<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/NCT02242929</url>
  </required_header>
  <id_info>
    <org_study_id>NL50433.068.14</org_study_id>
    <nct_id>NCT02242929</nct_id>
  </id_info>
  <brief_title>Surgery Versus Combined Treatment With Curettage and Imiquimod for Nodular Basal Cell Carcinoma</brief_title>
  <acronym>SCIN</acronym>
  <official_title>Surgical Excision Versus Combined Treatment With Curettage and Imiquimod for Nodular Basal Cell Carcinoma: an Open, Non-inferiority, Randomized Controlled Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Maastricht University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Maastricht University Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Basal cell carcinoma (BCC) is a slow-growing, locally invasive malignant epidermal skin&#xD;
      tumour. It is the most common malignant disease in Caucasians, representing approximately 80%&#xD;
      of all cases of skin cancer and is therefore an important health problem. In the Netherlands&#xD;
      incidence rates are 165 for men and 157 for women per 100.000 person-years, and these rates&#xD;
      are rising with 3-10% every year.&#xD;
&#xD;
      A simplified histological classification of BCCs includes the following three subtypes:&#xD;
      nodular, superficial and infiltrative variants, with the nodular variant being the most&#xD;
      frequent type. Although a characteristic feature of BCCs is their low risk to metastasize, if&#xD;
      untreated they may be locally invasive and may induce considerable functional and cosmetic&#xD;
      morbidity.&#xD;
&#xD;
      The gold standard treatment of all histological BCC subtypes is surgical excision (SE), but&#xD;
      not all patients are eligible for surgery. In patients with multiple BCCs and older patients,&#xD;
      surgery may lead to significant morbidity, and in some cases, it may result in disfiguring&#xD;
      scarring. For these reasons and to reduce workload and costs in the healthcare system, there&#xD;
      is a growing demand for alternative, non-invasive, treatments. An advantage of non-invasive&#xD;
      treatment options is that they can be performed by other healthcare professionals, such as&#xD;
      general practitioners and specialized nurses. For treatment of superficial BCCs (sBCC)&#xD;
      non-invasive treatments, such as topical imiquimod (IMQ), 5-fluorouracil (5-FU) or&#xD;
      photodynamic therapy (PDT) are already commonly used. Our group investigated the efficacy of&#xD;
      those three therapies and found that after 3 years, BCCs treated with IMQ had a significant&#xD;
      lower risk of recurrence, compared to the other therapies.&#xD;
&#xD;
      A recent study suggests that IMQ, besides being an immune-response modifier, also directly&#xD;
      inhibits sonic hedgehog (SHH) signalling, the most important pathway active in BCCs. This&#xD;
      targeted effect of IMQ very likely explains the superior therapeutic effect. Treatment of&#xD;
      nodular BCC (nBCC) with IMQ has been investigated. Without prior curettage, high efficacy&#xD;
      rates were found, although efficacy was still slightly inferior to SE.&#xD;
&#xD;
      The investigators hypothesize that the effectiveness of IMQ following prior curettage will&#xD;
      not be inferior to SE and that the benefits will be a higher patient satisfaction and lower&#xD;
      healthcare costs. A recently published discreet choice experiment showed that patients&#xD;
      preferred IMQ to surgery regardless of previous experience of BCC symptoms and treatment.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">January 2016</start_date>
  <completion_date type="Anticipated">December 2022</completion_date>
  <primary_completion_date type="Actual">December 2017</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Proportion of participants tumour-free</measure>
    <time_frame>At 1 year after end of treatment</time_frame>
    <description>The primary study endpoint is the proportion of participants tumour-free at 1 year after end of treatment (defined as absence of initial treatment failure or any clinical signs of local recurrence). For SE, routine histological examination of haematoxylin and eosin (H&amp;E)-stained sections of the lateral and deep margins will be used to assess treatment failure. For curettage &amp; IMQ 5% cream, initial treatment failure will be clinically assessed at a follow-up visit 3 months after end of treatment. Initial treatment failure or any clinical signs of subsequent local recurrence will be assessed and recorded separately by one investigator. In case there is clinical suspicion of BCC, a 3 mm punch biopsy will be taken for histological verification.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>The 5-year cumulative probability of recurrence free survival after end of treatment</measure>
    <time_frame>At 5 years after end of treatment</time_frame>
    <description>Any clinical signs of subsequent local recurrence will be assessed by one investigator. In case there is clinical suspicion of BCC, a 3 mm punch biopsy will be taken for histological verification.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Compliance</measure>
    <time_frame>At 3 months after end of treatment</time_frame>
    <description>Data for compliance with the prescribed regimens of IMQ 5% cream will be obtained from a personal diary kept by patients and completed daily during the six week IMQ 5% application period in subjects allocated to treatment with IMQ. Compliance will be calculated as the number of applications actually applied by the patient divided by the total prescribed number of cream applications. Furthermore sachets will be collected and counted by the investigator. This is a separate compliance assessment. The number of returned sachets will be divided by the total prescribed number of sachets. During the phone consultation by the investigator two weeks after start of application, treatment will be evaluated to ensure continuation of treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cosmetic appearance</measure>
    <time_frame>At 1 and 5 year after end of treatment</time_frame>
    <description>Cosmetic appearance of lesion site will be assessed independently by the participant and two independent investigators at 1 and 5 year follow-up using a Dutch four point scale and the Patient and Observer Scar Assessment Scale (POSAS).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient satisfaction</measure>
    <time_frame>At 1 and 5 year after end of treatment</time_frame>
    <description>Patient satisfaction will be assessed by the participant at 1 and 5 year follow-up on the basis of 3 statements. For the extent of agreement a 4-point rating scale is used, ranging from total disagreement to total agreement</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Level of Pain</measure>
    <time_frame>2 weeks after end of treatment</time_frame>
    <description>The proportion of patients experiencing a moderate or more severe level of pain. In the IMQ 5 % group, this will be measured daily during the application period and 2 weeks after end of treatment. In the SE group, pain during SE procedure will be measured and pain until the removal of the stiches will be measured daily. Furthermore pain will be measured at the time of removal of the stiches. Pain will be assessed using a 10 cm Visual Analogue Scale (VAS) where 0 represents 'no pain' and 10 represents, 'most severe pain imaginable'.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cost-effectiveness</measure>
    <time_frame>At 5 year after end of treatment</time_frame>
    <description>Data regarding resource use, i.e. outpatient visits, phone consultation, curettage, IMQ cream, SE and potential treatment of side-effects/adverse events will be recorded during the trial. Cost-prices will be derived from the manual for cost research in economic evaluations, the Pharmacotherapeutic Compass and the university hospital Maastricht. If necessary, cost-prices will be calculated based on real resource use. Total treatment costs will be estimated by multiplying volumes of use with the costs per unit. The cost-effectiveness ratio will be expressed as the incremental costs per additional tumour free patient. To quantify the uncertainty surrounding the incremental cost-effectiveness ratio (ICER) bootstrap analysis will be performed. Results of this analysis will be presented in cost-effectiveness planes and acceptability curves.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse events</measure>
    <time_frame>Up to 3 months after end of treatment</time_frame>
    <description>Adverse events, including local skin reactions, will be collected from all patients up to the 3 months follow-up visit and during phone consultation by the investigator (after two weeks of treatment in the IMQ group and during phone consultation about the histological examination of the excision specimen in the SE group). In case of an extra (phone) consultation of the patients as a result of severe adverse reactions, this will also be recorded. Serious events related to the investigative treatments (SUSAR) will be recorded during the entire follow-up period.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Baseline characteristics</measure>
    <time_frame>After inclusion visit</time_frame>
    <description>Baseline characteristics (ie. age, sex, amount of sun-exposure, size and localisation of the target tumour, medical history and concomitant medication) will be recorded.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">145</enrollment>
  <condition>Nodular Basal Cell Carcinoma</condition>
  <arm_group>
    <arm_group_label>Standard surgical excision</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Standard surgical &quot;elliptical&quot; excision including a 3-mm clinically tumour-free margin according to the current local hospital arrangements.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Imiquimod 5% cream with prior curettage</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Tumours will be partially debulked under local anaesthesia by removing all tumour tissue until normal dermis remains with a blunt curette. After curettage patients will receive an instruction sheet to apply imiquimod 5% cream once daily, 5 days a week, during 6 weeks, starting one week after the curettage procedure. Patients will be instructed to apply a thin layer to the tumour including 5-10mm of the surrounding skin at least 1 hour before going to bed at night. The lesion will not be covered (unless needed because of weeping or bleeding). Participants will be asked to wash their hands after applying the cream, and to wipe the cream off after 8 hours (in the morning).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Imiquimod 5% cream with prior curettage</intervention_name>
    <arm_group_label>Imiquimod 5% cream with prior curettage</arm_group_label>
    <other_name>Aldara</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Standard surgical excision</intervention_name>
    <arm_group_label>Standard surgical excision</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adults aged 18 years or older&#xD;
&#xD;
          -  Primary histologically proven nodular BCC ≥ 4mm and ≤ 20mm in diameter. (If the tumour&#xD;
             exhibits additional sBCC characteristics, but also contains nodular component that&#xD;
             extend into the reticular dermis, the tumour will be classified as nBCC with&#xD;
             superficial components and will be included).&#xD;
&#xD;
          -  Comorbidities may not interfere with study treatment&#xD;
&#xD;
          -  Capable to understand instructions&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  A nodular BCC located in the H-zone of the face or hairy scalp&#xD;
&#xD;
          -  Recurrent (previously treated) nBCC&#xD;
&#xD;
          -  Aggressive BCC subtypes (morphoea, micronodular, or BCC with squamous differentiation)&#xD;
&#xD;
          -  Life expectancy of less than five years&#xD;
&#xD;
          -  Breast-feeding or pregnant women&#xD;
&#xD;
          -  Serious comorbidities&#xD;
&#xD;
          -  Use of immunosuppressive medication during the trial period or within 30 days before&#xD;
             enrolment&#xD;
&#xD;
          -  Patients with genetic skin cancer disorders&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Klara Mosterd, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Maastricht University Medical Centre</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Maastricht University medical Centre</name>
      <address>
        <city>Maastricht</city>
        <state>Limburg</state>
        <zip>6202AZ</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <reference>
    <citation>Bath-Hextall F, Ozolins M, Armstrong SJ, Colver GB, Perkins W, Miller PS, Williams HC; Surgery versus Imiquimod for Nodular Superficial basal cell carcinoma (SINS) study group. Surgical excision versus imiquimod 5% cream for nodular and superficial basal-cell carcinoma (SINS): a multicentre, non-inferiority, randomised controlled trial. Lancet Oncol. 2014 Jan;15(1):96-105. doi: 10.1016/S1470-2045(13)70530-8. Epub 2013 Dec 11.</citation>
    <PMID>24332516</PMID>
  </reference>
  <verification_date>September 2021</verification_date>
  <study_first_submitted>September 15, 2014</study_first_submitted>
  <study_first_submitted_qc>September 16, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 17, 2014</study_first_posted>
  <last_update_submitted>September 23, 2021</last_update_submitted>
  <last_update_submitted_qc>September 23, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">September 24, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Nodular Basal Cell Carcinoma</keyword>
  <keyword>Treatment</keyword>
  <keyword>Imiquimod</keyword>
  <keyword>Curettage</keyword>
  <keyword>Surgery</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Carcinoma, Basal Cell</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Imiquimod</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02242929
org study id: NL50433.068.14
nct id: NCT02242929
lead sponsor: 
has dmc: Yes
Basal cell carcinoma (BCC) is a slow-growing, locally invasive malignant epidermal skin
      tumour. It is the most common malignant disease in Caucasians, representing approximately 80%
      of all cases of skin cancer and is therefore an important health problem. In the Netherlands
      incidence rates are 165 for men and 157 for women per 100.000 person-years, and these rates
      are rising with 3-10% every year.

      A simplified histological classification of BCCs includes the following three subtypes:
      nodular, superficial and infiltrative variants, with the nodular variant being the most
      frequent type. Although a characteristic feature of BCCs is their low risk to metastasize, if
      untreated they may be locally invasive and may induce considerable functional and cosmetic
      morbidity.

      The gold standard treatment of all histological BCC subtypes is surgical excision (SE), but
      not all patients are eligible for surgery. In patients with multiple BCCs and older patients,
      surgery may lead to significant morbidity, and in some cases, it may result in disfiguring
      scarring. For these reasons and to reduce workload and costs in the healthcare system, there
      is a growing demand for alternative, non-invasive, treatments. An advantage of non-invasive
      treatment options is that they can be performed by other healthcare professionals, such as
      general practitioners and specialized nurses. For treatment of superficial BCCs (sBCC)
      non-invasive treatments, such as topical imiquimod (IMQ), 5-fluorouracil (5-FU) or
      photodynamic therapy (PDT) are already commonly used. Our group investigated the efficacy of
      those three therapies and found that after 3 years, BCCs treated with IMQ had a significant
      lower risk of recurrence, compared to the other therapies.

      A recent study suggests that IMQ, besides being an immune-response modifier, also directly
      inhibits sonic hedgehog (SHH) signalling, the most important pathway active in BCCs. This
      targeted effect of IMQ very likely explains the superior therapeutic effect. Treatment of
      nodular BCC (nBCC) with IMQ has been investigated. Without prior curettage, high efficacy
      rates were found, although efficacy was still slightly inferior to SE.

      The investigators hypothesize that the effectiveness of IMQ following prior curettage will
      not be inferior to SE and that the benefits will be a higher patient satisfaction and lower
      healthcare costs. A recently published discreet choice experiment showed that patients
      preferred IMQ to surgery regardless of previous experience of BCC symptoms and treatment.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Proportion of participants tumour-free
time frame: At 1 year after end of treatment
description: The primary study endpoint is the proportion of participants tumour-free at 1 year after end of treatment (defined as absence of initial treatment failure or any clinical signs of local recurrence). For SE, routine histological examination of haematoxylin and eosin (H&E)-stained sections of the lateral and deep margins will be used to assess treatment failure. For curettage & IMQ 5% cream, initial treatment failure will be clinically assessed at a follow-up visit 3 months after end of treatment. Initial treatment failure or any clinical signs of subsequent local recurrence will be assessed and recorded separately by one investigator. In case there is clinical suspicion of BCC, a 3 mm punch biopsy will be taken for histological verification.
measure: The 5-year cumulative probability of recurrence free survival after end of treatment
time frame: At 5 years after end of treatment
description: Any clinical signs of subsequent local recurrence will be assessed by one investigator. In case there is clinical suspicion of BCC, a 3 mm punch biopsy will be taken for histological verification.
measure: Compliance
time frame: At 3 months after end of treatment
description: Data for compliance with the prescribed regimens of IMQ 5% cream will be obtained from a personal diary kept by patients and completed daily during the six week IMQ 5% application period in subjects allocated to treatment with IMQ. Compliance will be calculated as the number of applications actually applied by the patient divided by the total prescribed number of cream applications. Furthermore sachets will be collected and counted by the investigator. This is a separate compliance assessment. The number of returned sachets will be divided by the total prescribed number of sachets. During the phone consultation by the investigator two weeks after start of application, treatment will be evaluated to ensure continuation of treatment.
measure: Cosmetic appearance
time frame: At 1 and 5 year after end of treatment
description: Cosmetic appearance of lesion site will be assessed independently by the participant and two independent investigators at 1 and 5 year follow-up using a Dutch four point scale and the Patient and Observer Scar Assessment Scale (POSAS).
measure: Patient satisfaction
time frame: At 1 and 5 year after end of treatment
description: Patient satisfaction will be assessed by the participant at 1 and 5 year follow-up on the basis of 3 statements. For the extent of agreement a 4-point rating scale is used, ranging from total disagreement to total agreement
measure: Level of Pain
time frame: 2 weeks after end of treatment
description: The proportion of patients experiencing a moderate or more severe level of pain. In the IMQ 5 % group, this will be measured daily during the application period and 2 weeks after end of treatment. In the SE group, pain during SE procedure will be measured and pain until the removal of the stiches will be measured daily. Furthermore pain will be measured at the time of removal of the stiches. Pain will be assessed using a 10 cm Visual Analogue Scale (VAS) where 0 represents 'no pain' and 10 represents, 'most severe pain imaginable'.
measure: Cost-effectiveness
time frame: At 5 year after end of treatment
description: Data regarding resource use, i.e. outpatient visits, phone consultation, curettage, IMQ cream, SE and potential treatment of side-effects/adverse events will be recorded during the trial. Cost-prices will be derived from the manual for cost research in economic evaluations, the Pharmacotherapeutic Compass and the university hospital Maastricht. If necessary, cost-prices will be calculated based on real resource use. Total treatment costs will be estimated by multiplying volumes of use with the costs per unit. The cost-effectiveness ratio will be expressed as the incremental costs per additional tumour free patient. To quantify the uncertainty surrounding the incremental cost-effectiveness ratio (ICER) bootstrap analysis will be performed. Results of this analysis will be presented in cost-effectiveness planes and acceptability curves.
measure: Adverse events
time frame: Up to 3 months after end of treatment
description: Adverse events, including local skin reactions, will be collected from all patients up to the 3 months follow-up visit and during phone consultation by the investigator (after two weeks of treatment in the IMQ group and during phone consultation about the histological examination of the excision specimen in the SE group). In case of an extra (phone) consultation of the patients as a result of severe adverse reactions, this will also be recorded. Serious events related to the investigative treatments (SUSAR) will be recorded during the entire follow-up period.
measure: Baseline characteristics
time frame: After inclusion visit
description: Baseline characteristics (ie. age, sex, amount of sun-exposure, size and localisation of the target tumour, medical history and concomitant medication) will be recorded.
arm group label: Standard surgical excision
arm group type: Active Comparator
description: Standard surgical "elliptical" excision including a 3-mm clinically tumour-free margin according to the current local hospital arrangements.
arm group label: Imiquimod 5% cream with prior curettage
arm group type: Experimental
description: Tumours will be partially debulked under local anaesthesia by removing all tumour tissue until normal dermis remains with a blunt curette. After curettage patients will receive an instruction sheet to apply imiquimod 5% cream once daily, 5 days a week, during 6 weeks, starting one week after the curettage procedure. Patients will be instructed to apply a thin layer to the tumour including 5-10mm of the surrounding skin at least 1 hour before going to bed at night. The lesion will not be covered (unless needed because of weeping or bleeding). Participants will be asked to wash their hands after applying the cream, and to wipe the cream off after 8 hours (in the morning).
intervention type: Drug
intervention name: Imiquimod 5% cream with prior curettage
arm group label: Imiquimod 5% cream with prior curettage
other name: Aldara
intervention type: Procedure
intervention name: Standard surgical excision
arm group label: Standard surgical excision
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Klara Mosterd, MD, PhD
role: Principal Investigator
affiliation: Maastricht University Medical Centre
facility: 
country: Netherlands
citation: Bath-Hextall F, Ozolins M, Armstrong SJ, Colver GB, Perkins W, Miller PS, Williams HC; Surgery versus Imiquimod for Nodular Superficial basal cell carcinoma (SINS) study group. Surgical excision versus imiquimod 5% cream for nodular and superficial basal-cell carcinoma (SINS): a multicentre, non-inferiority, randomised controlled trial. Lancet Oncol. 2014 Jan;15(1):96-105. doi: 10.1016/S1470-2045(13)70530-8. Epub 2013 Dec 11.
PMID: 24332516
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Carcinoma, Basal Cell
mesh term: Imiquimod