<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/NCT01678053</url>
  </required_header>
  <id_info>
    <org_study_id>11-090H</org_study_id>
    <nct_id>NCT01678053</nct_id>
  </id_info>
  <brief_title>Efficacy Study of Botulinum Toxin (BOTOX) Injections to Treat Vocal Fold Granulomas</brief_title>
  <official_title>A Randomized Controlled Trial Comparing Proton Pump Inhibitor Therapy With and Without Interarytenoid Botulinum Toxin Injection for Vocal Fold Granuloma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Phillip Song, MD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Massachusetts Eye and Ear Infirmary</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Vocal process granulomas are inflammatory masses caused in part by vocal trauma that arise in&#xD;
      the posterior aspect of the vocal folds and result in throat pain, difficulty swallowing,&#xD;
      hoarseness, and globus sensation. Antireflux therapy treats most granulomas, but many are&#xD;
      recalcitrant to this therapy or take months to years to resolve. Botulinum toxin injection&#xD;
      into the thyroarytenoid muscle has been effectively employed for recalcitrant granuloma, but&#xD;
      causes significant voice loss, occasional difficulty swallowing and, in our clinical&#xD;
      experience, is associated with significant recurrence. The investigators propose injecting&#xD;
      another muscle in the larynx called the interarytenoid muscle with botulinum toxin type A to&#xD;
      maintain the benefit of injection with less loss of voice. The investigators have shown the&#xD;
      effectiveness of this treatment in a small, retrospective analysis.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Vocal fold granulomas may be due to reflux, voice trauma, intubation, multiple or unknown&#xD;
      etiologies. Regimens of voice therapy and anti-reflux medications have show resolution rates&#xD;
      varying from 38% to 100%, with recurrence rates of 15-20%, and up to 50-92% in&#xD;
      surgical-operated on recalcitrant granulomas. Nasri and colleagues first proposed&#xD;
      thyroarytenoid botulinum toxin type A (BOTOX) injections for vocal fold granulomas with&#xD;
      success. They posited that the chemically paralyzed muscle would result in limited contact at&#xD;
      the site of the granuloma, allowing for healing. Damrose and Damrose further showed that&#xD;
      thyroarytenoid BOTOX injections were effective in treating recalcitrant vocal fold&#xD;
      granulomas. Both of the above groups noted hoarseness as an expected side effect. Pham and&#xD;
      colleagues showed complete resolution of granulomas in 2-8 weeks after treatment with&#xD;
      thyroarytenoid BOTOX injections. This was compared to mean granuloma resolution of 5.7 months&#xD;
      proton pump inhibitor therapy alone. The investigators reviewed eight patients treated for&#xD;
      recalcitrant vocal fold granuloma at Mass Eye and Ear with interarytenoid BOTOX injections&#xD;
      and found no serious adverse effects and complete response in seven cases. The investigators&#xD;
      now seek to compare interarytenoid BOTOX injections to standard anti-reflux therapy alone to&#xD;
      see if the addition of IA Botox injections improves response rates at 3 months. The&#xD;
      investigators chose this timeframe since 86% of granulomas treated in our retrospective study&#xD;
      had resolved 3 months after initiation of treatment compared to 25% of granulomas treated&#xD;
      with medical management.&#xD;
&#xD;
      The investigators will not include a Thyroarytenoid injection arm in this study as this&#xD;
      technique has not been useful in our clinical experience.&#xD;
&#xD;
      For those who consent, a Voice Handicap Index survey (6 - see attached) will be completed.&#xD;
      Participants will then be randomized to undergo only medical therapy with omeprazole (40mg by&#xD;
      mouth twice daily ) or an interarytenoid BOTOX injection followed by the same reflux regimen.&#xD;
      Randomization will be performed by the Tufts online randomization plan, which may be found&#xD;
      at: http://www.tufts.edu/~gdallal/PLANDOC.HTM. This program generates a random order in which&#xD;
      participants will be enrolled in either of the two arms of the study.&#xD;
&#xD;
      The injection will consist of 10 units of botulinum toxin injected into the interarytenoid&#xD;
      muscle under fiberoptic visualization. All participants will remain on the PPI therapy for&#xD;
      the duration of the study. Participants will receive prescriptions for PPI medication from&#xD;
      the attending Laryngologist and participants will then be responsible for acquiring and&#xD;
      taking their medications.&#xD;
&#xD;
      Injections will be performed per standard MEEI Laryngology protocol for interarytenoid BOTOX&#xD;
      injection. Participants will then be evaluated at 1.5 months, 3 months and 6 months with&#xD;
      fiberoptic examination as well as Voice Handicap Index &amp; Reflux Symptom Index. Participants&#xD;
      in the medication only arm who continue to have a granuloma at 3 months will receive a BOTOX&#xD;
      injection. They will be re-evaluated 3 months after the injection. Examinations will be&#xD;
      recorded and reviewed by blinded reviewers.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Was not able to recruit patients for randomization.&#xD;
  </why_stopped>
  <start_date>September 2012</start_date>
  <completion_date type="Actual">January 2015</completion_date>
  <primary_completion_date type="Actual">January 2015</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>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Complete resolution of vocal fold granuloma</measure>
    <time_frame>3 months</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Voice Handicap Index score</measure>
    <time_frame>3 months</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Contact Ulcer of Vocal Folds</condition>
  <condition>Granuloma of Vocal Cords</condition>
  <condition>Granuloma, Laryngeal</condition>
  <condition>Granuloma</condition>
  <arm_group>
    <arm_group_label>PPI and BOTOX</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>onabotulinumtoxinA (BOTOX), injection, 10 units, one time; omeprazole 40mg po bid (standard of care) for 3 months</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Proton pump inhibitor only</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>omeprazole 40mg po bid for 3 months(standard of care)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>onabotulinumtoxinA</intervention_name>
    <description>Botulinum toxin A is injected into the larynx in order to treat vocal fold granulomas.</description>
    <arm_group_label>PPI and BOTOX</arm_group_label>
    <other_name>BOTOX</other_name>
    <other_name>Botulinum toxin A</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>omeprazole (proton pump inhibitor)</intervention_name>
    <description>Standard therapy of anti-reflux medications using omeprazole or equivalent PPI.</description>
    <arm_group_label>PPI and BOTOX</arm_group_label>
    <arm_group_label>Proton pump inhibitor only</arm_group_label>
    <other_name>omeprazole</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  adults age 18 years old and older with vocal fold granulomas&#xD;
&#xD;
          -  willing to attend all follow-up appointments&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  pregnant females&#xD;
&#xD;
          -  woman who are nursing&#xD;
&#xD;
          -  minors and other patients unable to give informed consent&#xD;
&#xD;
          -  patients taking Plavix&#xD;
&#xD;
          -  patients with:&#xD;
&#xD;
          -  impaired laryngeal motion as the result of neurological impairment&#xD;
&#xD;
          -  vocal fold immobility&#xD;
&#xD;
          -  pre-existing oropharyngeal swallowing problems&#xD;
&#xD;
          -  history of radiation therapy&#xD;
&#xD;
          -  history of aspiration pneumonia&#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>Phillip Song, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Massachusetts Eye and Ear Infirmary</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Massachusetts Eye and Ear Infirmary</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>de Lima Pontes PA, De Biase NG, Gadelha EC. Clinical evolution of laryngeal granulomas: treatment and prognosis. Laryngoscope. 1999 Feb;109(2 Pt 1):289-94. doi: 10.1097/00005537-199902000-00021.</citation>
    <PMID>10890781</PMID>
  </reference>
  <reference>
    <citation>Emami AJ, Morrison M, Rammage L, Bosch D. Treatment of laryngeal contact ulcers and granulomas: a 12-year retrospective analysis. J Voice. 1999 Dec;13(4):612-7. doi: 10.1016/s0892-1997(99)80015-0.</citation>
    <PMID>10622526</PMID>
  </reference>
  <reference>
    <citation>Pham J, Yin S, Morgan M, Stucker F, Nathan CO. Botulinum toxin: helpful adjunct to early resolution of laryngeal granulomas. J Laryngol Otol. 2004 Oct;118(10):781-5. doi: 10.1258/0022215042450788.</citation>
    <PMID>15550184</PMID>
  </reference>
  <reference>
    <citation>Nasri S, Sercarz JA, McAlpin T, Berke GS. Treatment of vocal fold granuloma using botulinum toxin type A. Laryngoscope. 1995 Jun;105(6):585-8. doi: 10.1288/00005537-199506000-00005.</citation>
    <PMID>7769940</PMID>
  </reference>
  <reference>
    <citation>Damrose EJ, Damrose JF. Botulinum toxin as adjunctive therapy in refractory laryngeal granuloma. J Laryngol Otol. 2008 Aug;122(8):824-8. doi: 10.1017/S0022215107000710. Epub 2007 Oct 2.</citation>
    <PMID>17908354</PMID>
  </reference>
  <reference>
    <citation>Ylitalo R, Lindestad PA. A retrospective study of contact granuloma. Laryngoscope. 1999 Mar;109(3):433-6. doi: 10.1097/00005537-199903000-00017.</citation>
    <PMID>10089971</PMID>
  </reference>
  <verification_date>March 2017</verification_date>
  <study_first_submitted>August 30, 2012</study_first_submitted>
  <study_first_submitted_qc>August 31, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 3, 2012</study_first_posted>
  <last_update_submitted>March 24, 2017</last_update_submitted>
  <last_update_submitted_qc>March 24, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">March 28, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Massachusetts Eye and Ear Infirmary</investigator_affiliation>
    <investigator_full_name>Phillip Song, MD</investigator_full_name>
    <investigator_title>Otolaryngologist</investigator_title>
  </responsible_party>
  <keyword>Botulinum Toxins, Type A</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Granuloma, Laryngeal</mesh_term>
    <mesh_term>Granuloma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Omeprazole</mesh_term>
    <mesh_term>Botulinum Toxins</mesh_term>
    <mesh_term>Botulinum Toxins, Type A</mesh_term>
    <mesh_term>abobotulinumtoxinA</mesh_term>
    <mesh_term>Proton Pump Inhibitors</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/NCT01678053
org study id: 11-090H
nct id: NCT01678053
lead sponsor: 
has dmc: Yes
Vocal process granulomas are inflammatory masses caused in part by vocal trauma that arise in
      the posterior aspect of the vocal folds and result in throat pain, difficulty swallowing,
      hoarseness, and globus sensation. Antireflux therapy treats most granulomas, but many are
      recalcitrant to this therapy or take months to years to resolve. Botulinum toxin injection
      into the thyroarytenoid muscle has been effectively employed for recalcitrant granuloma, but
      causes significant voice loss, occasional difficulty swallowing and, in our clinical
      experience, is associated with significant recurrence. The investigators propose injecting
      another muscle in the larynx called the interarytenoid muscle with botulinum toxin type A to
      maintain the benefit of injection with less loss of voice. The investigators have shown the
      effectiveness of this treatment in a small, retrospective analysis.
Vocal fold granulomas may be due to reflux, voice trauma, intubation, multiple or unknown
      etiologies. Regimens of voice therapy and anti-reflux medications have show resolution rates
      varying from 38% to 100%, with recurrence rates of 15-20%, and up to 50-92% in
      surgical-operated on recalcitrant granulomas. Nasri and colleagues first proposed
      thyroarytenoid botulinum toxin type A (BOTOX) injections for vocal fold granulomas with
      success. They posited that the chemically paralyzed muscle would result in limited contact at
      the site of the granuloma, allowing for healing. Damrose and Damrose further showed that
      thyroarytenoid BOTOX injections were effective in treating recalcitrant vocal fold
      granulomas. Both of the above groups noted hoarseness as an expected side effect. Pham and
      colleagues showed complete resolution of granulomas in 2-8 weeks after treatment with
      thyroarytenoid BOTOX injections. This was compared to mean granuloma resolution of 5.7 months
      proton pump inhibitor therapy alone. The investigators reviewed eight patients treated for
      recalcitrant vocal fold granuloma at Mass Eye and Ear with interarytenoid BOTOX injections
      and found no serious adverse effects and complete response in seven cases. The investigators
      now seek to compare interarytenoid BOTOX injections to standard anti-reflux therapy alone to
      see if the addition of IA Botox injections improves response rates at 3 months. The
      investigators chose this timeframe since 86% of granulomas treated in our retrospective study
      had resolved 3 months after initiation of treatment compared to 25% of granulomas treated
      with medical management.

      The investigators will not include a Thyroarytenoid injection arm in this study as this
      technique has not been useful in our clinical experience.

      For those who consent, a Voice Handicap Index survey (6 - see attached) will be completed.
      Participants will then be randomized to undergo only medical therapy with omeprazole (40mg by
      mouth twice daily ) or an interarytenoid BOTOX injection followed by the same reflux regimen.
      Randomization will be performed by the Tufts online randomization plan, which may be found
      at: http://www.tufts.edu/~gdallal/PLANDOC.HTM. This program generates a random order in which
      participants will be enrolled in either of the two arms of the study.

      The injection will consist of 10 units of botulinum toxin injected into the interarytenoid
      muscle under fiberoptic visualization. All participants will remain on the PPI therapy for
      the duration of the study. Participants will receive prescriptions for PPI medication from
      the attending Laryngologist and participants will then be responsible for acquiring and
      taking their medications.

      Injections will be performed per standard MEEI Laryngology protocol for interarytenoid BOTOX
      injection. Participants will then be evaluated at 1.5 months, 3 months and 6 months with
      fiberoptic examination as well as Voice Handicap Index & Reflux Symptom Index. Participants
      in the medication only arm who continue to have a granuloma at 3 months will receive a BOTOX
      injection. They will be re-evaluated 3 months after the injection. Examinations will be
      recorded and reviewed by blinded reviewers.
allocation: Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Complete resolution of vocal fold granuloma
time frame: 3 months
measure: Voice Handicap Index score
time frame: 3 months
arm group label: PPI and BOTOX
arm group type: Experimental
description: onabotulinumtoxinA (BOTOX), injection, 10 units, one time; omeprazole 40mg po bid (standard of care) for 3 months
arm group label: Proton pump inhibitor only
arm group type: Other
description: omeprazole 40mg po bid for 3 months(standard of care)
intervention type: Drug
intervention name: onabotulinumtoxinA
description: Botulinum toxin A is injected into the larynx in order to treat vocal fold granulomas.
arm group label: PPI and BOTOX
other name: BOTOX
other name: Botulinum toxin A
intervention type: Drug
intervention name: omeprazole (proton pump inhibitor)
description: Standard therapy of anti-reflux medications using omeprazole or equivalent PPI.
arm group label: PPI and BOTOX
arm group label: Proton pump inhibitor only
other name: omeprazole
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Phillip Song, M.D.
role: Principal Investigator
affiliation: Massachusetts Eye and Ear Infirmary
facility: 
country: United States
citation: de Lima Pontes PA, De Biase NG, Gadelha EC. Clinical evolution of laryngeal granulomas: treatment and prognosis. Laryngoscope. 1999 Feb;109(2 Pt 1):289-94. doi: 10.1097/00005537-199902000-00021.
PMID: 10890781
citation: Emami AJ, Morrison M, Rammage L, Bosch D. Treatment of laryngeal contact ulcers and granulomas: a 12-year retrospective analysis. J Voice. 1999 Dec;13(4):612-7. doi: 10.1016/s0892-1997(99)80015-0.
PMID: 10622526
citation: Pham J, Yin S, Morgan M, Stucker F, Nathan CO. Botulinum toxin: helpful adjunct to early resolution of laryngeal granulomas. J Laryngol Otol. 2004 Oct;118(10):781-5. doi: 10.1258/0022215042450788.
PMID: 15550184
citation: Nasri S, Sercarz JA, McAlpin T, Berke GS. Treatment of vocal fold granuloma using botulinum toxin type A. Laryngoscope. 1995 Jun;105(6):585-8. doi: 10.1288/00005537-199506000-00005.
PMID: 7769940
citation: Damrose EJ, Damrose JF. Botulinum toxin as adjunctive therapy in refractory laryngeal granuloma. J Laryngol Otol. 2008 Aug;122(8):824-8. doi: 10.1017/S0022215107000710. Epub 2007 Oct 2.
PMID: 17908354
citation: Ylitalo R, Lindestad PA. A retrospective study of contact granuloma. Laryngoscope. 1999 Mar;109(3):433-6. doi: 10.1097/00005537-199903000-00017.
PMID: 10089971
responsible party type: Sponsor-Investigator
investigator affiliation: Massachusetts Eye and Ear Infirmary
investigator full name: Phillip Song, MD
investigator title: Otolaryngologist
mesh term: Granuloma, Laryngeal
mesh term: Granuloma
mesh term: Omeprazole
mesh term: Botulinum Toxins
mesh term: Botulinum Toxins, Type A
mesh term: abobotulinumtoxinA
mesh term: Proton Pump Inhibitors