by the study doctor. Control lesions will be treated on the same subject as study lesions. Levulan will be incubated for 3-24 hours under occlusion, then gently rinsed with water and patted dry. Photoactivation of lesions treated with Levulan is then accomplished with 633 nm red light illumination. 633 nm light will be applied for 8 minutes to achieve a dose of 50 J/cm^2. There will be one treatment session per subject. Treatments will include a minimum of three test lesions and an additional three control lesions.</description>
    <arm_group_label>Part 2 Dose level 1 50 J/cm^2</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 2</intervention_name>
    <description>2-6 adult subjects with 3-8 lesions per (Levulan or control) group per subject. Controls will consist of lesions treated with vehicle only and light illumination, and will be paired with treatment lesions by the study doctor. Control lesions will be treated on the same subject as study lesions. Levulan will be incubated for 3-24 hours under occlusion, then gently rinsed with water and patted dry. Photoactivation of lesions treated with Levulan is then accomplished with 633 nm red light illumination. 633 nm light will be applied for 16 minutes to achieve a dose of 100 J/cm^2. There will be one treatment session per subject. Treatments will include a minimum of three test lesions and an additional three control lesions.</description>
    <arm_group_label>Part 2 Dose level 2 100 J/cm^2</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 3</intervention_name>
    <description>2-6 adult subjects with 3-8 lesions per (Levulan or control) group per subject. Controls will consist of lesions treated with vehicle only and light illumination, and will be paired with treatment lesions by the study doctor. Control lesions will be treated on the same subject as study lesions. Levulan will be incubated for 3-24 hours under occlusion, then gently rinsed with water and patted dry. Photoactivation of lesions treated with Levulan is then accomplished with 633 nm red light illumination. 633 nm light will be applied for 32 minutes to achieve a dose of 200 J/cm^2. There will be one treatment session per subject. Treatments will include a minimum of three test lesions and an additional three control lesions.</description>
    <arm_group_label>Part 2 Dose level 3 200 J/cm^2</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Subjects with NF1 will be selected for photodynamic therapy on the following criteria.&#xD;
&#xD;
          1. Age: 18 years or older.&#xD;
&#xD;
          2. NF1 will be diagnosed by American Academy of Neurology guidelines.&#xD;
&#xD;
          3. Location of tumor: cutaneous, trunk or limbs only.&#xD;
&#xD;
          4. Tumor type: superficial dermal neurofibromas, less than or equal to 4 mm deep.&#xD;
&#xD;
          5. Growth confirmation: direct measurement for the dermal neurofibromas, ruler and&#xD;
             photo-volumetric method.&#xD;
&#xD;
          6. Informed consent of subject.&#xD;
&#xD;
          7. Absence of any other malignancy.&#xD;
&#xD;
          8. Only failures to meet criteria 1-6 due to the primary disease will be disqualifying&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Subjects will be excluded from participation in the study on the basis of the following:&#xD;
&#xD;
          1. Life expectancy less than 1 year.&#xD;
&#xD;
          2. Pregnancy.&#xD;
&#xD;
          3. Inability to consent.&#xD;
&#xD;
          4. Cutaneous photosensitivity to the wavelengths used to activate PDT.&#xD;
&#xD;
          5. A diagnosis of porphyria.&#xD;
&#xD;
          6. Allergy to aminolevulinic acid or any of the Topical Solution Vehicle components.&#xD;
&#xD;
          7. Previous chemotherapy within 6 weeks of proposed PDT.&#xD;
&#xD;
          8. Other concurrent tumor therapy. -&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Harry T Whelan, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Medical College of Wisconsin</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>The Medical College of Wisconsin</name>
      <address>
        <city>Milwaukee</city>
        <state>Wisconsin</state>
        <zip>53226</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2021</verification_date>
  <study_first_submitted>September 5, 2012</study_first_submitted>
  <study_first_submitted_qc>September 10, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 11, 2012</study_first_posted>
  <results_first_submitted>February 16, 2021</results_first_submitted>
  <results_first_submitted_qc>June 16, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">June 18, 2021</results_first_posted>
  <last_update_submitted>June 16, 2021</last_update_submitted>
  <last_update_submitted_qc>June 16, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">June 18, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Medical College of Wisconsin</investigator_affiliation>
    <investigator_full_name>Harry T Whelan, MD</investigator_full_name>
    <investigator_title>Bleser Professor of Neurology</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neurofibromatoses</mesh_term>
    <mesh_term>Neurofibromatosis 1</mesh_term>
    <mesh_term>Neurofibroma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Aminolevulinic Acid</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <recruitment_details>A prospective, controlled, nonrandomized phase I clinical trial was conducted between March 2012 and July 2016. This study included adult patients from Froedtert Hospital in Milwaukee, Wisconsin. NF1 patients were recruited through referral by their physician.</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Part 1 Levulan Injection</title>
          <description>5-aminolevulinic acid uptake by control lesions after Levulan vehicle (placebo) injection and 3 hr incubation, and by Levulan treated lesions after 3 or 24 hr incubation.</description>
        </group>
        <group group_id="P2">
          <title>Part 1 Levulan Painting</title>
          <description>5-aminolevulinic acid uptake by control lesions after Levulan vehicle (placebo) surface application and 3 hr incubation, and by Levulan treated lesions and 3 or 24 hr incubation.</description>
        </group>
        <group group_id="P3">
          <title>Experimental: Part 1 Levulan Painted Twice</title>
          <description>5-aminolevulinic acid uptake by control lesions after Levulan vehicle (placebo) surface application twice or by Levulan treated lesions twice and 24 hr incubation.</description>
        </group>
        <group group_id="P4">
          <title>Part 1 Levulan Painted Twice With Microneedling</title>
          <description>5-aminolevulinic acid uptake by control lesions after Levulan vehicle (placebo) surface application twice or by Levulan treated lesions twice and 24 hr incubation. All lesions prepared with microneedling.</description>
        </group>
        <group group_id="P5">
          <title>Part 2 Dose Level 1 50 J/cm^2</title>
          <description>Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 1 - 50 J/cm^2 633 nm red light to Levulan vehicle (placebo) treated control lesions or Levulan treated lesions and 24 hr incubation. Follow-ups on day 2 for punch biopsies, 14-28 days for evaluation of cutaneous adverse events, and every 3 months up to one year for lesion measurements.</description>
        </group>
        <group group_id="P6">
          <title>Part 2 Dose Level 2 100 J/cm^2</title>
          <description>Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 2 - 100 J/cm^2 633 nm red light to Levulan vehicle (placebo) treated control lesions or Levulan treated lesions and 24 hr incubation. Follow-ups on day 2 for punch biopsies, 14-28 days for evaluation of cutaneous adverse events, and every 3 months up to one year for lesion measurements.</description>
        </group>
        <group group_id="P7">
          <title>Part 2 Dose Level 3 200 J/cm^2</title>
          <description>Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 3 - 200 J/cm^2 633 nm red light to Levulan vehicle (placebo) treated control lesions or Levulan treated lesions and 24 hr incubation. Follow-ups on day 2 for punch biopsies, 14-28 days for evaluation of cutaneous adverse events, and every 3 months up to one year for lesion measurements.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Part 1 Levulan Injection</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Control</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Treated 3 Hours</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Treated 24 Hours</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Part 1 Levulan Painting</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Control</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Treated 3 Hours</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Treated 24 Hours</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Part 1 Levulan Painted Twice</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="2"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Control</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="2"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Treated 24 Hours</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="2"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="2"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Part 1 Levulan Paint Twice Microneedling</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="2"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Control</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="2"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Treated 24 Hours</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="2"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="2"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Part 2 Dose Level 1</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="11"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Control</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="10"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Treated</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="10"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="11"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="1"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="4"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="6"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Part 2 Dose Level 2</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="3"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Control</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="3"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Treated</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="3"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="3"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="3"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Part 2 Dose Level 3</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Control</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Treated</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
                <participants group_id="P7" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>No subjects were enrolled into Part 2 Dose Level 3 as maximum tolerable dose had been established.</population>
      <group_list>
        <group group_id="B1">
          <title>Experimental: Part 1 Levulan Injection</title>
          <description>5-aminolevulinic acid uptake by control lesions after Levulan vehicle (placebo) injection and 3 hr incubation, and by Levulan treated lesions after 3 or 24 hr incubation.</description>
        </group>
        <group group_id="B2">
          <title>Part 1 Levulan Painting</title>
          <description>5-aminolevulinic acid uptake by control lesions after Levulan vehicle (placebo) surface application and 3 hr incubation, and by Levulan treated lesions and 3 or 24 hr incubation.</description>
        </group>
        <group group_id="B3">
          <title>Part 1 Levulan Painted Twice</title>
          <description>5-aminolevulinic acid uptake by control lesions after Levulan vehicle (placebo) surface application twice or by Levulan treated lesions twice and 24 hr incubation.</description>
        </group>
        <group group_id="B4">
          <title>Part 1 Levulan Painted Twice With Microneedling</title>
          <description>5-aminolevulinic acid uptake by control lesions after Levulan vehicle (placebo) surface application twice or by Levulan treated lesions twice and 24 hr incubation. All lesions prepared with microneedling.</description>
        </group>
        <group group_id="B5">
          <title>Part 2 Dose Level 1 50 J/cm^2</title>
          <description>Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 1 - 50 J/cm^2 633 nm red light to Levulan vehicle (placebo) treated control lesions or Levulan treated lesions and 24 hr incubation. Follow-ups on day 2 for punch biopsies, 14-28 days for evaluation of cutaneous adverse events, and every 3 months up to one year for lesion measurements.</description>
        </group>
        <group group_id="B6">
          <title>Part 2 Dose Level 2 100 J/cm^2</title>
          <description>Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 2 - 100 J/cm^2 633 nm red light to Levulan vehicle (placebo) treated control lesions or Levulan treated lesions and 24 hr incubation. Follow-ups on day 2 for punch biopsies, 14-28 days for evaluation of cutaneous adverse events, and every 3 months up to one year for lesion measurements.</description>
        </group>
        <group group_id="B7">
          <title>Part 2 Dose Level 3 200 J/cm^2</title>
          <description>Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 3 - 200 J/cm^2 633 nm red light to Levulan vehicle (placebo) treated control lesions or Levulan treated lesions and 24 hr incubation. Follow-ups on day 2 for punch biopsies, 14-28 days for evaluation of cutaneous adverse events, and every 3 months up to one year for lesion measurements.</description>
        </group>
        <group group_id="B8">
          <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="1"/>
            <count group_id="B2" value="1"/>
            <count group_id="B3" value="2"/>
            <count group_id="B4" value="2"/>
            <count group_id="B5" value="11"/>
            <count group_id="B6" value="3"/>
            <count group_id="B7" value="0"/>
            <count group_id="B8" value="20"/>
          </count_list>
        </analyzed>
        <analyzed>
          <units>lesions</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="9"/>
            <count group_id="B2" value="9"/>
            <count group_id="B3" value="12"/>
            <count group_id="B4" value="12"/>
            <count group_id="B5" value="60"/>
            <count group_id="B6" value="18"/>
            <count group_id="B7" value="0"/>
            <count group_id="B8" value="120"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <units_analyzed>Participants</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="B1" value="1"/>
                <count group_id="B2" value="1"/>
                <count group_id="B3" value="2"/>
                <count group_id="B4" value="2"/>
                <count group_id="B5" value="11"/>
                <count group_id="B6" value="3"/>
                <count group_id="B7" value="0"/>
                <count group_id="B8" value="20"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>lesions</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="B1" value="9"/>
                <count group_id="B2" value="9"/>
                <count group_id="B3" value="12"/>
                <count group_id="B4" value="12"/>
                <count group_id="B5" value="60"/>
                <count group_id="B6" value="18"/>
                <count group_id="B7" value="0"/>
                <count group_id="B8" value="120"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="0"/>
                    <measurement group_id="B7" value="0"/>
                    <measurement group_id="B8" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="7"/>
                    <measurement group_id="B6" value="2"/>
                    <measurement group_id="B7" value="0"/>
                    <measurement group_id="B8" value="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="4"/>
                    <measurement group_id="B6" value="1"/>
                    <measurement group_id="B7" value="0"/>
                    <measurement group_id="B8" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <units_analyzed>Participants</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="B1" value="1"/>
                <count group_id="B2" value="1"/>
                <count group_id="B3" value="2"/>
                <count group_id="B4" value="2"/>
                <count group_id="B5" value="11"/>
                <count group_id="B6" value="3"/>
                <count group_id="B7" value="0"/>
                <count group_id="B8" value="20"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>lesions</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="B1" value="9"/>
                <count group_id="B2" value="9"/>
                <count group_id="B3" value="12"/>
                <count group_id="B4" value="12"/>
                <count group_id="B5" value="60"/>
                <count group_id="B6" value="18"/>
                <count group_id="B7" value="0"/>
                <count group_id="B8" value="120"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="2"/>
                    <measurement group_id="B5" value="8"/>
                    <measurement group_id="B6" value="1"/>
                    <measurement group_id="B7" value="0"/>
                    <measurement group_id="B8" value="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="3"/>
                    <measurement group_id="B6" value="2"/>
                    <measurement group_id="B7" value="0"/>
                    <measurement group_id="B8" value="7"/>
                  </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>
          <units_analyzed>Participants</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="B1" value="0"/>
                <count group_id="B2" value="0"/>
                <count group_id="B3" value="0"/>
                <count group_id="B4" value="0"/>
                <count group_id="B5" value="0"/>
                <count group_id="B6" value="0"/>
                <count group_id="B7" value="0"/>
                <count group_id="B8" value="0"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>lesions</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="B1" value="9"/>
                <count group_id="B2" value="9"/>
                <count group_id="B3" value="12"/>
                <count group_id="B4" value="12"/>
                <count group_id="B5" value="60"/>
                <count group_id="B6" value="18"/>
                <count group_id="B7" value="0"/>
                <count group_id="B8" value="120"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B8" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <units_analyzed>Participants</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="B1" value="1"/>
                <count group_id="B2" value="1"/>
                <count group_id="B3" value="2"/>
                <count group_id="B4" value="2"/>
                <count group_id="B5" value="11"/>
                <count group_id="B6" value="3"/>
                <count group_id="B7" value="0"/>
                <count group_id="B8" value="20"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>lesions</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="B1" value="9"/>
                <count group_id="B2" value="9"/>
                <count group_id="B3" value="12"/>
                <count group_id="B4" value="12"/>
                <count group_id="B5" value="60"/>
                <count group_id="B6" value="18"/>
                <count group_id="B7" value="0"/>
                <count group_id="B8" value="120"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="2"/>
                    <measurement group_id="B5" value="11"/>
                    <measurement group_id="B6" value="3"/>
                    <measurement group_id="B8" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Part 1: Photosensitizer Uptake and Conversion to Protoporphyrin IX</title>
        <description>The average fluorescence value for PpIX positive tumor areas in excised, sectioned tumors, as determined by fluorescence microscopy. PpIX signals were detected with excitation at 405 nm and emission with a 600 nm long pass filter. PpIX positive areas were determined to be those exhibiting fluorescence above background levels.</description>
        <time_frame>24 hours</time_frame>
        <population>The first participant contributed three lesions to each of the first three groups. The second participant likewise for the second three groups. The next two participants contributed three lesions each to each of the next two groups. The next two participants contributed likewise for the last two groups. PpIX positive areas were detected only in the last group.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1 Levulan Injection Control Lesions</title>
            <description>5-aminolevulinic acid uptake by control lesions after Levulan vehicle (placebo) injection and 24 hr incubation.</description>
          </group>
          <group group_id="O2">
            <title>Part 1 Levulan Injection Treated Lesions 3 Hours</title>
            <description>5-aminolevulinic acid uptake by treated lesions after Levulan injection and 3 hr incubation.</description>
          </group>
          <group group_id="O3">
            <title>Part 1 Levulan Injection Treated Lesions 24 Hours</title>
            <description>5-aminolevulinic acid uptake by treated lesions after Levulan injection and 24 hr incubation.</description>
          </group>
          <group group_id="O4">
            <title>Part 1 Levulan Paint Control Lesions</title>
            <description>5-aminolevulinic acid uptake by control lesions after Levulan vehicle (placebo) surface application and 24 hr incubation.</description>
          </group>
          <group group_id="O5">
            <title>Part 1 Levulan Paint Treated Lesions 3 Hours</title>
            <description>5-aminolevulinic acid uptake by treated lesions after Levulan surface application and 3 hr incubation.</description>
          </group>
          <group group_id="O6">
            <title>Part 1 Levulan Paint Treated Lesions 24 Hours</title>
            <description>5-aminolevulinic acid uptake by treated lesions after Levulan surface application and 24 hr incubation.</description>
          </group>
          <group group_id="O7">
            <title>Part 1 Levulan Painted Twice Control Lesions</title>
            <description>5-aminolevulinic acid uptake by control lesions after Levulan vehicle (placebo) surface application twice and 3 hr incubation.</description>
          </group>
          <group group_id="O8">
            <title>Part 1 Levulan Painted Twice Treated Lesions</title>
            <description>5-aminolevulinic acid uptake by treated lesions after Levulan surface application twice and 3 hr incubation.</description>
          </group>
          <group group_id="O9">
            <title>Part 1 Levulan Painted Twice Control Lesions With Microneedling</title>
            <description>5-aminolevulinic acid uptake by control lesions after Levulan vehicle (placebo) surface application twice, on lesions prepared with microneedling, and 24 hr incubation.</description>
          </group>
          <group group_id="O10">
            <title>Part 1 Levulan Painted Twice Treated Lesions With Microneedling</title>
            <description>5-aminolevulinic acid uptake by treated lesions after Levulan surface application twice, on lesions prepared with microneedling, and 24 hr incubation.</description>
          </group>
        </group_list>
        <measure>
          <title>Part 1: Photosensitizer Uptake and Conversion to Protoporphyrin IX</title>
          <description>The average fluorescence value for PpIX positive tumor areas in excised, sectioned tumors, as determined by fluorescence microscopy. PpIX signals were detected with excitation at 405 nm and emission with a 600 nm long pass filter. PpIX positive areas were determined to be those exhibiting fluorescence above background levels.</description>
          <population>The first participant contributed three lesions to each of the first three groups. The second participant likewise for the second three groups. The next two participants contributed three lesions each to each of the next two groups. The next two participants contributed likewise for the last two groups. PpIX positive areas were detected only in the last group.</population>
          <units>Densitometry units/micrometer squared</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <units_analyzed>PpIX positive areas</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
                <count group_id="O2" value="1"/>
                <count group_id="O3" value="1"/>
                <count group_id="O4" value="1"/>
                <count group_id="O5" value="1"/>
                <count group_id="O6" value="1"/>
                <count group_id="O7" value="2"/>
                <count group_id="O8" value="2"/>
                <count group_id="O9" value="2"/>
                <count group_id="O10" value="2"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>PpIX positive areas</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
                <count group_id="O4" value="0"/>
                <count group_id="O5" value="0"/>
                <count group_id="O6" value="0"/>
                <count group_id="O7" value="0"/>
                <count group_id="O8" value="0"/>
                <count group_id="O9" value="0"/>
                <count group_id="O10" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O10" value="304" spread="94"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O10</group_id>
            </group_id_list>
            <groups_desc>One-sample t-test comparing the absolute value to an alternate expected value of zero.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.0001</p_value>
            <method>t-test, 1 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Part 2: Maximum Tolerated Dose (MTD) of 633 nm Red Light</title>
        <description>MTD was determined by testing increasing doses up to 200 J/cm^2 on dose escalation cohorts 1 to 3 with 3 to 6 participants each. MTD reflects the highest dose of red light that did not cause a Dose-Limiting Toxicity (DLT) in &gt; 33% of participants. DLT was defined as pain during irradiation requiring cessation of the light treatment, or any serious cutaneous adverse events.</description>
        <time_frame>48 hours</time_frame>
        <population>Of the 14 enrolled in Part 2, 5 did not receive red light treatment per protocol. No subjects were enrolled in cohort 3 (200 J/cm^2) due to marked pain in cohort 2. In the opinion of the clinical dermatologist, higher dose levels would likely not be tolerable, and it would be unethical to escalate the light dose further. It was decided that the MTD would be set at 100 J/cm^2, and the highest dose level foregone.</population>
        <group_list>
          <group group_id="O1">
            <title>All Participants</title>
            <description>All participants who received at least 1 dose of 633 nm red light, either at 50 J/cm^2, 100 J/cm^2, or 200 J/cm^2.</description>
          </group>
        </group_list>
        <measure>
          <title>Part 2: Maximum Tolerated Dose (MTD) of 633 nm Red Light</title>
          <description>MTD was determined by testing increasing doses up to 200 J/cm^2 on dose escalation cohorts 1 to 3 with 3 to 6 participants each. MTD reflects the highest dose of red light that did not cause a Dose-Limiting Toxicity (DLT) in &gt; 33% of participants. DLT was defined as pain during irradiation requiring cessation of the light treatment, or any serious cutaneous adverse events.</description>
          <population>Of the 14 enrolled in Part 2, 5 did not receive red light treatment per protocol. No subjects were enrolled in cohort 3 (200 J/cm^2) due to marked pain in cohort 2. In the opinion of the clinical dermatologist, higher dose levels would likely not be tolerable, and it would be unethical to escalate the light dose further. It was decided that the MTD would be set at 100 J/cm^2, and the highest dose level foregone.</population>
          <units>joules/cm squared</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="100"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Part 1: Optimal Occlusion Time</title>
        <description>An optimal occlusion time may be apparent from the results of the three time points. If no optimal occlusion time is seen, any occlusion time from 3-24 hours may be chosen for part 2. This secondary outcome measure is not critical to continuing the study, but may be useful in guiding treatment protocols</description>
        <time_frame>24 hours</time_frame>
        <population>The first participant contributed three lesions to each of the first three groups. The second participant contributed three lesions to each of the second three groups. Only the six groups in the first two arms are relevant to this outcome measure.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 1 Levulan Injection Control Lesions</title>
            <description>5-aminolevulinic acid uptake by control lesions after Levulan vehicle (placebo) injection and 24 hr incubation.</description>
          </group>
          <group group_id="O2">
            <title>Part 1 Levulan Injection Treated Lesions 3 Hours</title>
            <description>5-aminolevulinic acid uptake by treated lesions after Levulan injection and 3 hr incubation.</description>
          </group>
          <group group_id="O3">
            <title>Part 1 Levulan Injection Treated Lesions 24 Hours</title>
            <description>5-aminolevulinic acid uptake by treated lesions after Levulan injection and 24 hr incubation.</description>
          </group>
          <group group_id="O4">
            <title>Part 1 Levulan Paint Control Lesions</title>
            <description>5-aminolevulinic acid uptake by control lesions after Levulan vehicle (placebo) surface application and 24 hr incubation.</description>
          </group>
          <group group_id="O5">
            <title>Part 1 Levulan Paint Treated Lesions 3 Hours</title>
            <description>5-aminolevulinic acid uptake by treated lesions after Levulan surface application and 3 hr incubation.</description>
          </group>
          <group group_id="O6">
            <title>Part 1 Levulan Paint Treated Lesions 24 Hours</title>
            <description>5-aminolevulinic acid uptake by treated lesions after Levulan surface application and 24 hr incubation.</description>
          </group>
        </group_list>
        <measure>
          <title>Part 1: Optimal Occlusion Time</title>
          <description>An optimal occlusion time may be apparent from the results of the three time points. If no optimal occlusion time is seen, any occlusion time from 3-24 hours may be chosen for part 2. This secondary outcome measure is not critical to continuing the study, but may be useful in guiding treatment protocols</description>
          <population>The first participant contributed three lesions to each of the first three groups. The second participant contributed three lesions to each of the second three groups. Only the six groups in the first two arms are relevant to this outcome measure.</population>
          <units>hours</units>
          <param>Number</param>
          <units_analyzed>lesions</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
                <count group_id="O2" value="1"/>
                <count group_id="O3" value="1"/>
                <count group_id="O4" value="1"/>
                <count group_id="O5" value="1"/>
                <count group_id="O6" value="1"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>lesions</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="3"/>
                <count group_id="O3" value="3"/>
                <count group_id="O4" value="3"/>
                <count group_id="O5" value="3"/>
                <count group_id="O6" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA">No optimal occlusion time was determined as no lesions showed PpIX fluorescence.</measurement>
                    <measurement group_id="O2" value="NA">No optimal occlusion time was determined as no lesions showed PpIX fluorescence.</measurement>
                    <measurement group_id="O3" value="NA">No optimal occlusion time was determined as no lesions showed PpIX fluorescence.</measurement>
                    <measurement group_id="O4" value="NA">No optimal occlusion time was determined as no lesions showed PpIX fluorescence.</measurement>
                    <measurement group_id="O5" value="NA">No optimal occlusion time was determined as no lesions showed PpIX fluorescence.</measurement>
                    <measurement group_id="O6" value="NA">No optimal occlusion time was determined as no lesions showed PpIX fluorescence.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Part 2: Efficacy - Lesion Area Growth Rate</title>
        <description>Average lesion growth rates observed in ALA-treated lesions compared to vehicle-treated lesions within the same subjects.</description>
        <time_frame>12 weeks</time_frame>
        <population>Only 5 participants from Part 2 dose level 1 of the study had lesion sizes monitored during follow-up visits.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 2 Dose Level 1 50 J/cm^2 Control</title>
            <description>Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 1 - 50 J/cm^2 633 nm red light to Levulan vehicle (placebo) treated control lesions and 24 hr incubation. Follow-ups on day 2 for punch biopsies, 14-28 days for evaluation of cutaneous adverse events, and every 3 months up to one year for lesion measurements.</description>
          </group>
          <group group_id="O2">
            <title>Part 2 Dose Level 1 50 J/cm^2 Treated</title>
            <description>Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 1 - 50 J/cm^2 633 nm red light to Levulan treated lesions and 24 hr incubation. Follow-ups on day 2 for punch biopsies, 14-28 days for evaluation of cutaneous adverse events, and every 3 months up to one year for lesion measurements.</description>
          </group>
        </group_list>
        <measure>
          <title>Part 2: Efficacy - Lesion Area Growth Rate</title>
          <description>Average lesion growth rates observed in ALA-treated lesions compared to vehicle-treated lesions within the same subjects.</description>
          <population>Only 5 participants from Part 2 dose level 1 of the study had lesion sizes monitored during follow-up visits.</population>
          <units>millimeter squared/day post-treatment</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <units_analyzed>lesions</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="5"/>
                <count group_id="O2" value="5"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>lesions</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="14"/>
                <count group_id="O2" value="14"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.212" spread="0.364"/>
                    <measurement group_id="O2" value="0.081" spread="0.176"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Paired comparisons between treated and placebo lesions within subject.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.24</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Part 2: Cosmetic Improvement</title>
        <description>Potential cosmetic improvement using subject satisfaction scale.</description>
        <time_frame>1 year</time_frame>
        <population>No cosmetic improvement data was collected.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 2 Levulan (5-aminolevulinic Acid) Photodynamic Therapy.</title>
            <description>Levulan (5-aminolevulinic acid) photodynamic therapy. 2-18 adult subjects with 3-8 lesions per (Levulan or control) group per subject. Controls will consist of lesions treated with vehicle only and light illumination, and will be paired with treatment lesions by the study doctor. Control lesions will be treated on the same subject as study lesions. Levulan will be incubated for 3-24 hours under occlusion, then gently rinsed with water and patted dry. Photoactivation of lesions treated with Levulan is then accomplished with 630 nm red light illumination. 630 nm light will be applied for varying periods of time in order to achieve a dose of 25, 50, or 100 J/cm2. There will be one treatment session per subject. Treatments will include a minimum of three test lesions and an additional three control lesions.&#xD;
Subjects will be seen at 24-48 hrs (48-72 hrs after Levulan application), and two weeks to one month after treatment at which times evaluation regarding dose toxicity will be made. Evaluations will include direct measurement of lesions, pain score, and cosmetic improvement (patient satisfaction).&#xD;
At the 2 day follow up visit, tumors will be punch biopsied, samples preserved in paraffin or formalin, and evaluated for cell death using TUNEL assays, H &amp; E staining, or other methods.</description>
          </group>
        </group_list>
        <measure>
          <title>Part 2: Cosmetic Improvement</title>
          <description>Potential cosmetic improvement using subject satisfaction scale.</description>
          <population>No cosmetic improvement data was collected.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Part 2: Pain Reduction</title>
        <description>Potential pain reduction, as measured by standard visual analog 1-10 scale.</description>
        <time_frame>1 year</time_frame>
        <population>No pain reduction data was collected.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 2 Levulan (5-aminolevulinic Acid) Photodynamic Therapy.</title>
            <description>Levulan (5-aminolevulinic acid) photodynamic therapy. 2-18 adult subjects with 3-8 lesions per (Levulan or control) group per subject. Controls will consist of lesions treated with vehicle only and light illumination, and will be paired with treatment lesions by the study doctor. Control lesions will be treated on the same subject as study lesions. Levulan will be incubated for 3-24 hours under occlusion, then gently rinsed with water and patted dry. Photoactivation of lesions treated with Levulan is then accomplished with 630 nm red light illumination. 630 nm light will be applied for varying periods of time in order to achieve a dose of 25, 50, or 100 J/cm2. There will be one treatment session per subject. Treatments will include a minimum of three test lesions and an additional three control lesions.&#xD;
Subjects will be seen at 24-48 hrs (48-72 hrs after Levulan application), and two weeks to one month after treatment at which times evaluation regarding dose toxicity will be made. Evaluations will include direct measurement of lesions, pain score, and cosmetic improvement (patient satisfaction).&#xD;
At the 2 day follow up visit, tumors will be punch biopsied, samples preserved in paraffin or formalin, and evaluated for cell death using TUNEL assays, H &amp; E staining, or other methods.</description>
          </group>
        </group_list>
        <measure>
          <title>Part 2: Pain Reduction</title>
          <description>Potential pain reduction, as measured by standard visual analog 1-10 scale.</description>
          <population>No pain reduction data was collected.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Post-Hoc</type>
        <title>TUNEL Assay.</title>
        <description>Average number of apoptotic cells per visual field among all TUNEL-evaluated lesion samples.</description>
        <time_frame>48 hours</time_frame>
        <population>Only 5 participants from Part 2 dose level 1 of the study had biopsies performed and lesions analyzed.</population>
        <group_list>
          <group group_id="O1">
            <title>Part 2 Dose Level 1 50 J/cm^2 Control</title>
            <description>Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 1 - 50 J/cm^2 633 nm red light to Levulan vehicle (placebo) treated control lesions and 24 hr incubation. Follow-ups on day 2 for punch biopsies, 14-28 days for evaluation of cutaneous adverse events, and every 3 months up to one year for lesion measurements.</description>
          </group>
          <group group_id="O2">
            <title>Part 2 Dose Level 1 50 J/cm^2 Treated</title>
            <description>Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 1 - 50 J/cm^2 633 nm red light to Levulan treated lesions and 24 hr incubation. Follow-ups on day 2 for punch biopsies, 14-28 days for evaluation of cutaneous adverse events, and every 3 months up to one year for lesion measurements.</description>
          </group>
        </group_list>
        <measure>
          <title>TUNEL Assay.</title>
          <description>Average number of apoptotic cells per visual field among all TUNEL-evaluated lesion samples.</description>
          <population>Only 5 participants from Part 2 dose level 1 of the study had biopsies performed and lesions analyzed.</population>
          <units>apoptotic cells/visual field</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <units_analyzed>Lesions</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="5"/>
                <count group_id="O2" value="5"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>Lesions</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="15"/>
                <count group_id="O2" value="5"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="42.5" spread="19.9"/>
                    <measurement group_id="O2" value="1.1" spread="1.4"/>
                  </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>0.002</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>3 weeks.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Part 1 Levulan (5-aminolevulinic Acid) Uptake.</title>
          <description>Tumors will be incubated with Levulan or vehicle under occlusion for 3 or 24 hrs. A minimum of three tumors per treatment or control group will be treated on the same subject. Tumors will then be excised in the normal manner. Tumors will be sectioned vertically and checked for PpIX using fluorescence microscopy.</description>
        </group>
        <group group_id="E2">
          <title>Experimental: Part 2 Dose Level 1 50 J/cm^2</title>
          <description>Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 1 - 50 J/cm^2 633 nm red light to Levulan vehicle (placebo) treated control lesions or Levulan treated lesions and 24 hr incubation. Follow-ups on day 2 for punch biopsies, 14-28 days for evaluation of cutaneous adverse events, and every 3 months up to one year for lesion measurements.</description>
        </group>
        <group group_id="E3">
          <title>Part 2 Dose Level 2 100 J/cm^2</title>
          <description>Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 2 - 100 J/cm^2 633 nm red light to Levulan vehicle (placebo) treated control lesions or Levulan treated lesions and 24 hr incubation. Follow-ups on day 2 for punch biopsies, 14-28 days for evaluation of cutaneous adverse events, and every 3 months up to one year for lesion measurements.</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="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Skin burning with PDT - resolved</sub_title>
                <description>One participant in the first dose level cohort experienced pain upon red-light irradiation requiring cessation of PDT treatment. The pain resolved upon PDT cessation, with no sequelae.</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>No participants in part 2 completed 1 year of follow-up visits, and are reported as lost to follow-up. This necessarily limits all outcome measurements for part 2 other than the maximum tolerable dose measurement.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Harry T. Whelan MD, Bleser Professor of Neurology</name_or_title>
      <organization>Medical College of Wisconsin</organization>
      <phone>414-266-7544</phone>
      <email>hwhelan@mcw.edu</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/NCT01682811
org study id: PRO 14555
nct id: NCT01682811
lead sponsor: 
has dmc: No
GENERAL OBJECTIVE The general objective is to assess the safety and efficacy of photodynamic
      therapy (PDT) in the treatment of neurofibromatosis 1 (NF1) tumors in the skin.

      SPECIFIC OBJECTIVE This is a light dose escalation pilot study to determine the safety and
      efficacy of PDT using 5-aminolevulinic acid (ALA) and 633 nm light in the treatment of benign
      dermal neurofibromas.

      Specifically, the primary goal of the current study is to determine the maximum tolerable
      light doses that can be administered to subjects undergoing topical photoillumination
      photodynamic therapy with standard application of Levulan Kerastick (ALA) for Topical
      Solution.
STUDY DESIGN This protocol is a Phase I light dose escalation pilot study to determine the
      safety and, secondarily, the efficacy of PDT using Levulan and 633 nm light in the treatment
      of benign dermal neurofibromas. This protocol represents the first two parts of a planned
      three part study including both pediatric and adult subjects. Part 1 will consist of studying
      the penetration and uptake of the PS in neurofibromas that are scheduled for excision. These
      tumors will be excised for therapeutic reasons unrelated to this study, and so this study
      will place no further burden on the subject other than a 3-24 hr incubation of the Levulan on
      the tumor prior to excision. The primary hypothesis to be tested is whether Levulan will
      accumulate, and be converted to PpIX, by the tumor tissue more than by the surrounding normal
      tissue. Secondary hypotheses are that tumors incubated with Levulan will show greater
      fluorescence than untreated tumors and tumors incubated with vehicle only (placebo
      application).

      As the Institutional Review Boards involved generally desire pilot data on adult populations
      first, we will with then proceed with the adult clinical trial portion of this protocol as
      part 2. Part 2 will use the optimum incubation time, if one has been identified in part 1,
      and add a dose escalation study of the amount of red light used to activate the Levulan. Part
      3, with pediatric subjects, will commence at a future date, pending review of the initial
      adult study results.
allocation: Non-Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Part 1: Photosensitizer Uptake and Conversion to Protoporphyrin IX
time frame: 24 hours
description: The average fluorescence value for PpIX positive tumor areas in excised, sectioned tumors, as determined by fluorescence microscopy. PpIX signals were detected with excitation at 405 nm and emission with a 600 nm long pass filter. PpIX positive areas were determined to be those exhibiting fluorescence above background levels.
measure: Part 2: Maximum Tolerated Dose (MTD) of 633 nm Red Light
time frame: 48 hours
description: MTD was determined by testing increasing doses up to 200 J/cm^2 on dose escalation cohorts 1 to 3 with 3 to 6 participants each. MTD reflects the highest dose of red light that did not cause a Dose-Limiting Toxicity (DLT) in > 33% of participants. DLT was defined as pain during irradiation requiring cessation of the light treatment, or any serious cutaneous adverse events.
measure: Part 1: Optimal Occlusion Time
time frame: 24 hours
description: An optimal occlusion time may be apparent from the results of the three time points. If no optimal occlusion time is seen, any occlusion time from 3-24 hours may be chosen for part 2. This secondary outcome measure is not critical to continuing the study, but may be useful in guiding treatment protocols
measure: Part 2: Efficacy - Lesion Area Growth Rate
time frame: 12 weeks
description: Average lesion growth rates observed in ALA-treated lesions compared to vehicle-treated lesions within the same subjects.
measure: Part 2: Cosmetic Improvement
time frame: 1 year
description: Potential cosmetic improvement using subject satisfaction scale.
measure: Part 2: Pain Reduction
time frame: 1 year
description: Potential pain reduction, as measured by standard visual analog 1-10 scale.
arm group label: Part 1 Levulan injection
arm group type: Experimental
description: 5-aminolevulinic acid uptake by control lesions after Levulan vehicle (placebo) injection and 3 hr incubation, and by Levulan treated lesions after 3 or 24 hr incubation.
arm group label: Part 1 Levulan painting
arm group type: Experimental
description: 5-aminolevulinic acid uptake by control lesions after Levulan vehicle (placebo) surface application and 3 hr incubation, and by Levulan treated lesions and 3 or 24 hr incubation.
arm group label: Part 1 Levulan painted twice
arm group type: Experimental
description: 5-aminolevulinic acid uptake by control lesions after Levulan vehicle (placebo) surface application twice or by Levulan treated lesions twice and 24 hr incubation.
arm group label: Part 1 Levulan painted twice with microneedling
arm group type: Experimental
description: 5-aminolevulinic acid uptake by control lesions after Levulan vehicle (placebo) surface application twice or by Levulan treated lesions twice and 24 hr incubation. All lesions prepared with microneedling.
arm group label: Part 2 Dose level 1 50 J/cm^2
arm group type: Experimental
description: Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 1 - 50 J/cm^2 633 nm red light to Levulan vehicle (placebo) treated control lesions or Levulan treated lesions and 24 hr incubation. Follow-ups on day 2 for punch biopsies, 14-28 days for evaluation of cutaneous adverse events, and every 3 months up to one year for lesion measurements.
arm group label: Part 2 Dose level 2 100 J/cm^2
arm group type: Experimental
description: Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 2 - 100 J/cm^2 633 nm red light to Levulan vehicle (placebo) treated control lesions or Levulan treated lesions and 24 hr incubation. Follow-ups on day 2 for punch biopsies, 14-28 days for evaluation of cutaneous adverse events, and every 3 months up to one year for lesion measurements.
arm group label: Part 2 Dose level 3 200 J/cm^2
arm group type: Experimental
description: Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 3 - 200 J/cm^2 633 nm red light to Levulan vehicle (placebo) treated control lesions or Levulan treated lesions and 24 hr incubation. Follow-ups on day 2 for punch biopsies, 14-28 days for evaluation of cutaneous adverse events, and every 3 months up to one year for lesion measurements.
intervention type: Drug
intervention name: Part 1 Levulan injection
description: Control or treatment lesions will be injected with Levulan vehicle only or active drug and incubated under occlusion for 3 or 24 hrs. A minimum of three lesions per group on the same subject will be treated. Lesions will then be excised in the normal manner, sectioned vertically, and checked for Protoporphyrin IX using fluorescence microscopy.
arm group label: Part 1 Levulan injection
intervention type: Drug
intervention name: Part 1 Levulan surface application
description: Control or treatment lesions will be painted with Levulan vehicle only or active drug, allowed to dry, and incubated under occlusion for 3 or 24 hrs. A minimum of three lesions per group on the same subject will be treated. Lesions will then be excised in the normal manner, sectioned vertically, and checked for Protoporphyrin IX using fluorescence microscopy.
arm group label: Part 1 Levulan painting
intervention type: Drug
intervention name: Part 1 Levulan surface application twice
description: Control or treatment lesions will be painted twice with Levulan vehicle only or active drug, allowed to dry between and after applications, and incubated under occlusion for 3 hrs. A minimum of three tumors per group on the same subject will be treated. Lesions will then be excised in the normal manner, sectioned vertically, and checked for Protoporphyrin IX using fluorescence microscopy.
arm group label: Part 1 Levulan painted twice
intervention type: Drug
intervention name: Part 1 Levulan surface application twice with microneedling
description: Control or treatment lesions will be prepared with microneedling, painted twice with Levulan vehicle only or active drug, allowed to dry between and after applications, and incubated under occlusion for 24 hrs. A minimum of three tumors per group on the same subject will be treated. Lesions will then be excised in the normal manner, sectioned vertically, and checked for Protoporphyrin IX using fluorescence microscopy.
arm group label: Part 1 Levulan painted twice with microneedling
intervention type: Drug
intervention name: Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 1
description: 2-6 adult subjects with 3-8 lesions per (Levulan or control) group per subject. Controls will consist of lesions treated with vehicle only and light illumination, and will be paired with treatment lesions by the study doctor. Control lesions will be treated on the same subject as study lesions. Levulan will be incubated for 3-24 hours under occlusion, then gently rinsed with water and patted dry. Photoactivation of lesions treated with Levulan is then accomplished with 633 nm red light illumination. 633 nm light will be applied for 8 minutes to achieve a dose of 50 J/cm^2. There will be one treatment session per subject. Treatments will include a minimum of three test lesions and an additional three control lesions.
arm group label: Part 2 Dose level 1 50 J/cm^2
intervention type: Drug
intervention name: Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 2
description: 2-6 adult subjects with 3-8 lesions per (Levulan or control) group per subject. Controls will consist of lesions treated with vehicle only and light illumination, and will be paired with treatment lesions by the study doctor. Control lesions will be treated on the same subject as study lesions. Levulan will be incubated for 3-24 hours under occlusion, then gently rinsed with water and patted dry. Photoactivation of lesions treated with Levulan is then accomplished with 633 nm red light illumination. 633 nm light will be applied for 16 minutes to achieve a dose of 100 J/cm^2. There will be one treatment session per subject. Treatments will include a minimum of three test lesions and an additional three control lesions.
arm group label: Part 2 Dose level 2 100 J/cm^2
intervention type: Drug
intervention name: Levulan (5-aminolevulinic acid) photodynamic therapy - Dose level 3
description: 2-6 adult subjects with 3-8 lesions per (Levulan or control) group per subject. Controls will consist of lesions treated with vehicle only and light illumination, and will be paired with treatment lesions by the study doctor. Control lesions will be treated on the same subject as study lesions. Levulan will be incubated for 3-24 hours under occlusion, then gently rinsed with water and patted dry. Photoactivation of lesions treated with Levulan is then accomplished with 633 nm red light illumination. 633 nm light will be applied for 32 minutes to achieve a dose of 200 J/cm^2. There will be one treatment session per subject. Treatments will include a minimum of three test lesions and an additional three control lesions.
arm group label: Part 2 Dose level 3 200 J/cm^2
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: No
last name: Harry T Whelan, MD
role: Principal Investigator
affiliation: Medical College of Wisconsin
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: Medical College of Wisconsin
investigator full name: Harry T Whelan, MD
investigator title: Bleser Professor of Neurology
mesh term: Neurofibromatoses
mesh term: Neurofibromatosis 1
mesh term: Neurofibroma
mesh term: Aminolevulinic Acid
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: No participants in part 2 completed 1 year of follow-up visits, and are reported as lost to follow-up. This necessarily limits all outcome measurements for part 2 other than the maximum tolerable dose measurement.
point of contact: 