<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/NCT03266900</url>
  </required_header>
  <id_info>
    <org_study_id>17-5305.0</org_study_id>
    <nct_id>NCT03266900</nct_id>
  </id_info>
  <brief_title>A Superiority Trial to Compare Re-resection of High-grade T1 Bladder Urothelial Carcinoma to no Re-resection for Improving Progression Free Survival</brief_title>
  <acronym>RESECT</acronym>
  <official_title>A Pilot, Single-centre, Randomized, 5-year, Parallel-group, Superiority Trial to Compare Re-resection of High-grade T1 Bladder Urothelial Carcinoma to no Re-resection for Improving Progression Free Survival</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Health Network, Toronto</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bladder Cancer Canada</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Canadian Urological Association</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Canadian Urologic Oncology Group</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University Health Network, Toronto</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The investigators would like to compare the progression free survival, overall survival,&#xD;
      quality of life, and safety outcomes of patients receiving versus not receiving a 2nd&#xD;
      transurethral resection of bladder tumor.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background: Bladder cancer (BCa) is the 4th and 12th most common malignancies by incidence in&#xD;
      Canadian men and women, respectively. In Canada, the lifetime probability of developing BCa&#xD;
      is 1 in 27 men and 1 in 84 women. Urologists use a transurethral resection of bladder tumor&#xD;
      (TURBT) to diagnose and stage patients with non-muscle invasive bladder cancer (NMIBC). While&#xD;
      the value of repeat TURBT is not questioned for incomplete endoscopic resections,&#xD;
      retrospective studies have suggested value in repeat resection for high grade T1 (T1HG)&#xD;
      tumors even if they are completely resected, typically done within 6 weeks of the initial&#xD;
      resection. Repeat TURBT for T1HG BCa has been touted to detect understaged tumors, remove&#xD;
      occult residual disease, provide prognostic value and improve subsequent bladder therapy. To&#xD;
      date, there is a paucity of high quality level-1 evidence validating repeat TURBT for T1HG&#xD;
      compared to a single TURBT for improved long term disease specific outcomes.&#xD;
&#xD;
      Research Question: Among patients with T1HG BCa with completely resected tumor, is repeat&#xD;
      TURBT superior to single TURBT for improving 53-year progression free survival (PFS), defined&#xD;
      as &gt;/=T2 local disease or lymph node disease/distant metastasis? Study Design: The RESECT&#xD;
      trial is designed as a pilot, single-centre, 2-arm parallel-group, superiority randomized&#xD;
      trial, with random permuted blocks (lengths of 4 or 6) and balanced allocation (1:1),&#xD;
      conducted at the University Health Network.&#xD;
&#xD;
      Patient Population: Adult patients with completely resected T1HG bladder urothelial carcinoma&#xD;
      are eligible to participate. Patients with either lymph node/distant metastases at&#xD;
      presentation, variant histology, those that had their initial resection performed outside of&#xD;
      a study centre, or patients with severe comorbidities are excluded.&#xD;
&#xD;
      Intervention: Repeat TURBT (experimental) versus T1HG standard of care (active control).&#xD;
&#xD;
      Outcomes: The primary outcome is the difference between the two intervention arms with&#xD;
      regards to PFS over 5-years of follow-up. Secondary outcomes are the difference between the&#xD;
      two intervention arms in: (i) clinical measures; (ii) survival measures; (iii) perioperative&#xD;
      safety measures; and (iv) quality of life (QOL) questionnaires.&#xD;
&#xD;
      Randomization: Randomization will occur at the central coordinating site using a&#xD;
      computer-generated randomization schedule and random permuted blocks (of lengths 4 or 6). The&#xD;
      allocation sequence will be implemented using sequentially numbered, opaque, sealed&#xD;
      envelopes.&#xD;
&#xD;
      Blinding: Neither participants nor treating physicians will be blinded to treatment&#xD;
      allocation. The research/data analyst team will be blinded as will the radiologists that&#xD;
      assess surveillance imaging.&#xD;
&#xD;
      Sample Size: To test feasibility, a sample of 18 cases in 1 year is expected. Analysis:&#xD;
      Proportional outcomes will be analyzed with Chi-square or Fisher's exact test and continuous&#xD;
      variables will be analyzed with Student's t-test. Time to event outcomes will be analyzed&#xD;
      using log-rank tests on Kaplan-Meier estimates, followed by adjusted Cox proportional-hazard&#xD;
      models. Continuous variables with differences between two time periods will be analyzed suing&#xD;
      an analysis of covariance, with baseline values and centre adjusted for as covariates.&#xD;
      Continuous variable outcomes with values over multiple time periods will be analyzed using&#xD;
      repeated measures analysis of covariance.&#xD;
&#xD;
      Follow-Up: In addition to baseline assessment, each participant will be followed up at 3, 6,&#xD;
      9, 12, 15, 18, 21, 24, 30, 36, 48, 60 months after the intervention with cystoscopic&#xD;
      evaluation, and assessment of disease progression and QOL. Surveillance imaging will be every&#xD;
      6 months for the 5-year follow-up.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Difficulties with accrual&#xD;
  </why_stopped>
  <start_date type="Actual">November 16, 2017</start_date>
  <completion_date type="Actual">October 4, 2021</completion_date>
  <primary_completion_date type="Actual">October 4, 2021</primary_completion_date>
  <phase>Early Phase 1</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>5 year Progression Free Survival</measure>
    <time_frame>5 years</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Clinical Measures - These include recurrence free survival (in the bladder), time to cystectomy, and metastases-free survival as measured over time from intervention to 5-years post-intervention.</measure>
    <time_frame>5 years</time_frame>
    <description>Time to bladder recurrence (ie. BCG failure), measured over time from intervention to 5-years post-intervention.&#xD;
Time to cystectomy, measured over time from intervention to 5-years post-intervention.&#xD;
Time to metastasis (lymph node or distant metastasis), measured over time from intervention to 5-years post-intervention.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Survival Measures - These include disease specific survival and overall survival as measured over time from intervention to 5-years post-intervention.</measure>
    <time_frame>5 years</time_frame>
    <description>Time to bladder cancer-specific mortality, measured over time from intervention to 5-years post-intervention&#xD;
Time to death (examining overall survival), measured over time from intervention to 5-years post-intervention.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Perioperative Safety Measures - These include rate of major complications as defined by the Clavien-Dindo classification as grade 3, 4, and 5.</measure>
    <time_frame>5 years</time_frame>
    <description>Proportion with major complications, indicated by the Clavien-Dindo classification of grade 3, 4, and 5, measured during the repeat TURBT hospitalization period.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Change of Patient FACT BI Scores - This includes prospective collection with a validated BCa HRQOL instruments performed at each patient visit.</measure>
    <time_frame>5 years</time_frame>
    <description>1-year post-intervention from baseline&#xD;
Over time at each 3-month surveillance visit (during the first 2 years), each 6-month surveillance visit (during the year 2-3), and each annual surveillance visit (during year 4-5).&#xD;
The FACT-Bl metric is validated for measuring HRQOL of patients with BCa. This questionnaire is designed for patients with bladder cancer and includes assessment of four general domains (physical, social/family, emotional and function), with patients responding to statements on a five-point ordinal Likert scale ranging from zero to four. Additionally, there are statements concerning urinary tract symptoms, intestinal symptoms and sexual symptoms (10 statements), with two more for those with a stoma. With 39 statements, the highest score achievable is 156.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">2</enrollment>
  <condition>Bladder Cancer</condition>
  <condition>Bladder Urothelial Carcinoma</condition>
  <arm_group>
    <arm_group_label>re-TURBT</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients in this arm will receive a 2nd TURBT within 4-6 weeks of initial TURBT</description>
  </arm_group>
  <arm_group>
    <arm_group_label>6 BCG instillations</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients in this arm will not receive a 2nd TURBT, but will receive 6 instillations of BCG.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>re-TURBT</intervention_name>
    <description>2nd bladder biopsy within 4-6 weeks of initial biopsy</description>
    <arm_group_label>re-TURBT</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>6 weeks BCG instillation</intervention_name>
    <description>standard 6 weeks of BCG induction</description>
    <arm_group_label>6 BCG instillations</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Complete initial resection by a BCa-focused urologic oncologist; mandatory bladder&#xD;
             detrusor muscle in the initial TURBT specimen and complete visible resection&#xD;
             documented by the surgeon/OR staff by intra-operative photography.&#xD;
&#xD;
          -  Urothelial carcinoma as the predominant histology as determined by genitourinary&#xD;
             specific pathologist (e.g. small (&lt;50%) components of small cell, squamous cell or&#xD;
             adenocarcinoma are allowable).&#xD;
&#xD;
          -  Able and willing to consent.&#xD;
&#xD;
          -  ≥18 years old: BCa is primarily a disease of the elderly, thus we have elected to&#xD;
             include healthy octogenarian/nonagenarian patients. Additionally, since a TURBT can be&#xD;
             performed under general or spinal anesthesia, we feel that including these patients is&#xD;
             acceptable.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Lymph node or distant metastases at initial presentation - determined on standard BCa&#xD;
             staging evaluation with a CT-urogram of the abdomen/pelvis and/or a preoperative chest&#xD;
             x-ray demonstrating pulmonary metastases.&#xD;
&#xD;
          -  Extensive NMIBC disease warranting immediate cystectomy.&#xD;
&#xD;
          -  Variant histology (not urothelial carcinoma) - ie. micropapillary, plasmacytoid,&#xD;
             nested or sarcomatoid variants.&#xD;
&#xD;
          -  No muscularis propria (inadequate bladder staging) present in the initial TURBT&#xD;
             specimen.&#xD;
&#xD;
          -  Initial TURBT demonstrating T1HG disease performed outside of study centre - as per&#xD;
             study protocol, quality control of surgical performance for this trial requires the&#xD;
             TURBT to be performed by an experienced BCa-dedicated surgeon.&#xD;
&#xD;
          -  Patients with severe comorbidities, including but not limited to: (i) previous stroke&#xD;
             with persistent cognitive, motor, etc deficits; (ii) recent (&lt;6 months) myocardial&#xD;
             infarction or current unstable angina; (iii) liver cirrhosis; (iv) severe chronic&#xD;
             obstructive pulmonary disease (COPD)/respiratory disease. Patients must be suitable&#xD;
             candidates for either spinal or general anesthesia.&#xD;
&#xD;
          -  Pregnancy or lactation.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>100 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Girish Kulkarni, MD PhD FRCSC</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Health Network - Princess Margaret Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University Health Network</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G2M9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>April 2022</verification_date>
  <study_first_submitted>August 9, 2017</study_first_submitted>
  <study_first_submitted_qc>August 25, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 30, 2017</study_first_posted>
  <last_update_submitted>April 12, 2022</last_update_submitted>
  <last_update_submitted_qc>April 12, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">April 20, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Carcinoma, Transitional Cell</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03266900
org study id: 17-5305.0
nct id: NCT03266900
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The investigators would like to compare the progression free survival, overall survival,
      quality of life, and safety outcomes of patients receiving versus not receiving a 2nd
      transurethral resection of bladder tumor.
Background: Bladder cancer (BCa) is the 4th and 12th most common malignancies by incidence in
      Canadian men and women, respectively. In Canada, the lifetime probability of developing BCa
      is 1 in 27 men and 1 in 84 women. Urologists use a transurethral resection of bladder tumor
      (TURBT) to diagnose and stage patients with non-muscle invasive bladder cancer (NMIBC). While
      the value of repeat TURBT is not questioned for incomplete endoscopic resections,
      retrospective studies have suggested value in repeat resection for high grade T1 (T1HG)
      tumors even if they are completely resected, typically done within 6 weeks of the initial
      resection. Repeat TURBT for T1HG BCa has been touted to detect understaged tumors, remove
      occult residual disease, provide prognostic value and improve subsequent bladder therapy. To
      date, there is a paucity of high quality level-1 evidence validating repeat TURBT for T1HG
      compared to a single TURBT for improved long term disease specific outcomes.

      Research Question: Among patients with T1HG BCa with completely resected tumor, is repeat
      TURBT superior to single TURBT for improving 53-year progression free survival (PFS), defined
      as >/=T2 local disease or lymph node disease/distant metastasis? Study Design: The RESECT
      trial is designed as a pilot, single-centre, 2-arm parallel-group, superiority randomized
      trial, with random permuted blocks (lengths of 4 or 6) and balanced allocation (1:1),
      conducted at the University Health Network.

      Patient Population: Adult patients with completely resected T1HG bladder urothelial carcinoma
      are eligible to participate. Patients with either lymph node/distant metastases at
      presentation, variant histology, those that had their initial resection performed outside of
      a study centre, or patients with severe comorbidities are excluded.

      Intervention: Repeat TURBT (experimental) versus T1HG standard of care (active control).

      Outcomes: The primary outcome is the difference between the two intervention arms with
      regards to PFS over 5-years of follow-up. Secondary outcomes are the difference between the
      two intervention arms in: (i) clinical measures; (ii) survival measures; (iii) perioperative
      safety measures; and (iv) quality of life (QOL) questionnaires.

      Randomization: Randomization will occur at the central coordinating site using a
      computer-generated randomization schedule and random permuted blocks (of lengths 4 or 6). The
      allocation sequence will be implemented using sequentially numbered, opaque, sealed
      envelopes.

      Blinding: Neither participants nor treating physicians will be blinded to treatment
      allocation. The research/data analyst team will be blinded as will the radiologists that
      assess surveillance imaging.

      Sample Size: To test feasibility, a sample of 18 cases in 1 year is expected. Analysis:
      Proportional outcomes will be analyzed with Chi-square or Fisher's exact test and continuous
      variables will be analyzed with Student's t-test. Time to event outcomes will be analyzed
      using log-rank tests on Kaplan-Meier estimates, followed by adjusted Cox proportional-hazard
      models. Continuous variables with differences between two time periods will be analyzed suing
      an analysis of covariance, with baseline values and centre adjusted for as covariates.
      Continuous variable outcomes with values over multiple time periods will be analyzed using
      repeated measures analysis of covariance.

      Follow-Up: In addition to baseline assessment, each participant will be followed up at 3, 6,
      9, 12, 15, 18, 21, 24, 30, 36, 48, 60 months after the intervention with cystoscopic
      evaluation, and assessment of disease progression and QOL. Surveillance imaging will be every
      6 months for the 5-year follow-up.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: 5 year Progression Free Survival
time frame: 5 years
measure: Clinical Measures - These include recurrence free survival (in the bladder), time to cystectomy, and metastases-free survival as measured over time from intervention to 5-years post-intervention.
time frame: 5 years
description: Time to bladder recurrence (ie. BCG failure), measured over time from intervention to 5-years post-intervention.
Time to cystectomy, measured over time from intervention to 5-years post-intervention.
Time to metastasis (lymph node or distant metastasis), measured over time from intervention to 5-years post-intervention.
measure: Survival Measures - These include disease specific survival and overall survival as measured over time from intervention to 5-years post-intervention.
time frame: 5 years
description: Time to bladder cancer-specific mortality, measured over time from intervention to 5-years post-intervention
Time to death (examining overall survival), measured over time from intervention to 5-years post-intervention.
measure: Perioperative Safety Measures - These include rate of major complications as defined by the Clavien-Dindo classification as grade 3, 4, and 5.
time frame: 5 years
description: Proportion with major complications, indicated by the Clavien-Dindo classification of grade 3, 4, and 5, measured during the repeat TURBT hospitalization period.
measure: Mean Change of Patient FACT BI Scores - This includes prospective collection with a validated BCa HRQOL instruments performed at each patient visit.
time frame: 5 years
description: 1-year post-intervention from baseline
Over time at each 3-month surveillance visit (during the first 2 years), each 6-month surveillance visit (during the year 2-3), and each annual surveillance visit (during year 4-5).
The FACT-Bl metric is validated for measuring HRQOL of patients with BCa. This questionnaire is designed for patients with bladder cancer and includes assessment of four general domains (physical, social/family, emotional and function), with patients responding to statements on a five-point ordinal Likert scale ranging from zero to four. Additionally, there are statements concerning urinary tract symptoms, intestinal symptoms and sexual symptoms (10 statements), with two more for those with a stoma. With 39 statements, the highest score achievable is 156.
arm group label: re-TURBT
arm group type: Experimental
description: Patients in this arm will receive a 2nd TURBT within 4-6 weeks of initial TURBT
arm group label: 6 BCG instillations
arm group type: Active Comparator
description: Patients in this arm will not receive a 2nd TURBT, but will receive 6 instillations of BCG.
intervention type: Procedure
intervention name: re-TURBT
description: 2nd bladder biopsy within 4-6 weeks of initial biopsy
arm group label: re-TURBT
intervention type: Drug
intervention name: 6 weeks BCG instillation
description: standard 6 weeks of BCG induction
arm group label: 6 BCG instillations
criteria: 
gender: All
minimum age: 18 Years
maximum age: 100 Years
healthy volunteers: No
last name: Girish Kulkarni, MD PhD FRCSC
role: Principal Investigator
affiliation: University Health Network - Princess Margaret Hospital
facility: 
country: Canada
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Carcinoma, Transitional Cell
sharing ipd: No