<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/NCT03758235</url>
  </required_header>
  <id_info>
    <org_study_id>Inco_Ona</org_study_id>
    <nct_id>NCT03758235</nct_id>
  </id_info>
  <brief_title>Overactive Bladder Syndrome: Incobotulinumtoxin Versus Onabotulinumtoxin</brief_title>
  <official_title>Incobotulinumtoxin Versus Onabotulinumtoxin in the Treatment of Patients With Overactive Bladder Syndrome</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Of Perugia</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University Of Perugia</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The aim of the original study was to compare Incobot/A versus Onabot/A in order to evaluate&#xD;
      if the differences in the pharmacologic formulations between the two drugs could affect their&#xD;
      efficacy and safety in the treatment of neurogenic overactive bladder (OAB).&#xD;
&#xD;
      In the original study protocol two different dosages for either Incobot/A and Onabot/A (200 U&#xD;
      and 100 U) were considered, to treat patients with neurogenic detrusor overactivity&#xD;
      incontinence performing intermittent catheterization (IC) with higher dosages and those able&#xD;
      to void spontaneously with lower dosage, with the resulting four treatment groups. For such a&#xD;
      study, a very large sample of participants should have been treated and followed up, to have&#xD;
      adequate power to demonstrate the hypothesis. At the end of last February 2020, we had to&#xD;
      temporarily stop all the clinical activities related to the study and patients' recruitment,&#xD;
      due to the occurrence of Sars-Cov-2 pandemic in our Country. At that point, a non-inferiority&#xD;
      study seemed to be possible and adequate, and we adapted the protocol accordingly. In&#xD;
      addition, on the basis of previously published information, we could hypothesize that the new&#xD;
      drug (Incobot/A) would have had at least a roughly similar effect to the control drug&#xD;
      (Onabot/A). In order to perform a non-inferiority study, the power and sample size analysis&#xD;
      have been re-planned.&#xD;
&#xD;
      Thus, we perform a not planned interim analysis to show the preliminary results of an&#xD;
      ongoing, non-inferiority trial in which patients' recruitment temporarily stopped due to&#xD;
      incontrollable external factors. The present study will be aimed to assess the&#xD;
      non-inferiority of Incobot/A compared to Onabot/A on the efficacy and safety parameters, in&#xD;
      the treatment of patients with refractory NDOI performing IC, who are randomized to receive&#xD;
      200 U of Incobot/A or Onabot/A intradetrusor injections and who are followed up to 12 wks&#xD;
      after treatment&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a pilot, prospective, randomized, double blinded, multicentre, clinical trial. After&#xD;
      giving a written informed consent, all the patients will be randomized into two groups: Group&#xD;
      1, including patients who will be treated with the Incobot/A and Group 2, including patients&#xD;
      who will be treated with Onabot/A. The randomization process will be made by a computerized&#xD;
      system. Enrolling period: September 2018- April 2020.&#xD;
&#xD;
      Inclusion criteria:&#xD;
&#xD;
        -  patients (males and females) with neurogenic urge urinary incontinence (UUI) (with&#xD;
           urgency, increase in day- time and night- time urinary frequency) and with urodynamic&#xD;
           diagnosis of detrusor overactivity (DO);&#xD;
&#xD;
        -  18- 80 years;&#xD;
&#xD;
        -  women of childbearing age, who use a reliable method of contraception throughout the&#xD;
           study period (a pregnancy test must be performed during enrolment in the study);&#xD;
&#xD;
        -  spinal cord injury at or below T1, diagnosed at least 6 months before the screening in&#xD;
           case of a vesico-sphincter dysfunction due to spinal cord injury;&#xD;
&#xD;
        -  EDSS score ≤ 6, in MS patients;&#xD;
&#xD;
        -  patients refractory to anticholinergic therapy (≥ 1 anticholinergic agent)&#xD;
&#xD;
        -  application of intermittent catheterizations to empty the bladder. In the case of&#xD;
           spontaneous micturition, the patients should agree for the use of intermittent&#xD;
           catheterizations, in case this will be necessary after treatment with the detrusor&#xD;
           injection of botulinumtoxin A.&#xD;
&#xD;
      Urodynamic characteristics:&#xD;
&#xD;
      urodynamic diagnosis of DO, refractory to standard anticholinergics and naïve to&#xD;
      intradetrusor injection of onabotulinumtoxin A.&#xD;
&#xD;
      The wash- out period after anticholinergics should be of at least 3 weeks. It will be also&#xD;
      possible for patients continuing to assume previous anticholinergic therapy through the study&#xD;
      period.&#xD;
&#xD;
      Exclusion criteria:&#xD;
&#xD;
        -  recurring urinary tract infections (UTIs) (≥ 4 episodes/year);&#xD;
&#xD;
        -  spinal cord injuries above T1;&#xD;
&#xD;
        -  MS patients: EDSS score ≥ 6;&#xD;
&#xD;
        -  patients who won't or can't perform intermittent catheterization;&#xD;
&#xD;
        -  pregnancy or breast- feeding, if female patients&#xD;
&#xD;
        -  post- void residual volume (PRV) &gt; 150 ml, in the case of spontaneous micturition&#xD;
&#xD;
      Time 0 (pre-screening):&#xD;
&#xD;
        -  history and physical examination;&#xD;
&#xD;
        -  urinalysis and cultures (pregnancy test);&#xD;
&#xD;
        -  3- days voiding diary;&#xD;
&#xD;
        -  urodynamic study;&#xD;
&#xD;
        -  &quot;Incontinence Quality of Life&quot; (I- QoL) standardized Questionnaire;&#xD;
&#xD;
        -  Visual Analog Scale (VAS) for evaluation of treatment satisfaction.&#xD;
&#xD;
      Time 1. Treatment.&#xD;
&#xD;
      Patients will be randomized into two groups, assigned by a computerized system:&#xD;
&#xD;
      - Group 1- Incobot/A:&#xD;
&#xD;
      patients with spontaneous micturitions will undergo only one administration of Incobot/A 100&#xD;
      U diluted in 10 ml of sodium chloride solution 0.9% by endoscopic detrusor injections (20&#xD;
      injections, 0.5 ml of solution for each injection); patients who perform intermittent&#xD;
      catheterization will undergo only one administration of Incobot/A 200 U diluted in 30 ml of&#xD;
      sodium chloride solution 0.9% by endoscopic detrusor injections (30 injections, 1 ml of&#xD;
      solution for each injection)&#xD;
&#xD;
      - Group 2- Onabot/A:&#xD;
&#xD;
      patients with spontaneous micturitions will undergo only one administration of Onabot/A 100 U&#xD;
      diluted in 10 ml of sodium chloride solution 0.9% by endoscopic detrusor injections (20&#xD;
      injections, 0.5 ml of solution for each injection); patients who perform intermittent&#xD;
      catheterization will undergo only one administration of Onabot/A 200 U diluted in 30 ml of&#xD;
      sodium chloride solution 0.9% by endoscopic detrusor injections (30 injections, 1 ml of&#xD;
      solution for each injection)&#xD;
&#xD;
      Follow-up:&#xD;
&#xD;
      History and physical examination, 3-day voiding diary and VAS were repeated at 2, 4 and 12&#xD;
      weeks, in order to make better comparisons with previously published pivotal trials on Botox.&#xD;
      Urinalyses and cultures and I-QoL questionnaire were repeated at 2 and 12 weeks after&#xD;
      treatment; urodynamic examination was obtained at 12 weeks follow- up.&#xD;
&#xD;
      Outcomes of the study The primary outcome measure is change from baseline in the daily&#xD;
      frequency of UI at week 12. Secondary outcomes measures are: the occurrence of UTIs and other&#xD;
      treatment-related local and systemic adverse events following the two botulinum toxins A&#xD;
      injections, during the observation period; changes from baseline in I-QOL total score and VAS&#xD;
      scores (week 2 and week 12); changes from baseline in MCC, first volume and maximum pressure&#xD;
      of detrusor overactivity (weeks 12), following the two botulinum toxins A administration.&#xD;
&#xD;
      Statistical Analysis:&#xD;
&#xD;
      In a non- inferiority trial, it is recommended to set the non-inferiority limit below the&#xD;
      minimal clinically important difference such that, after the intervention, the two groups are&#xD;
      expected to differ by less than this difference. Group sample sizes of 50 and 50 subjects are&#xD;
      required to be 80% sure that the higher limit of 95% confidence interval was below the&#xD;
      clinically important non-inferiority limit of + one in UI episodes/day between the&#xD;
      experimental and the standard treatment. The true difference between the means is assumed to&#xD;
      be 0 with standard deviation (SD) of 2. The significance level (alpha) of the test is 0.05.&#xD;
      The sample size is calculated using PASS 11.0.7, Power Analysis and Sample Size Software&#xD;
      (2011). NCSS, LLC. Kaysville, Utah, USA. In establishing the non-inferiority margin, we have&#xD;
      considered one incontinence episodes/day as non-inferiority limit as the difference of one&#xD;
      less urinary incontinence episode represents the smallest difference that can be measured in&#xD;
      the count. Moreover, when considering the frequency of daily urinary incontinence (UI) at&#xD;
      baseline in both groups of treatment, one UI episode represents about 15%. In the present&#xD;
      study, due to the temporary stop of patients' recruitment, a not planned interim analysis of&#xD;
      the current data from the ongoing trial is conducted, in order to detect whether the research&#xD;
      outcomes will be addressed. The true difference between the means is assumed to be 0 with SD&#xD;
      of 2. The significance level (alpha) of the test is 0.05. The sample size is calculated using&#xD;
      PASS 11.0.7, Power Analysis and Sample Size Software (2011). NCSS, LLC. Kaysville, Utah, USA.&#xD;
      The primary endpoint was analysed using a standard analysis of covariance (ANCOVA) model,&#xD;
      including treatment group as fixed factors and baseline UI episodes/day as a covariate. If&#xD;
      the higher one-sided 95% confidence interval (CI) limit that is produced from the ANCOVA&#xD;
      model is lower than + one UI episode, the efficacy of the experimental treatment group is&#xD;
      considered not inferior to that of the standard treatment group. Mann-Whitney's U-test is&#xD;
      used for comparisons of unpaired data and Friedman and Wilcoxon tests for comparisons of&#xD;
      paired data, X2 with Yates' continuity correction or Fisher's exact test are used to analyse&#xD;
      categorical data. All statistical analyses are performed using IBM-SPSS® version 26.0 (IBM&#xD;
      Corp., Armonk, NY, USA, 2019). In all analyses, a two-sided p-value &lt;0.05 was considered&#xD;
      significant.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">September 1, 2018</start_date>
  <completion_date type="Anticipated">September 1, 2021</completion_date>
  <primary_completion_date type="Anticipated">September 1, 2021</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>
    <intervention_model_description>Participants are assigned to the 4 groups (Incobot/A Group different dosages, or Onabot/A Group different dosages ) in parallel for the duration of the study.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
    <masking_description>Partecipants, investigators and outcomes assessor</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change from baseline in the frequency of urinary incontinence episodes.</measure>
    <time_frame>24 weeks</time_frame>
    <description>change from baseline in the daily frequency of urinary incontinence episodes, as assessed by the 3-day voiding diary.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Evaluation of frequency of urinary tract infections in both arms of treatment.</measure>
    <time_frame>2, 12, 24 weeks</time_frame>
    <description>Measurement of eventual differencies between the two arms of treatment in the frequency of urinary tract infections at 2, 12 and 24 weeks after treatment</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change from baseline in urodynamic parameters.</measure>
    <time_frame>24 weeks</time_frame>
    <description>Significant improvements in urodynamic parameters (maximum cystometric capacity, maximum detrusor pressure during first involuntary detrusor contraction) at 12 and 24 weeks as compared to baseline.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change from baseline in Incontinence Quality of Life (I-QoL) questionnaire total score.</measure>
    <time_frame>2, 12, 24 weeks</time_frame>
    <description>Significant improvement in I-QoL total score at 2, 12 and 24 weeks as compared to baseline.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Recording of the adverse events.</measure>
    <time_frame>2, 12, 24 weeks</time_frame>
    <description>Assessment of possible adverse events-AE (systemic AEs: fatigue, weakness, dyspnoea, gastrointestinal irritation, Flu-like symptoms, dizziness; local AEs: haematuria, dysuria, urinary retention, post-void residual volume &gt; 150 ml) at 2, 12 and 24 weeks after treatment.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">140</enrollment>
  <condition>Overactive Bladder Syndrome</condition>
  <arm_group>
    <arm_group_label>Incobot/A 100 U</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Incobot/A 100 U diluted in 10 ml of sodium chloride solution 0.9% by endoscopic detrusor injections (20 injections, 0.5 ml of solution for each injection) will be administered in patients able to perform spontaneous micturitions</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Incobot/A 200 U</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Incobot/A 200 U diluted in 30 ml of sodium chloride solution 0.9% by endoscopic detrusor injections (30 injections, 1 ml of solution for each injection) will be administered in patients performin intermittent catheterization.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Onabot/A 100 U</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Onabot/A 100 U diluted in 10 ml of sodium chloride solution 0.9% by endoscopic detrusor injections (20 injections, 0.5 ml of solution for each injection) will be administered in patients able to perform spontaneous micturitions</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Onabot/A 200 U</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Onabot/A 200 U diluted in 30 ml of sodium chloride solution 0.9% by endoscopic detrusor injections (30 injections, 1 ml of solution for each injection) will be administered to patients performing intermittent catheterization</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>IncobotulinumtoxinA 100 UNT Injection [Xeomin]</intervention_name>
    <description>Incobot/A intradetrusor injections under cystscopic guidance, with local anaethesia in an outpatient basis</description>
    <arm_group_label>Incobot/A 100 U</arm_group_label>
    <arm_group_label>Incobot/A 200 U</arm_group_label>
    <other_name>Incobot/A</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>OnabotulinumtoxinA 100 UNT [Botox]</intervention_name>
    <description>Onabot/A intradetrusor injections under cystscopic guidance, with local anaethesia in an outpatient basis</description>
    <arm_group_label>Onabot/A 100 U</arm_group_label>
    <arm_group_label>Onabot/A 200 U</arm_group_label>
    <other_name>Onabot/A</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  patients (males and females) with neurogenic urge urinary incontinence (UUI) (with&#xD;
             urgency, increase in day- time and night- time urinary frequency) and with urodynamic&#xD;
             diagnosis of DO;&#xD;
&#xD;
          -  18- 80 years;&#xD;
&#xD;
          -  women of childbearing age, who use a reliable method of contraception throughout the&#xD;
             study period (a pregnancy test must be performed during enrolment in the study);&#xD;
&#xD;
          -  spinal cord injury at or below T1, diagnosed at least 6 months before the screening in&#xD;
             case of a vesico-sphincter dysfunction due to spinal cord injury;&#xD;
&#xD;
          -  EDSS score ≤ 6, in MS patients;&#xD;
&#xD;
          -  patients refractory to anticholinergic therapy (≥ 1 anticholinergic agent)&#xD;
&#xD;
          -  application of intermittent catheterizations to empty the bladder. In the case of&#xD;
             spontaneous micturition, the patients should agree for the use of intermittent&#xD;
             catheterizations, in case this will be necessary after treatment with the detrusor&#xD;
             injection of botulinumtoxin A.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  recurring urinary tract infections (UTIs) (≥ 4 episodes/year);&#xD;
&#xD;
          -  spinal cord injuries above T1;&#xD;
&#xD;
          -  MS patients: EDSS score ≥ 6;&#xD;
&#xD;
          -  patients who won't or can't perform intermittent catheterization;&#xD;
&#xD;
          -  pregnancy or breast- feeding, if female patients;&#xD;
&#xD;
          -  post- void residual volume (PRV) &gt; 150 ml, in the case of spontaneous micturition;&#xD;
&#xD;
          -  hypersensitivity to the active substance or to any of the excipients (listed in&#xD;
             section 6.1 of RCP);&#xD;
&#xD;
          -  generalized diseases of muscular activity (e.g. myasthenia gravis, Lambert-Eaton&#xD;
             syndrome);&#xD;
&#xD;
          -  presence of infection or inflammation at the injection site;&#xD;
&#xD;
          -  patients with acute urinary retention at the time of treatment, not routinely&#xD;
             subjected to catheterization;&#xD;
&#xD;
          -  men with overactive bladder and signs or symptoms of urinary obstruction should not be&#xD;
             treated;&#xD;
&#xD;
          -  documented or suspected active malignant neoplasia or previous history, within 2 years&#xD;
             prior to screening;&#xD;
&#xD;
          -  patients who must or want to continue taking illegal drugs or drugs that may interfere&#xD;
             with the proper conduct of the study;&#xD;
&#xD;
          -  chronic abuse of alcohol or drugs or any condition that in the opinion of the&#xD;
             investigator doctor makes an unreliable subject in correctly completing the study&#xD;
             procedures;&#xD;
&#xD;
          -  any other clinical condition that would endanger the safety of patients in&#xD;
             participating in the study or that could prevent the subjects from adhering to the&#xD;
             protocol.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Antonella Giannantoni, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Siena</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Emanuele Rubilotta, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Universita di Verona</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Matteo Balzarro, MD</last_name>
    <role>Study Director</role>
    <affiliation>Universita di Verona</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Antonella Giannantoni</name>
      <address>
        <city>Siena</city>
        <state>SI</state>
        <zip>53100</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <reference>
    <citation>Mohee A, Khan A, Harris N, Eardley I. Long-term outcome of the use of intravesical botulinum toxin for the treatment of overactive bladder (OAB). BJU Int. 2013 Jan;111(1):106-13. doi: 10.1111/j.1464-410X.2012.11282.x. Epub 2012 Jun 6.</citation>
    <PMID>22672569</PMID>
  </reference>
  <results_reference>
    <citation>Thuroff JW, Abrams P, Andersson KE, Artibani W, Chapple CR, Drake MJ, Hampel C, Neisius A, Schroder A, Tubaro A. EAU guidelines on urinary incontinence. Eur Urol. 2011 Mar;59(3):387-400. doi: 10.1016/j.eururo.2010.11.021. Epub 2010 Nov 24.</citation>
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  <results_reference>
    <citation>Gormley EA, Lightner DJ, Faraday M, Vasavada SP; American Urological Association; Society of Urodynamics, Female Pelvic Medicine. Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline amendment. J Urol. 2015 May;193(5):1572-80. doi: 10.1016/j.juro.2015.01.087. Epub 2015 Jan 23.</citation>
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  </results_reference>
  <results_reference>
    <citation>Benecke R. Clinical relevance of botulinum toxin immunogenicity. BioDrugs. 2012 Apr 1;26(2):e1-9. doi: 10.2165/11599840-000000000-00000.</citation>
    <PMID>22385408</PMID>
  </results_reference>
  <results_reference>
    <citation>Wang L, Sun Y, Yang W, Lindo P, Singh BR. Type A botulinum neurotoxin complex proteins differentially modulate host response of neuronal cells. Toxicon. 2014 May;82:52-60. doi: 10.1016/j.toxicon.2014.02.004. Epub 2014 Feb 21.</citation>
    <PMID>24560879</PMID>
  </results_reference>
  <results_reference>
    <citation>Jost WH, Blumel J, Grafe S. Botulinum neurotoxin type A free of complexing proteins (XEOMIN) in focal dystonia. Drugs. 2007;67(5):669-83. doi: 10.2165/00003495-200767050-00003.</citation>
    <PMID>17385940</PMID>
  </results_reference>
  <results_reference>
    <citation>Kumar R, Zhou Y, Ghosal K, Cai S, Singh BR. Anti-apoptotic activity of hemagglutinin-33 and botulinum neurotoxin and its implications to therapeutic and countermeasure issues. Biochem Biophys Res Commun. 2012 Jan 13;417(2):726-31. doi: 10.1016/j.bbrc.2011.12.020. Epub 2011 Dec 11.</citation>
    <PMID>22182409</PMID>
  </results_reference>
  <results_reference>
    <citation>Campanati A, Giuliodori K, Martina E, Giuliano A, Ganzetti G, Offidani A. Onabotulinumtoxin type A (Botox((R))) versus Incobotulinumtoxin type A (Xeomin((R))) in the treatment of focal idiopathic palmar hyperhidrosis: results of a comparative double-blind clinical trial. J Neural Transm (Vienna). 2014 Jan;121(1):21-6. doi: 10.1007/s00702-013-1074-1. Epub 2013 Sep 20.</citation>
    <PMID>24052109</PMID>
  </results_reference>
  <verification_date>November 2020</verification_date>
  <study_first_submitted>November 27, 2018</study_first_submitted>
  <study_first_submitted_qc>November 27, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 29, 2018</study_first_posted>
  <last_update_submitted>November 5, 2020</last_update_submitted>
  <last_update_submitted_qc>November 5, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">November 6, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University Of Perugia</investigator_affiliation>
    <investigator_full_name>Antonella Giannantoni</investigator_full_name>
    <investigator_title>PA</investigator_title>
  </responsible_party>
  <keyword>overactive bladder syndrome</keyword>
  <keyword>botulinum toxin type A</keyword>
  <keyword>onabotulinumtoxin/A</keyword>
  <keyword>incobotulinumtoxin/A</keyword>
  <keyword>treatment</keyword>
  <keyword>neurogenic detrusor overactivity incontinence</keyword>
  <keyword>urinary incontinence</keyword>
  <keyword>urinary tract infections</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Urinary Bladder, Overactive</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Botulinum Toxins, Type A</mesh_term>
    <mesh_term>incobotulinumtoxinA</mesh_term>
    <mesh_term>abobotulinumtoxinA</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03758235
org study id: Inco_Ona
nct id: NCT03758235
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
The aim of the original study was to compare Incobot/A versus Onabot/A in order to evaluate
      if the differences in the pharmacologic formulations between the two drugs could affect their
      efficacy and safety in the treatment of neurogenic overactive bladder (OAB).

      In the original study protocol two different dosages for either Incobot/A and Onabot/A (200 U
      and 100 U) were considered, to treat patients with neurogenic detrusor overactivity
      incontinence performing intermittent catheterization (IC) with higher dosages and those able
      to void spontaneously with lower dosage, with the resulting four treatment groups. For such a
      study, a very large sample of participants should have been treated and followed up, to have
      adequate power to demonstrate the hypothesis. At the end of last February 2020, we had to
      temporarily stop all the clinical activities related to the study and patients' recruitment,
      due to the occurrence of Sars-Cov-2 pandemic in our Country. At that point, a non-inferiority
      study seemed to be possible and adequate, and we adapted the protocol accordingly. In
      addition, on the basis of previously published information, we could hypothesize that the new
      drug (Incobot/A) would have had at least a roughly similar effect to the control drug
      (Onabot/A). In order to perform a non-inferiority study, the power and sample size analysis
      have been re-planned.

      Thus, we perform a not planned interim analysis to show the preliminary results of an
      ongoing, non-inferiority trial in which patients' recruitment temporarily stopped due to
      incontrollable external factors. The present study will be aimed to assess the
      non-inferiority of Incobot/A compared to Onabot/A on the efficacy and safety parameters, in
      the treatment of patients with refractory NDOI performing IC, who are randomized to receive
      200 U of Incobot/A or Onabot/A intradetrusor injections and who are followed up to 12 wks
      after treatment
This is a pilot, prospective, randomized, double blinded, multicentre, clinical trial. After
      giving a written informed consent, all the patients will be randomized into two groups: Group
      1, including patients who will be treated with the Incobot/A and Group 2, including patients
      who will be treated with Onabot/A. The randomization process will be made by a computerized
      system. Enrolling period: September 2018- April 2020.

      Inclusion criteria:

        -  patients (males and females) with neurogenic urge urinary incontinence (UUI) (with
           urgency, increase in day- time and night- time urinary frequency) and with urodynamic
           diagnosis of detrusor overactivity (DO);

        -  18- 80 years;

        -  women of childbearing age, who use a reliable method of contraception throughout the
           study period (a pregnancy test must be performed during enrolment in the study);

        -  spinal cord injury at or below T1, diagnosed at least 6 months before the screening in
           case of a vesico-sphincter dysfunction due to spinal cord injury;

        -  EDSS score ≤ 6, in MS patients;

        -  patients refractory to anticholinergic therapy (≥ 1 anticholinergic agent)

        -  application of intermittent catheterizations to empty the bladder. In the case of
           spontaneous micturition, the patients should agree for the use of intermittent
           catheterizations, in case this will be necessary after treatment with the detrusor
           injection of botulinumtoxin A.

      Urodynamic characteristics:

      urodynamic diagnosis of DO, refractory to standard anticholinergics and naïve to
      intradetrusor injection of onabotulinumtoxin A.

      The wash- out period after anticholinergics should be of at least 3 weeks. It will be also
      possible for patients continuing to assume previous anticholinergic therapy through the study
      period.

      Exclusion criteria:

        -  recurring urinary tract infections (UTIs) (≥ 4 episodes/year);

        -  spinal cord injuries above T1;

        -  MS patients: EDSS score ≥ 6;

        -  patients who won't or can't perform intermittent catheterization;

        -  pregnancy or breast- feeding, if female patients

        -  post- void residual volume (PRV) > 150 ml, in the case of spontaneous micturition

      Time 0 (pre-screening):

        -  history and physical examination;

        -  urinalysis and cultures (pregnancy test);

        -  3- days voiding diary;

        -  urodynamic study;

        -  "Incontinence Quality of Life" (I- QoL) standardized Questionnaire;

        -  Visual Analog Scale (VAS) for evaluation of treatment satisfaction.

      Time 1. Treatment.

      Patients will be randomized into two groups, assigned by a computerized system:

      - Group 1- Incobot/A:

      patients with spontaneous micturitions will undergo only one administration of Incobot/A 100
      U diluted in 10 ml of sodium chloride solution 0.9% by endoscopic detrusor injections (20
      injections, 0.5 ml of solution for each injection); patients who perform intermittent
      catheterization will undergo only one administration of Incobot/A 200 U diluted in 30 ml of
      sodium chloride solution 0.9% by endoscopic detrusor injections (30 injections, 1 ml of
      solution for each injection)

      - Group 2- Onabot/A:

      patients with spontaneous micturitions will undergo only one administration of Onabot/A 100 U
      diluted in 10 ml of sodium chloride solution 0.9% by endoscopic detrusor injections (20
      injections, 0.5 ml of solution for each injection); patients who perform intermittent
      catheterization will undergo only one administration of Onabot/A 200 U diluted in 30 ml of
      sodium chloride solution 0.9% by endoscopic detrusor injections (30 injections, 1 ml of
      solution for each injection)

      Follow-up:

      History and physical examination, 3-day voiding diary and VAS were repeated at 2, 4 and 12
      weeks, in order to make better comparisons with previously published pivotal trials on Botox.
      Urinalyses and cultures and I-QoL questionnaire were repeated at 2 and 12 weeks after
      treatment; urodynamic examination was obtained at 12 weeks follow- up.

      Outcomes of the study The primary outcome measure is change from baseline in the daily
      frequency of UI at week 12. Secondary outcomes measures are: the occurrence of UTIs and other
      treatment-related local and systemic adverse events following the two botulinum toxins A
      injections, during the observation period; changes from baseline in I-QOL total score and VAS
      scores (week 2 and week 12); changes from baseline in MCC, first volume and maximum pressure
      of detrusor overactivity (weeks 12), following the two botulinum toxins A administration.

      Statistical Analysis:

      In a non- inferiority trial, it is recommended to set the non-inferiority limit below the
      minimal clinically important difference such that, after the intervention, the two groups are
      expected to differ by less than this difference. Group sample sizes of 50 and 50 subjects are
      required to be 80% sure that the higher limit of 95% confidence interval was below the
      clinically important non-inferiority limit of + one in UI episodes/day between the
      experimental and the standard treatment. The true difference between the means is assumed to
      be 0 with standard deviation (SD) of 2. The significance level (alpha) of the test is 0.05.
      The sample size is calculated using PASS 11.0.7, Power Analysis and Sample Size Software
      (2011). NCSS, LLC. Kaysville, Utah, USA. In establishing the non-inferiority margin, we have
      considered one incontinence episodes/day as non-inferiority limit as the difference of one
      less urinary incontinence episode represents the smallest difference that can be measured in
      the count. Moreover, when considering the frequency of daily urinary incontinence (UI) at
      baseline in both groups of treatment, one UI episode represents about 15%. In the present
      study, due to the temporary stop of patients' recruitment, a not planned interim analysis of
      the current data from the ongoing trial is conducted, in order to detect whether the research
      outcomes will be addressed. The true difference between the means is assumed to be 0 with SD
      of 2. The significance level (alpha) of the test is 0.05. The sample size is calculated using
      PASS 11.0.7, Power Analysis and Sample Size Software (2011). NCSS, LLC. Kaysville, Utah, USA.
      The primary endpoint was analysed using a standard analysis of covariance (ANCOVA) model,
      including treatment group as fixed factors and baseline UI episodes/day as a covariate. If
      the higher one-sided 95% confidence interval (CI) limit that is produced from the ANCOVA
      model is lower than + one UI episode, the efficacy of the experimental treatment group is
      considered not inferior to that of the standard treatment group. Mann-Whitney's U-test is
      used for comparisons of unpaired data and Friedman and Wilcoxon tests for comparisons of
      paired data, X2 with Yates' continuity correction or Fisher's exact test are used to analyse
      categorical data. All statistical analyses are performed using IBM-SPSS® version 26.0 (IBM
      Corp., Armonk, NY, USA, 2019). In all analyses, a two-sided p-value <0.05 was considered
      significant.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Participants are assigned to the 4 groups (Incobot/A Group different dosages, or Onabot/A Group different dosages ) in parallel for the duration of the study.
primary purpose: Treatment
masking: Double (Participant, Investigator)
masking description: Partecipants, investigators and outcomes assessor
measure: Change from baseline in the frequency of urinary incontinence episodes.
time frame: 24 weeks
description: change from baseline in the daily frequency of urinary incontinence episodes, as assessed by the 3-day voiding diary.
measure: Evaluation of frequency of urinary tract infections in both arms of treatment.
time frame: 2, 12, 24 weeks
description: Measurement of eventual differencies between the two arms of treatment in the frequency of urinary tract infections at 2, 12 and 24 weeks after treatment
measure: Change from baseline in urodynamic parameters.
time frame: 24 weeks
description: Significant improvements in urodynamic parameters (maximum cystometric capacity, maximum detrusor pressure during first involuntary detrusor contraction) at 12 and 24 weeks as compared to baseline.
measure: Change from baseline in Incontinence Quality of Life (I-QoL) questionnaire total score.
time frame: 2, 12, 24 weeks
description: Significant improvement in I-QoL total score at 2, 12 and 24 weeks as compared to baseline.
measure: Recording of the adverse events.
time frame: 2, 12, 24 weeks
description: Assessment of possible adverse events-AE (systemic AEs: fatigue, weakness, dyspnoea, gastrointestinal irritation, Flu-like symptoms, dizziness; local AEs: haematuria, dysuria, urinary retention, post-void residual volume > 150 ml) at 2, 12 and 24 weeks after treatment.
arm group label: Incobot/A 100 U
arm group type: Experimental
description: Incobot/A 100 U diluted in 10 ml of sodium chloride solution 0.9% by endoscopic detrusor injections (20 injections, 0.5 ml of solution for each injection) will be administered in patients able to perform spontaneous micturitions
arm group label: Incobot/A 200 U
arm group type: Experimental
description: Incobot/A 200 U diluted in 30 ml of sodium chloride solution 0.9% by endoscopic detrusor injections (30 injections, 1 ml of solution for each injection) will be administered in patients performin intermittent catheterization.
arm group label: Onabot/A 100 U
arm group type: Active Comparator
description: Onabot/A 100 U diluted in 10 ml of sodium chloride solution 0.9% by endoscopic detrusor injections (20 injections, 0.5 ml of solution for each injection) will be administered in patients able to perform spontaneous micturitions
arm group label: Onabot/A 200 U
arm group type: Active Comparator
description: Onabot/A 200 U diluted in 30 ml of sodium chloride solution 0.9% by endoscopic detrusor injections (30 injections, 1 ml of solution for each injection) will be administered to patients performing intermittent catheterization
intervention type: Drug
intervention name: IncobotulinumtoxinA 100 UNT Injection [Xeomin]
description: Incobot/A intradetrusor injections under cystscopic guidance, with local anaethesia in an outpatient basis
arm group label: Incobot/A 100 U
arm group label: Incobot/A 200 U
other name: Incobot/A
intervention type: Drug
intervention name: OnabotulinumtoxinA 100 UNT [Botox]
description: Onabot/A intradetrusor injections under cystscopic guidance, with local anaethesia in an outpatient basis
arm group label: Onabot/A 100 U
arm group label: Onabot/A 200 U
other name: Onabot/A
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Antonella Giannantoni, M.D.
role: Principal Investigator
affiliation: University of Siena
last name: Emanuele Rubilotta, MD
role: Study Chair
affiliation: Universita di Verona
last name: Matteo Balzarro, MD
role: Study Director
affiliation: Universita di Verona
facility: 
country: Italy
citation: Mohee A, Khan A, Harris N, Eardley I. Long-term outcome of the use of intravesical botulinum toxin for the treatment of overactive bladder (OAB). BJU Int. 2013 Jan;111(1):106-13. doi: 10.1111/j.1464-410X.2012.11282.x. Epub 2012 Jun 6.
PMID: 22672569
citation: Thuroff JW, Abrams P, Andersson KE, Artibani W, Chapple CR, Drake MJ, Hampel C, Neisius A, Schroder A, Tubaro A. EAU guidelines on urinary incontinence. Eur Urol. 2011 Mar;59(3):387-400. doi: 10.1016/j.eururo.2010.11.021. Epub 2010 Nov 24.
PMID: 21130559
citation: Gormley EA, Lightner DJ, Faraday M, Vasavada SP; American Urological Association; Society of Urodynamics, Female Pelvic Medicine. Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline amendment. J Urol. 2015 May;193(5):1572-80. doi: 10.1016/j.juro.2015.01.087. Epub 2015 Jan 23.
PMID: 25623739
citation: Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, van Kerrebroeck P, Victor A, Wein A; Standardisation Sub-committee of the International Continence Society. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn. 2002;21(2):167-78. doi: 10.1002/nau.10052. No abstract available.
PMID: 11857671
citation: Haylen BT, de Ridder D, Freeman RM, Swift SE, Berghmans B, Lee J, Monga A, Petri E, Rizk DE, Sand PK, Schaer GN; International Urogynecological Association; International Continence Society. An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for female pelvic floor dysfunction. Neurourol Urodyn. 2010;29(1):4-20. doi: 10.1002/nau.20798.
PMID: 19941278
citation: Lemack GE, Dewey RB Jr, Roehrborn CG, O'Suilleabhain PE, Zimmern PE. Questionnaire-based assessment of bladder dysfunction in patients with mild to moderate Parkinson's disease. Urology. 2000 Aug 1;56(2):250-4. doi: 10.1016/s0090-4295(00)00641-5.
PMID: 10925088
citation: Aharony SM, Lam O, Corcos J. Evaluation of lower urinary tract symptoms in multiple sclerosis patients: Review of the literature and current guidelines. Can Urol Assoc J. 2017 Jan-Feb;11(1-2):61-64. doi: 10.5489/cuaj.4058.
PMID: 28443147
citation: Wyndaele JJ. The management of neurogenic lower urinary tract dysfunction after spinal cord injury. Nat Rev Urol. 2016 Dec;13(12):705-714. doi: 10.1038/nrurol.2016.206. Epub 2016 Oct 25.
PMID: 27779229
citation: Campos-Sousa RN, Quagliato E, da Silva BB, de Carvalho RM Jr, Ribeiro SC, de Carvalho DF. Urinary symptoms in Parkinson's disease: prevalence and associated factors. Arq Neuropsiquiatr. 2003 Jun;61(2B):359-63. doi: 10.1590/s0004-282x2003000300007. Epub 2003 Jul 28.
PMID: 12894267
citation: Kanai A, Andersson KE. Bladder afferent signaling: recent findings. J Urol. 2010 Apr;183(4):1288-95. doi: 10.1016/j.juro.2009.12.060. Epub 2010 Feb 19.
PMID: 20171668
citation: Veenboer PW, Bosch JL. Long-term adherence to antimuscarinic therapy in everyday practice: a systematic review. J Urol. 2014 Apr;191(4):1003-8. doi: 10.1016/j.juro.2013.10.046. Epub 2013 Oct 16.
PMID: 24140548
citation: Di Stasi SM, Giannantoni A, Vespasiani G, Navarra P, Capelli G, Massoud R, Stephen RL. Intravesical electromotive administration of oxybutynin in patients with detrusor hyperreflexia unresponsive to standard anticholinergic regimens. J Urol. 2001 Feb;165(2):491-8. doi: 10.1097/00005392-200102000-00032.
PMID: 11176403
citation: Jost WH, Benecke R, Hauschke D, Jankovic J, Kanovsky P, Roggenkamper P, Simpson DM, Comella CL. Clinical and pharmacological properties of incobotulinumtoxinA and its use in neurological disorders. Drug Des Devel Ther. 2015 Apr 1;9:1913-26. doi: 10.2147/DDDT.S79193. eCollection 2015.
PMID: 25897202
citation: Veeratterapillay R, Harding C, Teo L, Vasdev N, Abroaf A, Dorkin TJ, Pickard RS, Hasan T, Thorpe AC. Discontinuation rates and inter-injection interval for repeated intravesical botulinum toxin type A injections for detrusor overactivity. Int J Urol. 2014 Feb;21(2):175-8. doi: 10.1111/iju.12205. Epub 2013 Jul 2.
PMID: 23819724
citation: Frevert J. Response to Commentary by W. Jost on: Pharmaceutical, Biological, and Clinical Properties of Botulinum Neurotoxin Type A Products. Drugs R D. 2015 Jun;15(2):217-8. doi: 10.1007/s40268-015-0091-y. No abstract available.
PMID: 25851380
citation: Benecke R. Clinical relevance of botulinum toxin immunogenicity. BioDrugs. 2012 Apr 1;26(2):e1-9. doi: 10.2165/11599840-000000000-00000.
PMID: 22385408
citation: Wang L, Sun Y, Yang W, Lindo P, Singh BR. Type A botulinum neurotoxin complex proteins differentially modulate host response of neuronal cells. Toxicon. 2014 May;82:52-60. doi: 10.1016/j.toxicon.2014.02.004. Epub 2014 Feb 21.
PMID: 24560879
citation: Jost WH, Blumel J, Grafe S. Botulinum neurotoxin type A free of complexing proteins (XEOMIN) in focal dystonia. Drugs. 2007;67(5):669-83. doi: 10.2165/00003495-200767050-00003.
PMID: 17385940
citation: Kumar R, Zhou Y, Ghosal K, Cai S, Singh BR. Anti-apoptotic activity of hemagglutinin-33 and botulinum neurotoxin and its implications to therapeutic and countermeasure issues. Biochem Biophys Res Commun. 2012 Jan 13;417(2):726-31. doi: 10.1016/j.bbrc.2011.12.020. Epub 2011 Dec 11.
PMID: 22182409
citation: Campanati A, Giuliodori K, Martina E, Giuliano A, Ganzetti G, Offidani A. Onabotulinumtoxin type A (Botox((R))) versus Incobotulinumtoxin type A (Xeomin((R))) in the treatment of focal idiopathic palmar hyperhidrosis: results of a comparative double-blind clinical trial. J Neural Transm (Vienna). 2014 Jan;121(1):21-6. doi: 10.1007/s00702-013-1074-1. Epub 2013 Sep 20.
PMID: 24052109
responsible party type: Principal Investigator
investigator affiliation: University Of Perugia
investigator full name: Antonella Giannantoni
investigator title: PA
mesh term: Urinary Bladder, Overactive
mesh term: Syndrome
mesh term: Botulinum Toxins, Type A
mesh term: incobotulinumtoxinA
mesh term: abobotulinumtoxinA
sharing ipd: No