<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/NCT03007004</url>
  </required_header>
  <id_info>
    <org_study_id>D2016017</org_study_id>
    <nct_id>NCT03007004</nct_id>
  </id_info>
  <brief_title>Effect and Safety of Local Injection of Botulinum Toxin Type B Against Digital Ulcer in Systemic Sclerosis</brief_title>
  <official_title>Trial to Confirm the Effect and Safety of Local Injection of Botulinum Toxin Type B Against Digital Ulcer in Systemic Sclerosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Gunma University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Gunma University</source>
  <brief_summary>
    <textblock>
      Efficacy and safety of local infusion of botulinum toxin type B in patients with systemic&#xD;
      sclerosis (SSc) with digital ulcer is evaluated by a randomized, double-blind study.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      To assess the efficacy and safety of local injection of botulinum toxin type B (BTX-B)&#xD;
      against digital ulcers (DUs) and Raynaud's phenomenon (RP) in patients with systemic&#xD;
      sclerosis (SSc).&#xD;
&#xD;
      In a randomized, double-blind, placebo-controlled, investigator-initiated clinical trial&#xD;
      (phase II), 10 patients with SSc and RP-related DUs were randomly and evenly assigned to a&#xD;
      placebo control group or treatment group taking BTX-B injections. The degree of improvement&#xD;
      in DU, change in size, number of new DUs, improvement in symptoms of RP, and adverse events&#xD;
      were recorded.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 12, 2016</start_date>
  <completion_date type="Actual">May 14, 2019</completion_date>
  <primary_completion_date type="Actual">May 14, 2019</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Percentage of subjects who completely lost index ulcer 8 weeks after administration</measure>
    <time_frame>8 weeks after administration</time_frame>
    <description>The primary end point was the percentage of subjects with complete disappearance of index ulcer 8 weeks after administration. The index ulcer was defined as the largest DUs in the hand. The size of DU was measured as both the longest diameter of the ulcer and the diameter perpendicular to the center of the ulcer's diameter. Complete disappearance is defined as the disappearance of the area of the ulcer that has become epithelialized and covered by the epidermis from the periphery of the ulcer and continued coverage of the ulcer surface area that has been restored.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>the percentage of subjects with complete disappearance of index ulcer at 4, 12, and 16 weeks after administration</measure>
    <time_frame>at 4, 12, and 16 weeks after administration</time_frame>
    <description>the percentage of subjects with complete disappearance of index ulcer at 4, 12, and 16 weeks after administration</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>the rate of change in the number of DUs per hand</measure>
    <time_frame>at 4, 8, 12, and 16 weeks after administration</time_frame>
    <description>the rate of change in the number of DUs per hand</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>the number of newly formed DUs</measure>
    <time_frame>at 4, 8, 12, and 16 weeks after administration</time_frame>
    <description>the number of newly formed DUs</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>the number of newly formed DUs per hand</measure>
    <time_frame>at 4, 8, 12, and 16 weeks after administration</time_frame>
    <description>the number of newly formed DUs per hand</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>the changes in RP severity were assessed using Raynaud's Condition Score [RCS]</measure>
    <time_frame>at 4, 8, 12, and 16 weeks after administration</time_frame>
    <description>the changes in RP severity were assessed using Raynaud's Condition Score [RCS]. RCS is a daily self-assessment of RP activity using a 0-10 ordinal scale. RCS incorporates the cumulative daily frequency, duration, severity, and effect of RP attacks. RCS was averaged over a 7-day period preceding the baseline and each subsequent visit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>the changes of investigator rating Raynaud's Condition Score [RCS]</measure>
    <time_frame>at 4, 8, 12, and 16 weeks after administration</time_frame>
    <description>the changes of investigator rating Raynaud's Condition Score [RCS]. Investigator rating RCS was also assessed by the investigator (SM).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>the changes in the score of pain/numbness severity assessed using the 100-mm Visual Analog Scale (VAS)</measure>
    <time_frame>at 4, 8, 12, and 16 weeks after administration</time_frame>
    <description>Pain/numbness severity was assessed using the 100-mm Visual Analog Scale (VAS). Pain/numbness severity was assessed using the 100-mm Visual Analog Scale (VAS) (range 0-100; 0 refers to no pain/numbness, and 100 refers to worst imaginable pain/numbness)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>the changes of the recovery of skin temperature in the finger with the index ulcer</measure>
    <time_frame>at 4, 8, 12, and 16 weeks after administration</time_frame>
    <description>the skin temperature of the finger was measured just after and 10 minutes after an ice-bath immersion</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>the changes in the attack duration of Raynaud's phenomenon</measure>
    <time_frame>at 4, 8, 12, and 16 weeks after administration</time_frame>
    <description>the changes in the attack duration of Raynaud's phenomenon</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>the changes in the number of attacks of Raynaud's phenomenon per day</measure>
    <time_frame>at 4, 8, 12, and 16 weeks after administration</time_frame>
    <description>the number of attacks of Raynaud's phenomenon per day was assessed for 7days</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">10</enrollment>
  <condition>Systemic Sclerosis Patients With Digital Ulcers</condition>
  <arm_group>
    <arm_group_label>Botulinum toxin group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>400 units in one injection site（0.2mL） Total 2000 units（1.0mL） （For both hands total 4000 units; 2.0 mL）</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Physiological saline (control drug) group</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>0.2mL in one injection site&#xD;
Total 1.0mL (For both hands total 2.0 mL)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Botulinum toxin type B (2500 units / vial)</intervention_name>
    <description>BTX-B (E2014, Eisai, NerBloc®) was injected subcutaneously from the palmar side into seven locations around interphalangeal metacarpophalangeal joints, targeting the neurovascular bundles just proximal to the A1 pulley (the radial and ulnar sides of the first finger, the radial side of second finger, the ulnar side of the fifth finger and between the second to fifth fingers). Three locations between the second and third fingers, the third and fourth fingers, and the fourth and fifth fingers were injected with 400 U (0.2 ml) of BTX-B. In addition, the radial and ulnar sides of the first finger, the radial side of the second finger, and the ulnar side of the fifth finger were injected with half a dose of BTX-B (200 units; 0.1 ml). A total of 2000 U (1.0 ml) of BTX-B was injected into one hand. Injections were performed using a 30-gauge needle.</description>
    <arm_group_label>Botulinum toxin group</arm_group_label>
    <other_name>BTX-B (E2014, Eisai, NerBloc®)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Physiological saline</intervention_name>
    <description>Saline solution was injected subcutaneously from the palmar side into seven locations around interphalangeal metacarpophalangeal joints, targeting the neurovascular bundles just proximal to the A1 pulley (the radial and ulnar sides of the first finger, the radial side of second finger, the ulnar side of the fifth finger and between the second to fifth fingers). Three locations between the second and third fingers, the third and fourth fingers, and the fourth and fifth fingers were injected with saline (0.2 ml). In addition, the radial and ulnar sides of the first finger, the radial side of the second finger, and the ulnar side of the fifth finger were injected with half a dose of saline (0.1 ml). A total of 1.0 ml of saline was injected into one hand. Injections were performed using a 30-gauge needle.</description>
    <arm_group_label>Physiological saline (control drug) group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patients diagnosed with SSc in diagnostic criteria (Appendix 1) by the&#xD;
             American-European Rheumatology Association&#xD;
&#xD;
          2. Patients who have Raynaud's phenomenon from consultation, inquiries, etc. judged by&#xD;
             Clinical responsibility (sharing) doctor&#xD;
&#xD;
          3. Patients with digital ulcer at acquiring consent The criteria for digital ulcers are&#xD;
             as follows.&#xD;
&#xD;
               -  It is a peripheral ulcer from the proximal interphalangeal joint and the thumb&#xD;
                  interphalangeal joint (including the interphalangeal joint).&#xD;
&#xD;
               -  The continuity of coating by the epithelium has been lost and there is a depth&#xD;
                  that is visible to the eye. Incidentally, when exposed, cases covered with eschar&#xD;
                  or necrotic tissue are also included.&#xD;
&#xD;
               -  If the exposure is not clearly recognized (crusted or covered with necrotic&#xD;
                  tissue), the investigational responsibility (shared) doctor can judge that the&#xD;
                  epidermis and the dermis are missing.&#xD;
&#xD;
               -  It should not be the paronychia、crack、digital pitting scars.&#xD;
&#xD;
               -  It should not be attached to the projection of the calcification.&#xD;
&#xD;
               -  Size: The maximum diameter (major axis) is 0.5 cm or more.&#xD;
&#xD;
               -  Bones, tendons and joints are not exposed.&#xD;
&#xD;
               -  It is not accompanied by obvious infection findings.&#xD;
&#xD;
          4. At the time of acquiring consent Patients over 18 years old&#xD;
&#xD;
          5. Patients for whom consent has been obtained in writing on participation of this trial&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients with Raynaud's phenomenon due to diseases other than SSc&#xD;
&#xD;
          2. Patients with systemic neuromuscular junction disorder (myasthenia gravis,&#xD;
             Lambert-Eaton syndrome, amyotrophic lateral sclerosis etc.)&#xD;
&#xD;
          3. Patients with advanced respiratory dysfunction&#xD;
&#xD;
          4. Patients with a history of hypersensitivity to components of botulinum toxin type B&#xD;
             (botulinum toxin type B, human serum albumin, succinate buffer) or other botulinum&#xD;
             toxin&#xD;
&#xD;
          5. Patients who received botulinum toxin formulation within 4 months before study drug&#xD;
             administration or who have continued efficacy of botulinum toxin at the time of&#xD;
             administration of investigational drug even when administered more than 4 months ago&#xD;
&#xD;
          6. Patients who received endothelin receptor antagonist within 60 days before study drug&#xD;
             administration&#xD;
&#xD;
          7. Patients who received the following medications within 14 days prior to study drug&#xD;
             administration&#xD;
&#xD;
               -  Argatroban hydrate injection&#xD;
&#xD;
               -  Prostaglandin E1 Injection (eg alprostadil injection)&#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_official>
    <last_name>Sei-ichiro Motegi</last_name>
    <role>Principal Investigator</role>
    <affiliation>Gunma University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Gunma University Graduate school of Medicine</name>
      <address>
        <city>Showa</city>
        <state>Gunma</state>
        <zip>371-8511</zip>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Japan</country>
  </location_countries>
  <verification_date>May 2020</verification_date>
  <study_first_submitted>December 28, 2016</study_first_submitted>
  <study_first_submitted_qc>December 28, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 30, 2016</study_first_posted>
  <last_update_submitted>May 12, 2020</last_update_submitted>
  <last_update_submitted_qc>May 12, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">May 14, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Gunma University</investigator_affiliation>
    <investigator_full_name>Sei-ichiro Motegi</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <keyword>Systemic aclerosis</keyword>
  <keyword>digital ulcer</keyword>
  <keyword>botulinum toxin</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Scleroderma, Systemic</mesh_term>
    <mesh_term>Scleroderma, Diffuse</mesh_term>
    <mesh_term>Skin Ulcer</mesh_term>
    <mesh_term>Sclerosis</mesh_term>
    <mesh_term>Ulcer</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>rimabotulinumtoxinB</mesh_term>
    <mesh_term>Botulinum Toxins</mesh_term>
    <mesh_term>Botulinum Toxins, Type A</mesh_term>
    <mesh_term>abobotulinumtoxinA</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03007004
org study id: D2016017
nct id: NCT03007004
lead sponsor: 
Efficacy and safety of local infusion of botulinum toxin type B in patients with systemic
      sclerosis (SSc) with digital ulcer is evaluated by a randomized, double-blind study.
To assess the efficacy and safety of local injection of botulinum toxin type B (BTX-B)
      against digital ulcers (DUs) and Raynaud's phenomenon (RP) in patients with systemic
      sclerosis (SSc).

      In a randomized, double-blind, placebo-controlled, investigator-initiated clinical trial
      (phase II), 10 patients with SSc and RP-related DUs were randomly and evenly assigned to a
      placebo control group or treatment group taking BTX-B injections. The degree of improvement
      in DU, change in size, number of new DUs, improvement in symptoms of RP, and adverse events
      were recorded.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Percentage of subjects who completely lost index ulcer 8 weeks after administration
time frame: 8 weeks after administration
description: The primary end point was the percentage of subjects with complete disappearance of index ulcer 8 weeks after administration. The index ulcer was defined as the largest DUs in the hand. The size of DU was measured as both the longest diameter of the ulcer and the diameter perpendicular to the center of the ulcer's diameter. Complete disappearance is defined as the disappearance of the area of the ulcer that has become epithelialized and covered by the epidermis from the periphery of the ulcer and continued coverage of the ulcer surface area that has been restored.
measure: the percentage of subjects with complete disappearance of index ulcer at 4, 12, and 16 weeks after administration
time frame: at 4, 12, and 16 weeks after administration
description: the percentage of subjects with complete disappearance of index ulcer at 4, 12, and 16 weeks after administration
measure: the rate of change in the number of DUs per hand
time frame: at 4, 8, 12, and 16 weeks after administration
description: the rate of change in the number of DUs per hand
measure: the number of newly formed DUs
time frame: at 4, 8, 12, and 16 weeks after administration
description: the number of newly formed DUs
measure: the number of newly formed DUs per hand
time frame: at 4, 8, 12, and 16 weeks after administration
description: the number of newly formed DUs per hand
measure: the changes in RP severity were assessed using Raynaud's Condition Score [RCS]
time frame: at 4, 8, 12, and 16 weeks after administration
description: the changes in RP severity were assessed using Raynaud's Condition Score [RCS]. RCS is a daily self-assessment of RP activity using a 0-10 ordinal scale. RCS incorporates the cumulative daily frequency, duration, severity, and effect of RP attacks. RCS was averaged over a 7-day period preceding the baseline and each subsequent visit.
measure: the changes of investigator rating Raynaud's Condition Score [RCS]
time frame: at 4, 8, 12, and 16 weeks after administration
description: the changes of investigator rating Raynaud's Condition Score [RCS]. Investigator rating RCS was also assessed by the investigator (SM).
measure: the changes in the score of pain/numbness severity assessed using the 100-mm Visual Analog Scale (VAS)
time frame: at 4, 8, 12, and 16 weeks after administration
description: Pain/numbness severity was assessed using the 100-mm Visual Analog Scale (VAS). Pain/numbness severity was assessed using the 100-mm Visual Analog Scale (VAS) (range 0-100; 0 refers to no pain/numbness, and 100 refers to worst imaginable pain/numbness)
measure: the changes of the recovery of skin temperature in the finger with the index ulcer
time frame: at 4, 8, 12, and 16 weeks after administration
description: the skin temperature of the finger was measured just after and 10 minutes after an ice-bath immersion
measure: the changes in the attack duration of Raynaud's phenomenon
time frame: at 4, 8, 12, and 16 weeks after administration
description: the changes in the attack duration of Raynaud's phenomenon
measure: the changes in the number of attacks of Raynaud's phenomenon per day
time frame: at 4, 8, 12, and 16 weeks after administration
description: the number of attacks of Raynaud's phenomenon per day was assessed for 7days
arm group label: Botulinum toxin group
arm group type: Experimental
description: 400 units in one injection site（0.2mL） Total 2000 units（1.0mL） （For both hands total 4000 units; 2.0 mL）
arm group label: Physiological saline (control drug) group
arm group type: Sham Comparator
description: 0.2mL in one injection site
Total 1.0mL (For both hands total 2.0 mL)
intervention type: Drug
intervention name: Botulinum toxin type B (2500 units / vial)
description: BTX-B (E2014, Eisai, NerBloc®) was injected subcutaneously from the palmar side into seven locations around interphalangeal metacarpophalangeal joints, targeting the neurovascular bundles just proximal to the A1 pulley (the radial and ulnar sides of the first finger, the radial side of second finger, the ulnar side of the fifth finger and between the second to fifth fingers). Three locations between the second and third fingers, the third and fourth fingers, and the fourth and fifth fingers were injected with 400 U (0.2 ml) of BTX-B. In addition, the radial and ulnar sides of the first finger, the radial side of the second finger, and the ulnar side of the fifth finger were injected with half a dose of BTX-B (200 units; 0.1 ml). A total of 2000 U (1.0 ml) of BTX-B was injected into one hand. Injections were performed using a 30-gauge needle.
arm group label: Botulinum toxin group
other name: BTX-B (E2014, Eisai, NerBloc®)
intervention type: Drug
intervention name: Physiological saline
description: Saline solution was injected subcutaneously from the palmar side into seven locations around interphalangeal metacarpophalangeal joints, targeting the neurovascular bundles just proximal to the A1 pulley (the radial and ulnar sides of the first finger, the radial side of second finger, the ulnar side of the fifth finger and between the second to fifth fingers). Three locations between the second and third fingers, the third and fourth fingers, and the fourth and fifth fingers were injected with saline (0.2 ml). In addition, the radial and ulnar sides of the first finger, the radial side of the second finger, and the ulnar side of the fifth finger were injected with half a dose of saline (0.1 ml). A total of 1.0 ml of saline was injected into one hand. Injections were performed using a 30-gauge needle.
arm group label: Physiological saline (control drug) group
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Sei-ichiro Motegi
role: Principal Investigator
affiliation: Gunma University
facility: 
country: Japan
responsible party type: Principal Investigator
investigator affiliation: Gunma University
investigator full name: Sei-ichiro Motegi
investigator title: Associate Professor
mesh term: Scleroderma, Systemic
mesh term: Scleroderma, Diffuse
mesh term: Skin Ulcer
mesh term: Sclerosis
mesh term: Ulcer
mesh term: rimabotulinumtoxinB
mesh term: Botulinum Toxins
mesh term: Botulinum Toxins, Type A
mesh term: abobotulinumtoxinA