xml: <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/NCT05962541</url>
    </required_header>
    <id_info>
      <org_study_id>N764J-20022023</org_study_id>
      <nct_id>NCT05962541</nct_id>
    </id_info>
    <brief_title>Vesical Imaging-Reporting and Data System (VI-RADS) Followed by Photodynamic Trans-urethral Resection of Bladder Tumours (PDD-TURBT) to Avoid Secondary Resections (Re-TURBT) in Non-Muscle Invasive Bladder Cancers (NMIBCs)</brief_title>
    <acronym>CUT-less</acronym>
    <official_title>Non-inferiority, Phase IV, Open-label, Randomized Controlled Trial of Vesical Imaging- Reporting and Data System (VI-RADS) Followed by Primary Photodynamic Trans-urethral Resection of Bladder Tumours (PDD-TURBT) Versus Conventional White-light TURBT Plus Repeated-TURBT (Re-TURBT) in Non-Muscle Invasive Bladder Cancers (NMIBCs) Candidate for Second Look and Resection</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>University of Roma La Sapienza</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>University of Roma La Sapienza</source>
    <oversight_info>
      <has_dmc>No</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
      <is_us_export>No</is_us_export>
    </oversight_info>
    <brief_summary>
      <textblock>
        Background: In European Association of Urology (EAU) Guidelines, the vast majority of&#xD;
        non-muscle-invasive bladder cancers (NMIBCs) undergo a primary transurethral resection of the&#xD;
        bladder tumor (TURBT) followed by a repeat TURBT (Re-TURBT). The Re-TURBT is recommended due&#xD;
        to the possibility of residual bladder cancer but is unnecessary in many cases by&#xD;
        constituting overtreatment. Currently, no diagnostic strategy or predictive tools have been&#xD;
        implemented to further stratify who does or does not benefit from Re-TURBT. Recently, an&#xD;
        MRI-based Vesical Imaging Reporting and Data System (VI-RADS) score has been developed to&#xD;
        stage as to the preoperative probability of muscle invasion, which could potentially exclude&#xD;
        those who do not require a Re-TURBT when a primary high-quality resection is delivered. As&#xD;
        such, performing TURBT with standard white light (WL) cystoscopy is known to miss many&#xD;
        bladder tumours, which may be poorly visible, and a technique known as with photodynamic&#xD;
        diagnosis (PDD) results in lower residual tumor and lower early intravesical recurrence&#xD;
        rates. PDD is performed using violet light to improve the detection of these lesions not&#xD;
        easily visible with WL cystoscopy.&#xD;
  &#xD;
        Methods/Aims: The investigators propose an Italian, single-center, phase IV, open-label,&#xD;
        non-inferiority, randomized controlled trial, in which participants (n=112) who had already&#xD;
        received a mpMRI/VI-RADS score, are randomized to receive PDD-TURBT, no Re-TURBT versus&#xD;
        standard of care represented by conventional WL-TURBT followed by WL-Re-TURBT. The primary&#xD;
        outcome is proportions of early recurrence in the urinary bladder. Secondary outcomes will&#xD;
        include proportions of late BCa recurrence, late disease-free interval, time to progression&#xD;
        to MIBC, patient's quality of life assessment, and cost-analysis.&#xD;
  &#xD;
        Perspective: The CUT-less trial aims to respond to this unmet need through a non-inferiority&#xD;
        randomized clinical study potentially shaping the perspective for a paradigm shift towards a&#xD;
        more personalized, socially, and economically sustainable updated NMIBC therapeutic pathway.&#xD;
  &#xD;
        Implications: The current clinical trial proposal is aiming to achieve a paradigm shift in&#xD;
        the oncological and socio-economical management of urothelial malignancies of the urinary&#xD;
        bladder. Our first concern is indeed to guarantee a safe and ground-breaking strategy to&#xD;
        manage the pathway of such patients in order to guarantee the non-inferior oncologic safety&#xD;
        (and possibly superiority) when compared to the current standard of care.&#xD;
  &#xD;
        Additionally, if our hypotheses are confirmed, the investigators will be able to&#xD;
        significantly relieve these patients from the oncologic burden of an already invasive and&#xD;
        arduous bladder cancer care path. Finally, safely avoiding an unnecessary, expensive surgical&#xD;
        procedure will bring significant social and economic benefits to the EU healthcare system and&#xD;
        possibly worldwide.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        BACKGROUND, STATE OF THE ART and RATIONALE FOR THE INTERVENTIONS&#xD;
  &#xD;
        The vast majority (75-80%) of bladder cancers (BCa) patients present with disease confined&#xD;
        either to the mucosa (stage Ta, carcinoma in situ [CIS]) or the submucosa (stage T1)&#xD;
        according to the tumor, node, and metastasis (TNM) classification system. These tumours that&#xD;
        do not invade the detrusor muscle of the urinary bladder are defined as superficial,&#xD;
        non-invasive, or non-muscle invasive bladder cancers (NMIBC) to differentiate them from the&#xD;
        less common, but significantly more deadly muscle invasive bladder cancers (MIBC; stage T2 -&#xD;
        T4).&#xD;
  &#xD;
        Although the initial procedure for surgical management of both NMIBC and MIBC tumours is a&#xD;
        trans-urethral resection of bladder tumor (TURBT), it serves different purposes for NMIBC&#xD;
        when compared with MIBC. For NMIBC, TURBT acts as both a diagnostic and a therapeutic&#xD;
        procedure, but for MIBC patients, TURBT is only a diagnostic procedure, as additional radical&#xD;
        intervention, such as radical cystectomy (RC), are usually required.&#xD;
  &#xD;
        However, there are many potential issues that can affect TURBT performance, including a high&#xD;
        degree of operator dependence for optimal outcomes. Along these lines, one particular issue&#xD;
        is that many of the so-called early BCa recurrences are actually incomplete resections during&#xD;
        initial TURBT. Incomplete resections can lead also to understaging (i.e., inaccurate&#xD;
        discrimination between NMIBC and MIBC), which can adversely affect the survival of the&#xD;
        patient. Incomplete tumor resection and residual tumor rates vary between 33% and 76% for all&#xD;
        cases, with rates of 27-72% and 33-78% for Ta and T1 tumours, respectively. Also,&#xD;
        underestimation of tumor depth invasion at first TURBT has been demonstrated in up to 7-30%&#xD;
        of cases, increasing up to 45-51% in those with T1 tumours where no detrusor muscle was&#xD;
        sampled in the specimen after initial TURBT.&#xD;
  &#xD;
        Based on these above issues, European Association of Urology (EAU) Guidelines recommend a&#xD;
        second look and resection (i.e., re-do TURBT [Re-TURBT]) 2 to 6 weeks following the primary&#xD;
        TURBT in cases of (I) incomplete initial TURBT or doubt about completeness of a TURBT, (II)&#xD;
        if there is no detrusor muscle in the specimen after initial TURBT, and (III) in all T1&#xD;
        tumours.&#xD;
  &#xD;
        As such, if Re-TURBT is to be considered an &quot;emergency rescue&quot; performed because of the&#xD;
        suboptimal quality of the initial TURBT, this can result in significant detriments to the&#xD;
        patient's quality of life (QoL) (e.g., second hospitalization, second anesthesia, potential&#xD;
        risk for complications, delay in definitive treatment etc.). These can result in additional&#xD;
        negative social implications (e.g., productivity loss, indirect costs etc.) and&#xD;
        health-care-related costs (e.g., surgical procedure costs, in-hospital recovery costs,&#xD;
        postoperative care etc.).&#xD;
  &#xD;
        The CUT-less study aims to address these major oncological, economic, and social unmet needs&#xD;
        related to the current EAU BCa algorithm throughout a phase IV, open-label, non-inferiority&#xD;
        randomized controlled trial. In particular, one of our aims is trying to avoid unnecessary&#xD;
        Re-TURBT by utilizing intraoperative visually enhanced photodynamic assisted TURBT&#xD;
        (PDD-TURBT) among those who had already been evaluated by multiparametric magnetic resonance&#xD;
        (mpMR) image-based staging before the initial TURBT as a combined novel strategy. In doing&#xD;
        so, the investigators hope to select for those in whom a Re-TURBT would normally be&#xD;
        recommended, unnecessarily. The investigators will compare this cohort to one that follows&#xD;
        the current standard of care algorithm, (i.e., conventional white light [WL] initial TURBT&#xD;
        followed by WL-Re-TURBT). The investigators will examine the relative proportions of early&#xD;
        BCa recurrence within the first 4.5 months after randomization. This would be the time&#xD;
        between randomization, surgical TURBTs (i.e., 1.5 months) and first follow-up cystoscopy&#xD;
        which is set at 3 months according to the International NMIBC Clinical trial Guidelines.&#xD;
  &#xD;
        The primary objectives of the CUT-less trial are indeed to provide the highest level of&#xD;
        evidence demonstrating non-inferiority between of this novel multidisciplinary and&#xD;
        translational approach integrating functional MRI and intraoperative visually assisted&#xD;
        enhanced trans-urethral surgery and the current EAU BCa pathway. This will potentially lead&#xD;
        to the redefinition of the criteria for Re-TURBT selection and will avoid unnecessary&#xD;
        surgical procedures in up to half of diagnosed NMIBCs. The impact of such paradigm shift will&#xD;
        transform the patient's perspective in their own BCa care and will limit the social and&#xD;
        economic burden of BCa management across the EU and hopefully worldwide.&#xD;
  &#xD;
        STUDY AIMS, DESIGN and METHODOLOGICAL FRAMEWORK&#xD;
  &#xD;
        Overall aim To utilize our expertise in mpMRI of the bladder diagnostics for pre-TURBT&#xD;
        staging purposes, intraoperative TURBT optical imaging enhancement by PDD-guided primary&#xD;
        resection in order to potentially shift clinical practice. In doing so, the investigators&#xD;
        seek to improve the therapeutic algorithm and personalization for NMIBC treatment by not&#xD;
        performing those Re-TURBT procedures which could be safely omitted.&#xD;
  &#xD;
        Sample Size Calculation The cohort of interest will be represented by intermediate/high-risk&#xD;
        NMIBCs who are currently those eligible for Re-TURBT according to EUA Guidelines. For the&#xD;
        primary outcome of the proportion of early BCa recurrence (i.e., within 4.5 months follow-up)&#xD;
        between the two arms, the investigators acknowledge that rates of early BCa recurrence&#xD;
        detection among NMIBCs undergoing TURBT along with adjuvant intravesical BCG immunotherapy in&#xD;
        a population, with equally distributed literature-defined risk factors for BCa recurrences,&#xD;
        have been shown to be 10% according to available literature.&#xD;
  &#xD;
        For the non-inferiority hypothesis, using 80% power and a 5% one sided-alpha, using an&#xD;
        estimate for detection rate of early BCa recurrence among intermediate/high-risk NMIBCs of&#xD;
        7.5% and using a margin of clinical unimportance of 10%, n=112 patients per arm will be&#xD;
        required. The choice of 10% as the margin of non-inferiority represents a difference that&#xD;
        would be considered clinically unimportant in the detection rate for the event of early BCa&#xD;
        recurrence in a population already screened by mpMRI and VI-RADS score determination for the&#xD;
        risk of disease understaging.&#xD;
  &#xD;
        To achieve this, prior to randomization, the investigators will screen potential eligible&#xD;
        participants by VI-RADS score determination and will exclude patients suspected for MIBC&#xD;
        (15-20%) and, from the remaining NMIBCs, exclude low risk disease (25-30%). Furthermore, the&#xD;
        investigators predict 35-40% of these patients will be recruited based on willingness to&#xD;
        participate or missed opportunities for recruitment.&#xD;
  &#xD;
        Thus, total subjects required in study would be n=224. Accounting for 15% withdrawal/loss to&#xD;
        follow up, n=258 men will need to be recruited.&#xD;
  &#xD;
        GROUND-BREAKING AMBITION OF THE PROPOSAL AND ADVANCEMENT OF KNOWLEDGE OVER THE STATE OF THE&#xD;
        ART&#xD;
  &#xD;
        BCa is a high priority area for research into both clinical and cost-effective management and&#xD;
        the findings from the CUT-less trial will be relevant and important to patient needs over the&#xD;
        next years across the EU and worldwide.&#xD;
  &#xD;
        TURBT is the standard of care both to diagnose and treat the vast majority of NMIBCs.&#xD;
        Nonetheless, to overcome the intrinsic limitations of TURBT, to achieve the desired complete&#xD;
        resection, and to correct potential staging errors, a second endoscopic procedure (i.e.,&#xD;
        Re-TURBT) is recommended by EUA Guidelines for most intermediate and high-risk NMIBCs&#xD;
        categories. However, there is still no currently available strategy to select the ideal&#xD;
        candidate for this.&#xD;
  &#xD;
        Notably, from a patient perspective, there are often considerable anxieties about&#xD;
        transurethral resection procedures, risk of recurrences, and progression requiring additional&#xD;
        therapies with potential mortality and long-term morbidity. TURBTs in general, are associated&#xD;
        with possible significant postoperative and long-term complications and morbidity ranging&#xD;
        from 5.1% to 43.3% according to the different series. Specifically, the potential for&#xD;
        complications during Re-TURBT is not trivial and hemorrhage, the need for blood transfusion,&#xD;
        or bladder perforation can negatively impact patient care and lead to delays in treatment,&#xD;
        ultimately influencing survival outcomes. Any TUR itself is therefore associated with reduced&#xD;
        QoL, including in both mental and physical health domains. Substantial reductions in health&#xD;
        related QoL are most likely to come from repeated hospitalizations, surgical complications,&#xD;
        invasive adjuvant intravesical treatments, and radical or palliative treatments for&#xD;
        progression. As consequence, a secondary resection performed 2 to 6 weeks from the primary&#xD;
        resection represents an additional burden in an already arduous BCa pathway. To our knowledge&#xD;
        this surgical scenario has never been scrutinized in the framework of a RCT despite the lack&#xD;
        of evidence to uniformly support Re-TURBT in every case. Moreover, both European and American&#xD;
        series had reported that performing Re-TURBT did not impact long-term progression-free&#xD;
        survival and that the tumor status at repeat TUR had only a marginal role in influencing&#xD;
        long-term cancer-specific survival.&#xD;
  &#xD;
        Additionally, NMIBC is one of the most expensive cancers to manage on a per patient basis&#xD;
        because of its high prevalence, high recurrence rate, need for adjuvant treatments, and the&#xD;
        requirement for long-term surveillance protocols. Because of the protracted clinical course&#xD;
        of early-stage disease, its prevalence relative to MIBC, and its procedure-oriented&#xD;
        surveillance, the associated cumulative medical payments are generally more substantial than&#xD;
        those for advanced disease. The average per capita spending for NMIBC is increasing in the&#xD;
        last two decades, from €7000 to €9000. These increasing costs are mainly attributable to the&#xD;
        more frequent use of endoscopy (e.g., cystoscopy, TURBT, Re-TURBT) and the adjuvant&#xD;
        intravesical therapies. TURBT accounts for a substantial portion of total bladder treatment&#xD;
        costs ranging from €3000 to €6000 depending on whether patients are discharged following the&#xD;
        procedure or admitted for inpatient care.&#xD;
  &#xD;
        Given these urgent needs for optimizing the NMIBC algorithm, the CUT-less trial will explore&#xD;
        a novel multidisciplinary approach for minimizing the burden of surgical exposure to patients&#xD;
        and for resizing the costs to the EU health care systems by redefining the selection criteria&#xD;
        for NMIBC candidates for Re-TURBT procedures.&#xD;
  &#xD;
        In conclusion, the currently available EAU Guidelines rely on conflicting and out of date&#xD;
        evidence which do not offer a contemporary viewpoint as to the role of Re-TURBT. Our updated&#xD;
        protocol which utilizes both mpMRI diagnostic imaging and PDD guided resections will be&#xD;
        closely examined in the CUT-less trial, with goal of more personalized, both socially and&#xD;
        economically sustainable updated NMIBC therapeutic pathways for use in the EU.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">February 2024</start_date>
    <completion_date type="Anticipated">February 2030</completion_date>
    <primary_completion_date type="Anticipated">February 2027</primary_completion_date>
    <phase>Phase 4</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>
      <intervention_model_description>Italian, single-center, phase IV, open-label, randomized controlled trial, with patients randomized in a 1:1 ratio to one of two arms</intervention_model_description>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Proportion of EARLY Bladder Cancer (BCa) recurrences</measure>
      <time_frame>within 4.5 months following primary intervention</time_frame>
      <description>The proportion of early BCa recurrences (i.e., within 4.5 months follow-up) in those non-muscle invasive bladder cancer (NMIBC) treated by standard of care (i.e., TURBT followed by Re-TURBT) compared to our novel algorithm proposal (i.e., primary PDD-TURBT followed by no Re-TURBT).</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Proportion of LATE BCa recurrences</measure>
      <time_frame>after 4.5 months following primary intervention</time_frame>
      <description>To determine the proportion of BCa late recurrences (i.e., after 4.5 months follow-up) in patients with NMIBC treated by standard of care compared to our novel algorithm proposal</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Proportion of progression from NMIBC to MIBC</measure>
      <time_frame>over 3 years follow-up</time_frame>
      <description>To determine the proportion of progression from NMIBC to MIBC in patients with NMIBC treated by standard of care compared to our novel algorithm proposal.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Changes in health-related quality of life (HRQoL)</measure>
      <time_frame>over 3 years follow-up</time_frame>
      <description>To determine changes in health-related quality of life (HRQoL) resulting from the physical and psychological benefit together with any harms associated with each strategy and with subsequent additional interventions. We will use generic QoL for cost-effectiveness analysis (i.e., EuroQoL Group [EQ]-5D-3L).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Changes in health-related quality of life (HRQoL)</measure>
      <time_frame>over 3 years follow-up</time_frame>
      <description>To determine changes in health-related quality of life (HRQoL) resulting from the physical and psychological benefit together with any harms associated with each strategy and with subsequent additional interventions. We will use and specific validated questionnaires to assess the outcomes of interest in the NMIBC population (i.e., European Organisation for Research and Treatment of Cancer [EORTC]-QLQ-C30).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Changes in health-related quality of life (HRQoL)</measure>
      <time_frame>over 3 years follow-up</time_frame>
      <description>To determine changes in health-related quality of life (HRQoL) resulting from the physical and psychological benefit together with any harms associated with each strategy and with subsequent additional interventions. We will use and specific validated questionnaires to assess the outcomes of interest in the NMIBC population (i.e., European Organisation for Research and Treatment of Cancer [EORTC] QLQ-NMIBC24).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Cost-effectiveness analysis</measure>
      <time_frame>over 3 years follow-up</time_frame>
      <description>To perform a within-trial cost-effectiveness analysis to calculate incremental cost per Re-TURBT avoided and the cost-utility of the experimental approach as measured by the incremental cost per quality-adjusted life year (QALY) gained at 2 years and over patients' lifetime.</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">258</enrollment>
    <condition>Non-muscle-invasive Bladder Cancer</condition>
    <condition>Non-Muscle Invasive Bladder Urothelial Carcinoma</condition>
    <condition>High Risk Non-Muscle Invasive Bladder Urothelial Carcinoma</condition>
    <arm_group>
      <arm_group_label>PPD-TURBT (no Re-TURBT)</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Primary PDD-TURBT, not followed by Re-TURBT</description>
    </arm_group>
    <arm_group>
      <arm_group_label>WL TURBT plus Re-TURBT (Standard of Care)</arm_group_label>
      <arm_group_type>No Intervention</arm_group_type>
      <description>Standard of care consisting in primary WL TURBT followed by WL Re-TURBT within 2 - 6 weeks from initial WL TURBT</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>PDD-TURBT with hexaminolevulinate (Hexvix®)</intervention_name>
      <description>In order to undergo PDD-TURBT, all eligible patients in the experimental arm will be administered the photosensitizer hexaminolevulinate (85 mg in 50 ml of phosphate buffered saline, Hexvix®) on an inpatient setting through a urethral catheterization of the participant's bladder. During the PDD-TURBT surgery, the bladder will be illuminated with blue light (wavelength 380-450 nm). The operating rooms of the participant institutions will therefore need to have the specialized equipment consisting in the blue-light source (POWER LED SAPHIRA [TM]).</description>
      <arm_group_label>PPD-TURBT (no Re-TURBT)</arm_group_label>
      <other_name>Hexvix®</other_name>
    </intervention>
    <intervention>
      <intervention_type>Device</intervention_type>
      <intervention_name>Power Led Saphira (TM) from KARL STORZ</intervention_name>
      <description>This is a light source based on LED technology. It can be used for both White Light (WL) and fluorescence applications in blue light (i.e., Photodynamic diagnosis PDD) for visualizing tumor lesions during trans-urethral resection of bladder tumors (PPD- TURBT).</description>
      <arm_group_label>PPD-TURBT (no Re-TURBT)</arm_group_label>
      <other_name>Power Led Saphira (TM)</other_name>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            1. Female and Male patients at least 18 years old referred for clinical suspicion of&#xD;
               primary or recurrent BCa who have been advised to undergo TURBT.&#xD;
  &#xD;
            2. Patients with a TUR-confirmed diagnosis of NMIBC and candidate for second look and&#xD;
               resection (Re-TURBT) according to EAU Guidelines [6].&#xD;
  &#xD;
            3. No imaging evidence (i.e., mpMRI/VI-RADS score 1 or 2) of muscle-invasive, locally&#xD;
               advanced, or metastatic BCa (i.e., only confirmed CIS, Ta, T1, N0, M0 will be&#xD;
               considered eligible).&#xD;
  &#xD;
            4. Patients who never received adjuvant Bacillus of Calmette-Guérin (BCG) immunotherapy&#xD;
               (i.e., BCG naïve patients) for previous BCa history.&#xD;
  &#xD;
            5. Fit to undergo all procedures listed in protocol.&#xD;
  &#xD;
            6. Able to provide written informed consent.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            1. Contraindication to TURBT and/or Re-TURBT.&#xD;
  &#xD;
            2. Initial TURBT diagnosis of MIBC (i.e., T2) or locally advanced BCa (i.e., T3-T4).&#xD;
  &#xD;
            3. Preoperative evidence of metastatic disease (i.e., cN1 - N3 and/or cM1).&#xD;
  &#xD;
            4. Visual evidence of low-risk NMIBC (solitary tumor, &lt; 1 cm) before initial TURBT.&#xD;
  &#xD;
            5. Visual evidence of MIBC on preliminary cystoscopy (i.e., non-papillary or sessile mass&#xD;
               attached directly by its base without a stalk).&#xD;
  &#xD;
            6. TURBT diagnosis of NMIBCs not eligible for Re-TURBT according to EAU Guidelines (i.e.,&#xD;
               Ta-LG; Ta-HG with detrusor muscle in the specimen; primary CIS) [6].&#xD;
  &#xD;
            7. Concomitant Upper tract (kidney or ureteric) tumours on imaging.&#xD;
  &#xD;
            8. Contraindication to adjuvant intravesical BCG immunotherapy.&#xD;
  &#xD;
            9. Unfit to undergo any procedures listed in protocol.&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_contact>
      <last_name>Francesco Del Giudice, MD</last_name>
      <phone>+39 3395382464</phone>
      <email>francesco.delgiudice@uniroma1.it</email>
    </overall_contact>
    <reference>
      <citation>Epstein JI, Amin MB, Reuter VR, Mostofi FK. The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Bladder Consensus Conference Committee. Am J Surg Pathol. 1998 Dec;22(12):1435-48. doi: 10.1097/00000478-199812000-00001.</citation>
      <PMID>9850170</PMID>
    </reference>
    <reference>
      <citation>Mariappan P, Zachou A, Grigor KM; Edinburgh Uro-Oncology Group. Detrusor muscle in the first, apparently complete transurethral resection of bladder tumour specimen is a surrogate marker of resection quality, predicts risk of early recurrence, and is dependent on operator experience. Eur Urol. 2010 May;57(5):843-9. doi: 10.1016/j.eururo.2009.05.047. Epub 2009 Jun 6.</citation>
      <PMID>19524354</PMID>
    </reference>
    <reference>
      <citation>Brausi M, Collette L, Kurth K, van der Meijden AP, Oosterlinck W, Witjes JA, Newling D, Bouffioux C, Sylvester RJ; EORTC Genito-Urinary Tract Cancer Collaborative Group. Variability in the recurrence rate at first follow-up cystoscopy after TUR in stage Ta T1 transitional cell carcinoma of the bladder: a combined analysis of seven EORTC studies. Eur Urol. 2002 May;41(5):523-31. doi: 10.1016/s0302-2838(02)00068-4.</citation>
      <PMID>12074794</PMID>
    </reference>
    <reference>
      <citation>Cumberbatch MGK, Foerster B, Catto JWF, Kamat AM, Kassouf W, Jubber I, Shariat SF, Sylvester RJ, Gontero P. Repeat Transurethral Resection in Non-muscle-invasive Bladder Cancer: A Systematic Review. Eur Urol. 2018 Jun;73(6):925-933. doi: 10.1016/j.eururo.2018.02.014. Epub 2018 Mar 6.</citation>
      <PMID>29523366</PMID>
    </reference>
    <reference>
      <citation>Naselli A, Hurle R, Paparella S, Buffi NM, Lughezzani G, Lista G, Casale P, Saita A, Lazzeri M, Guazzoni G. Role of Restaging Transurethral Resection for T1 Non-muscle invasive Bladder Cancer: A Systematic Review and Meta-analysis. Eur Urol Focus. 2018 Jul;4(4):558-567. doi: 10.1016/j.euf.2016.12.011. Epub 2017 Jan 13.</citation>
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      <citation>Skolarus TA, Ye Z, Zhang S, Hollenbeck BK. Regional differences in early stage bladder cancer care and outcomes. Urology. 2010 Aug;76(2):391-6. doi: 10.1016/j.urology.2009.12.079. Epub 2010 Apr 14.</citation>
      <PMID>20394976</PMID>
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      <citation>Babjuk M, Burger M, Capoun O, Cohen D, Comperat EM, Dominguez Escrig JL, Gontero P, Liedberg F, Masson-Lecomte A, Mostafid AH, Palou J, van Rhijn BWG, Roupret M, Shariat SF, Seisen T, Soukup V, Sylvester RJ. European Association of Urology Guidelines on Non-muscle-invasive Bladder Cancer (Ta, T1, and Carcinoma in Situ). Eur Urol. 2022 Jan;81(1):75-94. doi: 10.1016/j.eururo.2021.08.010. Epub 2021 Sep 10.</citation>
      <PMID>34511303</PMID>
    </reference>
    <verification_date>July 2023</verification_date>
    <study_first_submitted>July 13, 2023</study_first_submitted>
    <study_first_submitted_qc>July 24, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">July 27, 2023</study_first_posted>
    <last_update_submitted>July 24, 2023</last_update_submitted>
    <last_update_submitted_qc>July 24, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">July 27, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>University of Roma La Sapienza</investigator_affiliation>
      <investigator_full_name>Francesco Del Giudice</investigator_full_name>
      <investigator_title>Chief Investigator, PhD student</investigator_title>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Carcinoma</mesh_term>
      <mesh_term>Urinary Bladder Neoplasms</mesh_term>
      <mesh_term>Carcinoma, Transitional Cell</mesh_term>
      <mesh_term>Non-Muscle Invasive Bladder Neoplasms</mesh_term>
    </condition_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT05962541
  org study id: N764J-20022023
  nct id: NCT05962541
  lead sponsor: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  is us export: No
  Background: In European Association of Urology (EAU) Guidelines, the vast majority of
        non-muscle-invasive bladder cancers (NMIBCs) undergo a primary transurethral resection of the
        bladder tumor (TURBT) followed by a repeat TURBT (Re-TURBT). The Re-TURBT is recommended due
        to the possibility of residual bladder cancer but is unnecessary in many cases by
        constituting overtreatment. Currently, no diagnostic strategy or predictive tools have been
        implemented to further stratify who does or does not benefit from Re-TURBT. Recently, an
        MRI-based Vesical Imaging Reporting and Data System (VI-RADS) score has been developed to
        stage as to the preoperative probability of muscle invasion, which could potentially exclude
        those who do not require a Re-TURBT when a primary high-quality resection is delivered. As
        such, performing TURBT with standard white light (WL) cystoscopy is known to miss many
        bladder tumours, which may be poorly visible, and a technique known as with photodynamic
        diagnosis (PDD) results in lower residual tumor and lower early intravesical recurrence
        rates. PDD is performed using violet light to improve the detection of these lesions not
        easily visible with WL cystoscopy.
  
        Methods/Aims: The investigators propose an Italian, single-center, phase IV, open-label,
        non-inferiority, randomized controlled trial, in which participants (n=112) who had already
        received a mpMRI/VI-RADS score, are randomized to receive PDD-TURBT, no Re-TURBT versus
        standard of care represented by conventional WL-TURBT followed by WL-Re-TURBT. The primary
        outcome is proportions of early recurrence in the urinary bladder. Secondary outcomes will
        include proportions of late BCa recurrence, late disease-free interval, time to progression
        to MIBC, patient's quality of life assessment, and cost-analysis.
  
        Perspective: The CUT-less trial aims to respond to this unmet need through a non-inferiority
        randomized clinical study potentially shaping the perspective for a paradigm shift towards a
        more personalized, socially, and economically sustainable updated NMIBC therapeutic pathway.
  
        Implications: The current clinical trial proposal is aiming to achieve a paradigm shift in
        the oncological and socio-economical management of urothelial malignancies of the urinary
        bladder. Our first concern is indeed to guarantee a safe and ground-breaking strategy to
        manage the pathway of such patients in order to guarantee the non-inferior oncologic safety
        (and possibly superiority) when compared to the current standard of care.
  
        Additionally, if our hypotheses are confirmed, the investigators will be able to
        significantly relieve these patients from the oncologic burden of an already invasive and
        arduous bladder cancer care path. Finally, safely avoiding an unnecessary, expensive surgical
        procedure will bring significant social and economic benefits to the EU healthcare system and
        possibly worldwide.
  BACKGROUND, STATE OF THE ART and RATIONALE FOR THE INTERVENTIONS
  
        The vast majority (75-80%) of bladder cancers (BCa) patients present with disease confined
        either to the mucosa (stage Ta, carcinoma in situ [CIS]) or the submucosa (stage T1)
        according to the tumor, node, and metastasis (TNM) classification system. These tumours that
        do not invade the detrusor muscle of the urinary bladder are defined as superficial,
        non-invasive, or non-muscle invasive bladder cancers (NMIBC) to differentiate them from the
        less common, but significantly more deadly muscle invasive bladder cancers (MIBC; stage T2 -
        T4).
  
        Although the initial procedure for surgical management of both NMIBC and MIBC tumours is a
        trans-urethral resection of bladder tumor (TURBT), it serves different purposes for NMIBC
        when compared with MIBC. For NMIBC, TURBT acts as both a diagnostic and a therapeutic
        procedure, but for MIBC patients, TURBT is only a diagnostic procedure, as additional radical
        intervention, such as radical cystectomy (RC), are usually required.
  
        However, there are many potential issues that can affect TURBT performance, including a high
        degree of operator dependence for optimal outcomes. Along these lines, one particular issue
        is that many of the so-called early BCa recurrences are actually incomplete resections during
        initial TURBT. Incomplete resections can lead also to understaging (i.e., inaccurate
        discrimination between NMIBC and MIBC), which can adversely affect the survival of the
        patient. Incomplete tumor resection and residual tumor rates vary between 33% and 76% for all
        cases, with rates of 27-72% and 33-78% for Ta and T1 tumours, respectively. Also,
        underestimation of tumor depth invasion at first TURBT has been demonstrated in up to 7-30%
        of cases, increasing up to 45-51% in those with T1 tumours where no detrusor muscle was
        sampled in the specimen after initial TURBT.
  
        Based on these above issues, European Association of Urology (EAU) Guidelines recommend a
        second look and resection (i.e., re-do TURBT [Re-TURBT]) 2 to 6 weeks following the primary
        TURBT in cases of (I) incomplete initial TURBT or doubt about completeness of a TURBT, (II)
        if there is no detrusor muscle in the specimen after initial TURBT, and (III) in all T1
        tumours.
  
        As such, if Re-TURBT is to be considered an "emergency rescue" performed because of the
        suboptimal quality of the initial TURBT, this can result in significant detriments to the
        patient's quality of life (QoL) (e.g., second hospitalization, second anesthesia, potential
        risk for complications, delay in definitive treatment etc.). These can result in additional
        negative social implications (e.g., productivity loss, indirect costs etc.) and
        health-care-related costs (e.g., surgical procedure costs, in-hospital recovery costs,
        postoperative care etc.).
  
        The CUT-less study aims to address these major oncological, economic, and social unmet needs
        related to the current EAU BCa algorithm throughout a phase IV, open-label, non-inferiority
        randomized controlled trial. In particular, one of our aims is trying to avoid unnecessary
        Re-TURBT by utilizing intraoperative visually enhanced photodynamic assisted TURBT
        (PDD-TURBT) among those who had already been evaluated by multiparametric magnetic resonance
        (mpMR) image-based staging before the initial TURBT as a combined novel strategy. In doing
        so, the investigators hope to select for those in whom a Re-TURBT would normally be
        recommended, unnecessarily. The investigators will compare this cohort to one that follows
        the current standard of care algorithm, (i.e., conventional white light [WL] initial TURBT
        followed by WL-Re-TURBT). The investigators will examine the relative proportions of early
        BCa recurrence within the first 4.5 months after randomization. This would be the time
        between randomization, surgical TURBTs (i.e., 1.5 months) and first follow-up cystoscopy
        which is set at 3 months according to the International NMIBC Clinical trial Guidelines.
  
        The primary objectives of the CUT-less trial are indeed to provide the highest level of
        evidence demonstrating non-inferiority between of this novel multidisciplinary and
        translational approach integrating functional MRI and intraoperative visually assisted
        enhanced trans-urethral surgery and the current EAU BCa pathway. This will potentially lead
        to the redefinition of the criteria for Re-TURBT selection and will avoid unnecessary
        surgical procedures in up to half of diagnosed NMIBCs. The impact of such paradigm shift will
        transform the patient's perspective in their own BCa care and will limit the social and
        economic burden of BCa management across the EU and hopefully worldwide.
  
        STUDY AIMS, DESIGN and METHODOLOGICAL FRAMEWORK
  
        Overall aim To utilize our expertise in mpMRI of the bladder diagnostics for pre-TURBT
        staging purposes, intraoperative TURBT optical imaging enhancement by PDD-guided primary
        resection in order to potentially shift clinical practice. In doing so, the investigators
        seek to improve the therapeutic algorithm and personalization for NMIBC treatment by not
        performing those Re-TURBT procedures which could be safely omitted.
  
        Sample Size Calculation The cohort of interest will be represented by intermediate/high-risk
        NMIBCs who are currently those eligible for Re-TURBT according to EUA Guidelines. For the
        primary outcome of the proportion of early BCa recurrence (i.e., within 4.5 months follow-up)
        between the two arms, the investigators acknowledge that rates of early BCa recurrence
        detection among NMIBCs undergoing TURBT along with adjuvant intravesical BCG immunotherapy in
        a population, with equally distributed literature-defined risk factors for BCa recurrences,
        have been shown to be 10% according to available literature.
  
        For the non-inferiority hypothesis, using 80% power and a 5% one sided-alpha, using an
        estimate for detection rate of early BCa recurrence among intermediate/high-risk NMIBCs of
        7.5% and using a margin of clinical unimportance of 10%, n=112 patients per arm will be
        required. The choice of 10% as the margin of non-inferiority represents a difference that
        would be considered clinically unimportant in the detection rate for the event of early BCa
        recurrence in a population already screened by mpMRI and VI-RADS score determination for the
        risk of disease understaging.
  
        To achieve this, prior to randomization, the investigators will screen potential eligible
        participants by VI-RADS score determination and will exclude patients suspected for MIBC
        (15-20%) and, from the remaining NMIBCs, exclude low risk disease (25-30%). Furthermore, the
        investigators predict 35-40% of these patients will be recruited based on willingness to
        participate or missed opportunities for recruitment.
  
        Thus, total subjects required in study would be n=224. Accounting for 15% withdrawal/loss to
        follow up, n=258 men will need to be recruited.
  
        GROUND-BREAKING AMBITION OF THE PROPOSAL AND ADVANCEMENT OF KNOWLEDGE OVER THE STATE OF THE
        ART
  
        BCa is a high priority area for research into both clinical and cost-effective management and
        the findings from the CUT-less trial will be relevant and important to patient needs over the
        next years across the EU and worldwide.
  
        TURBT is the standard of care both to diagnose and treat the vast majority of NMIBCs.
        Nonetheless, to overcome the intrinsic limitations of TURBT, to achieve the desired complete
        resection, and to correct potential staging errors, a second endoscopic procedure (i.e.,
        Re-TURBT) is recommended by EUA Guidelines for most intermediate and high-risk NMIBCs
        categories. However, there is still no currently available strategy to select the ideal
        candidate for this.
  
        Notably, from a patient perspective, there are often considerable anxieties about
        transurethral resection procedures, risk of recurrences, and progression requiring additional
        therapies with potential mortality and long-term morbidity. TURBTs in general, are associated
        with possible significant postoperative and long-term complications and morbidity ranging
        from 5.1% to 43.3% according to the different series. Specifically, the potential for
        complications during Re-TURBT is not trivial and hemorrhage, the need for blood transfusion,
        or bladder perforation can negatively impact patient care and lead to delays in treatment,
        ultimately influencing survival outcomes. Any TUR itself is therefore associated with reduced
        QoL, including in both mental and physical health domains. Substantial reductions in health
        related QoL are most likely to come from repeated hospitalizations, surgical complications,
        invasive adjuvant intravesical treatments, and radical or palliative treatments for
        progression. As consequence, a secondary resection performed 2 to 6 weeks from the primary
        resection represents an additional burden in an already arduous BCa pathway. To our knowledge
        this surgical scenario has never been scrutinized in the framework of a RCT despite the lack
        of evidence to uniformly support Re-TURBT in every case. Moreover, both European and American
        series had reported that performing Re-TURBT did not impact long-term progression-free
        survival and that the tumor status at repeat TUR had only a marginal role in influencing
        long-term cancer-specific survival.
  
        Additionally, NMIBC is one of the most expensive cancers to manage on a per patient basis
        because of its high prevalence, high recurrence rate, need for adjuvant treatments, and the
        requirement for long-term surveillance protocols. Because of the protracted clinical course
        of early-stage disease, its prevalence relative to MIBC, and its procedure-oriented
        surveillance, the associated cumulative medical payments are generally more substantial than
        those for advanced disease. The average per capita spending for NMIBC is increasing in the
        last two decades, from €7000 to €9000. These increasing costs are mainly attributable to the
        more frequent use of endoscopy (e.g., cystoscopy, TURBT, Re-TURBT) and the adjuvant
        intravesical therapies. TURBT accounts for a substantial portion of total bladder treatment
        costs ranging from €3000 to €6000 depending on whether patients are discharged following the
        procedure or admitted for inpatient care.
  
        Given these urgent needs for optimizing the NMIBC algorithm, the CUT-less trial will explore
        a novel multidisciplinary approach for minimizing the burden of surgical exposure to patients
        and for resizing the costs to the EU health care systems by redefining the selection criteria
        for NMIBC candidates for Re-TURBT procedures.
  
        In conclusion, the currently available EAU Guidelines rely on conflicting and out of date
        evidence which do not offer a contemporary viewpoint as to the role of Re-TURBT. Our updated
        protocol which utilizes both mpMRI diagnostic imaging and PDD guided resections will be
        closely examined in the CUT-less trial, with goal of more personalized, both socially and
        economically sustainable updated NMIBC therapeutic pathways for use in the EU.
  allocation: Randomized
  intervention model: Parallel Assignment
  intervention model description: Italian, single-center, phase IV, open-label, randomized controlled trial, with patients randomized in a 1:1 ratio to one of two arms
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Proportion of EARLY Bladder Cancer (BCa) recurrences
  time frame: within 4.5 months following primary intervention
  description: The proportion of early BCa recurrences (i.e., within 4.5 months follow-up) in those non-muscle invasive bladder cancer (NMIBC) treated by standard of care (i.e., TURBT followed by Re-TURBT) compared to our novel algorithm proposal (i.e., primary PDD-TURBT followed by no Re-TURBT).
  measure: Proportion of LATE BCa recurrences
  time frame: after 4.5 months following primary intervention
  description: To determine the proportion of BCa late recurrences (i.e., after 4.5 months follow-up) in patients with NMIBC treated by standard of care compared to our novel algorithm proposal
  measure: Proportion of progression from NMIBC to MIBC
  time frame: over 3 years follow-up
  description: To determine the proportion of progression from NMIBC to MIBC in patients with NMIBC treated by standard of care compared to our novel algorithm proposal.
  measure: Changes in health-related quality of life (HRQoL)
  time frame: over 3 years follow-up
  description: To determine changes in health-related quality of life (HRQoL) resulting from the physical and psychological benefit together with any harms associated with each strategy and with subsequent additional interventions. We will use generic QoL for cost-effectiveness analysis (i.e., EuroQoL Group [EQ]-5D-3L).
  measure: Changes in health-related quality of life (HRQoL)
  time frame: over 3 years follow-up
  description: To determine changes in health-related quality of life (HRQoL) resulting from the physical and psychological benefit together with any harms associated with each strategy and with subsequent additional interventions. We will use and specific validated questionnaires to assess the outcomes of interest in the NMIBC population (i.e., European Organisation for Research and Treatment of Cancer [EORTC]-QLQ-C30).
  measure: Changes in health-related quality of life (HRQoL)
  time frame: over 3 years follow-up
  description: To determine changes in health-related quality of life (HRQoL) resulting from the physical and psychological benefit together with any harms associated with each strategy and with subsequent additional interventions. We will use and specific validated questionnaires to assess the outcomes of interest in the NMIBC population (i.e., European Organisation for Research and Treatment of Cancer [EORTC] QLQ-NMIBC24).
  measure: Cost-effectiveness analysis
  time frame: over 3 years follow-up
  description: To perform a within-trial cost-effectiveness analysis to calculate incremental cost per Re-TURBT avoided and the cost-utility of the experimental approach as measured by the incremental cost per quality-adjusted life year (QALY) gained at 2 years and over patients' lifetime.
  arm group label: PPD-TURBT (no Re-TURBT)
  arm group type: Experimental
  description: Primary PDD-TURBT, not followed by Re-TURBT
  arm group label: WL TURBT plus Re-TURBT (Standard of Care)
  arm group type: No Intervention
  description: Standard of care consisting in primary WL TURBT followed by WL Re-TURBT within 2 - 6 weeks from initial WL TURBT
  intervention type: Drug
  intervention name: PDD-TURBT with hexaminolevulinate (Hexvix®)
  description: In order to undergo PDD-TURBT, all eligible patients in the experimental arm will be administered the photosensitizer hexaminolevulinate (85 mg in 50 ml of phosphate buffered saline, Hexvix®) on an inpatient setting through a urethral catheterization of the participant's bladder. During the PDD-TURBT surgery, the bladder will be illuminated with blue light (wavelength 380-450 nm). The operating rooms of the participant institutions will therefore need to have the specialized equipment consisting in the blue-light source (POWER LED SAPHIRA [TM]).
  arm group label: PPD-TURBT (no Re-TURBT)
  other name: Hexvix®
  intervention type: Device
  intervention name: Power Led Saphira (TM) from KARL STORZ
  description: This is a light source based on LED technology. It can be used for both White Light (WL) and fluorescence applications in blue light (i.e., Photodynamic diagnosis PDD) for visualizing tumor lesions during trans-urethral resection of bladder tumors (PPD- TURBT).
  arm group label: PPD-TURBT (no Re-TURBT)
  other name: Power Led Saphira (TM)
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Francesco Del Giudice, MD
  phone: +39 3395382464
  email: francesco.delgiudice@uniroma1.it
  citation: Epstein JI, Amin MB, Reuter VR, Mostofi FK. The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Bladder Consensus Conference Committee. Am J Surg Pathol. 1998 Dec;22(12):1435-48. doi: 10.1097/00000478-199812000-00001.
  PMID: 9850170
  citation: Mariappan P, Zachou A, Grigor KM; Edinburgh Uro-Oncology Group. Detrusor muscle in the first, apparently complete transurethral resection of bladder tumour specimen is a surrogate marker of resection quality, predicts risk of early recurrence, and is dependent on operator experience. Eur Urol. 2010 May;57(5):843-9. doi: 10.1016/j.eururo.2009.05.047. Epub 2009 Jun 6.
  PMID: 19524354
  citation: Brausi M, Collette L, Kurth K, van der Meijden AP, Oosterlinck W, Witjes JA, Newling D, Bouffioux C, Sylvester RJ; EORTC Genito-Urinary Tract Cancer Collaborative Group. Variability in the recurrence rate at first follow-up cystoscopy after TUR in stage Ta T1 transitional cell carcinoma of the bladder: a combined analysis of seven EORTC studies. Eur Urol. 2002 May;41(5):523-31. doi: 10.1016/s0302-2838(02)00068-4.
  PMID: 12074794
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  responsible party type: Principal Investigator
  investigator affiliation: University of Roma La Sapienza
  investigator full name: Francesco Del Giudice
  investigator title: Chief Investigator, PhD student
  mesh term: Carcinoma
  mesh term: Urinary Bladder Neoplasms
  mesh term: Carcinoma, Transitional Cell
  mesh term: Non-Muscle Invasive Bladder Neoplasms
  sharing ipd: No