<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/NCT02999815</url>
  </required_header>
  <id_info>
    <org_study_id>03TS</org_study_id>
    <nct_id>NCT02999815</nct_id>
  </id_info>
  <brief_title>Intrathecal Tetanus Immunoglobulin to Treat Tetanus</brief_title>
  <acronym>ITITTT</acronym>
  <official_title>Intrathecal Immunoglobulin for Treatment of Adult Patients With Tetanus: a Randomized Controlled 2x2 Factorial Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Oxford University Clinical Research Unit, Vietnam</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Oxford University Clinical Research Unit, Vietnam</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      To establish whether the addition of intrathecal tetanus antitoxin reduces the need for&#xD;
      mechanical ventilation in patients with tetanus&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The investigators will conduct a randomised partially-blinded controlled 2x2 factorial trial.&#xD;
      First, adults admitted to the Intensive Care Unit at the Hospital for Tropical Diseases Ho&#xD;
      Chi Minh City will be randomized to receive either human (3000 IU) or equine (21,000 units)&#xD;
      intramuscular antitoxin. Second, participants will be randomized to receive either standard&#xD;
      treatment with intramuscular antitoxin alone or with the addition of 500 IU intrathecal human&#xD;
      antitoxin. Patients with prior antitoxin treatment and those with contra-indications to&#xD;
      lumbar puncture or antitoxin treatment will be excluded.&#xD;
&#xD;
      All patients will receive other standard tetanus treatment as deemed necessary by the&#xD;
      attending physicians. Spasms will be treated with benzodiazepines as first-line therapy.&#xD;
      Patients with spasms not controlled with benzodiazepines will receive tracheostomy,&#xD;
      paralysis, magnesium sulphate and mechanical ventilation. Heart rate, BP, temperature and&#xD;
      daily drug use will be recorded throughout the ICU stay. Patients will be followed following&#xD;
      discharge from hospital until 240 days for disability/ death.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 13, 2017</start_date>
  <completion_date type="Actual">May 1, 2020</completion_date>
  <primary_completion_date type="Actual">December 31, 2019</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Factorial Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Requirement for mechanical ventilation during ICU stay</measure>
    <time_frame>During ICU stay, an average of 3 weeks</time_frame>
    <description>Criteria for mechanical ventilation are oxygen saturation (SpO2) &lt;90%; or partial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2) &lt;250; or excessive spasms necessitating muscle paralysis.&#xD;
These criteria are intended as a guide and the final decision to ventilate a patient rests with the individual doctor responsible for the patient.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Duration of ICU stay</measure>
    <time_frame>During ICU stay, an average of 3 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of hospital stay</measure>
    <time_frame>During hospital stay, an average of 5 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of mechanical ventilation</measure>
    <time_frame>During hospital stay, an average of 5 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>In hospital and 240 day mortality</measure>
    <time_frame>240 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>In hospital and 240 day disability</measure>
    <time_frame>240 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>New antibiotic prescription during ICU stay</measure>
    <time_frame>During ICU stay, an average of 3 weeks</time_frame>
    <description>New antibiotic prescription during ICU stay (excluding antibiotics for tetanus or initial entry site infection)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of Ventilator Associated Pneumonia</measure>
    <time_frame>During hospital stay, an average of 5 weeks</time_frame>
    <description>Definition of Ventilator associated pneumonia (VAP):&#xD;
Mechanical ventilation for at least 48 hours and with the tube in place within the last 48 hours and 2 of:&#xD;
Temperature &gt; 38°C or &lt; 36°C&#xD;
White blood cell count &lt;4.0 x 109/L or ≥12 x 109/L&#xD;
Purulent respiratory secretions&#xD;
New or progressive changes on chest radiography (for VAP) Plus for microbiologically confirmed VAP&#xD;
Bacterial growth of ≥105 cfu/ml from endotracheal aspirate (ETA) (or ≥104 cfu/ml from Broncho Alveolar Lavage (BAL))</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of clinical syndrome of autonomic nervous system dysfunction</measure>
    <time_frame>240 days</time_frame>
    <description>At least 3 of the following criteria:&#xD;
Tachycardia Heart Rate (HR)&gt; 100 bpm&#xD;
Hypertension Systolic Blood Pressure (SBP) &gt; 140 mmHg&#xD;
Hypotension Mean Arterial Pressure (MAP) &lt; 60 mmHg&#xD;
Pyrexia &gt; 38°C&#xD;
Alteration between hypertension and hypotension</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total dose of benzodiazepines and pipecuronium during hospital stay</measure>
    <time_frame>During hospital stay, an average of 5 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of adverse events</measure>
    <time_frame>During hospital stay, an average of 5 weeks</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">272</enrollment>
  <condition>Tetanus</condition>
  <arm_group>
    <arm_group_label>Human tetanus immunoglobulin</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Human tetanus immunoglobulin (Tetagam-P): Injection (prefilled syringe) 250 IU in 1 ml - Intrathecal 500 IU</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Intramuscular antitoxin</arm_group_label>
    <arm_group_type>Sham Comparator</arm_group_type>
    <description>Human tetanus immunoglobulin (Tetagam-P): Injection (prefilled syringe) 250 IU in 1 ml - Intramuscular 3000 IU OR Equine antiserum - 21,000 units</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Human tetanus immunoglobulin</intervention_name>
    <description>Adults admitted to ICU at Hospital for Tropical Diseases will be randomized to receive either human (3000 IU) or equine (21,000 units) intramuscular antitoxin. Second, participants will be randomized to receive the addition of 500 IU intrathecal human antitoxin.</description>
    <arm_group_label>Human tetanus immunoglobulin</arm_group_label>
    <arm_group_label>Intramuscular antitoxin</arm_group_label>
    <other_name>Human tetanus immunoglobulin (Tetagam-P)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Intramuscular antitoxin</intervention_name>
    <description>First, adults admitted to ICU at Hospital for Tropical Diseases will be randomized to receive either human (3000 IU) or equine (21,000 units) intramuscular antitoxin including a 0.05ml test dose (ie 75 units equine antitoxin or 12.5 IU human antitoxin). Second, participants will be randomized with sham procedure</description>
    <arm_group_label>Intramuscular antitoxin</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  All adult patients (≥16 years old) with a clinical diagnosis of generalized tetanus&#xD;
             admitted to the intensive care unit (ICU) at the Hospital for Tropical Diseases, Ho&#xD;
             Chi Minh City, Vietnam&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior administration of antitoxin during this episode&#xD;
&#xD;
          -  Contra-indication to use of human or equine antitoxin&#xD;
&#xD;
          -  Contra-indication to lumbar puncture&#xD;
&#xD;
          -  Already receiving mechanical ventilation or expected to require this before&#xD;
             intrathecal injection can be given&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Informed consent not obtained&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>16 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Minh Yen Lam, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Oxford University Clinical Research Unit</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hospital for Tropical Diseases</name>
      <address>
        <city>Ho Chi Minh</city>
        <zip>700000</zip>
        <country>Vietnam</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Vietnam</country>
  </location_countries>
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  <reference>
    <citation>Ahmad A, Qaisar I, Naeem M, Mazhar AU, Ashfaq M. Intrathecal anti-tetanus human immunoglobulin in the treatment of neonatal tetanus. J Coll Physicians Surg Pak. 2011 Sep;21(9):539-41.</citation>
    <PMID>21914410</PMID>
  </reference>
  <reference>
    <citation>Mongi PS, Mbise RL, Msengi AE, Do Amsi DM. Tetanus neonatorum--experience with intrathecal serotherapy at Muhimbili Medical Centre, Dar es Salaam, Tanzania. Ann Trop Paediatr. 1987 Mar;7(1):27-31. doi: 10.1080/02724936.1987.11748469.</citation>
    <PMID>2439000</PMID>
  </reference>
  <reference>
    <citation>Rowbotham MC. Pain's policy on the spinal administration of drugs. Pain. 2010 Jun;149(3):415-416. doi: 10.1016/j.pain.2010.02.027. Epub 2010 Mar 3. No abstract available.</citation>
    <PMID>20202752</PMID>
  </reference>
  <reference>
    <citation>Eisenach JC, Shafer SL, Yaksh T. The need for a journal policy on intrathecal, epidural, and perineural administration of non-approved drugs. Pain. 2010 Jun;149(3):417-419. doi: 10.1016/j.pain.2010.02.028. Epub 2010 Mar 15. No abstract available.</citation>
    <PMID>20227830</PMID>
  </reference>
  <reference>
    <citation>Geeta MG, Krishnakumar P, Mathews L. Intrathecal tetanus immunoglobulins in the management of tetanus. Indian J Pediatr. 2007 Jan;74(1):43-5. doi: 10.1007/s12098-007-0025-y.</citation>
    <PMID>17264452</PMID>
  </reference>
  <reference>
    <citation>Turillazzi E, Neri M, Pomara C, Riezzo I, Fineschi V. An immunohistochemical study on a tetanus fatal case using toxin fragment C (TTC). Should it be a useful diagnostic tool? Neuropathology. 2009 Feb;29(1):68-71. doi: 10.1111/j.1440-1789.2008.00912.x. Epub 2008 Apr 15.</citation>
    <PMID>18422910</PMID>
  </reference>
  <verification_date>May 2020</verification_date>
  <study_first_submitted>December 14, 2016</study_first_submitted>
  <study_first_submitted_qc>December 18, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 21, 2016</study_first_posted>
  <last_update_submitted>May 28, 2020</last_update_submitted>
  <last_update_submitted_qc>May 28, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">May 29, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Tetanus</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tetanus</mesh_term>
    <mesh_term>Tetany</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Immunoglobulins</mesh_term>
    <mesh_term>Immunoglobulins, Intravenous</mesh_term>
    <mesh_term>Antibodies</mesh_term>
    <mesh_term>Antitoxins</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT02999815
org study id: 03TS
nct id: NCT02999815
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
To establish whether the addition of intrathecal tetanus antitoxin reduces the need for
      mechanical ventilation in patients with tetanus
The investigators will conduct a randomised partially-blinded controlled 2x2 factorial trial.
      First, adults admitted to the Intensive Care Unit at the Hospital for Tropical Diseases Ho
      Chi Minh City will be randomized to receive either human (3000 IU) or equine (21,000 units)
      intramuscular antitoxin. Second, participants will be randomized to receive either standard
      treatment with intramuscular antitoxin alone or with the addition of 500 IU intrathecal human
      antitoxin. Patients with prior antitoxin treatment and those with contra-indications to
      lumbar puncture or antitoxin treatment will be excluded.

      All patients will receive other standard tetanus treatment as deemed necessary by the
      attending physicians. Spasms will be treated with benzodiazepines as first-line therapy.
      Patients with spasms not controlled with benzodiazepines will receive tracheostomy,
      paralysis, magnesium sulphate and mechanical ventilation. Heart rate, BP, temperature and
      daily drug use will be recorded throughout the ICU stay. Patients will be followed following
      discharge from hospital until 240 days for disability/ death.
allocation: Randomized
intervention model: Factorial Assignment
primary purpose: Treatment
masking: Double (Care Provider, Investigator)
measure: Requirement for mechanical ventilation during ICU stay
time frame: During ICU stay, an average of 3 weeks
description: Criteria for mechanical ventilation are oxygen saturation (SpO2) <90%; or partial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2) <250; or excessive spasms necessitating muscle paralysis.
These criteria are intended as a guide and the final decision to ventilate a patient rests with the individual doctor responsible for the patient.
measure: Duration of ICU stay
time frame: During ICU stay, an average of 3 weeks
measure: Duration of hospital stay
time frame: During hospital stay, an average of 5 weeks
measure: Duration of mechanical ventilation
time frame: During hospital stay, an average of 5 weeks
measure: In hospital and 240 day mortality
time frame: 240 days
measure: In hospital and 240 day disability
time frame: 240 days
measure: New antibiotic prescription during ICU stay
time frame: During ICU stay, an average of 3 weeks
description: New antibiotic prescription during ICU stay (excluding antibiotics for tetanus or initial entry site infection)
measure: Incidence of Ventilator Associated Pneumonia
time frame: During hospital stay, an average of 5 weeks
description: Definition of Ventilator associated pneumonia (VAP):
Mechanical ventilation for at least 48 hours and with the tube in place within the last 48 hours and 2 of:
Temperature > 38°C or < 36°C
White blood cell count <4.0 x 109/L or ≥12 x 109/L
Purulent respiratory secretions
New or progressive changes on chest radiography (for VAP) Plus for microbiologically confirmed VAP
Bacterial growth of ≥105 cfu/ml from endotracheal aspirate (ETA) (or ≥104 cfu/ml from Broncho Alveolar Lavage (BAL))
measure: Incidence of clinical syndrome of autonomic nervous system dysfunction
time frame: 240 days
description: At least 3 of the following criteria:
Tachycardia Heart Rate (HR)> 100 bpm
Hypertension Systolic Blood Pressure (SBP) > 140 mmHg
Hypotension Mean Arterial Pressure (MAP) < 60 mmHg
Pyrexia > 38°C
Alteration between hypertension and hypotension
measure: Total dose of benzodiazepines and pipecuronium during hospital stay
time frame: During hospital stay, an average of 5 weeks
measure: Incidence of adverse events
time frame: During hospital stay, an average of 5 weeks
arm group label: Human tetanus immunoglobulin
arm group type: Active Comparator
description: Human tetanus immunoglobulin (Tetagam-P): Injection (prefilled syringe) 250 IU in 1 ml - Intrathecal 500 IU
arm group label: Intramuscular antitoxin
arm group type: Sham Comparator
description: Human tetanus immunoglobulin (Tetagam-P): Injection (prefilled syringe) 250 IU in 1 ml - Intramuscular 3000 IU OR Equine antiserum - 21,000 units
intervention type: Procedure
intervention name: Human tetanus immunoglobulin
description: Adults admitted to ICU at Hospital for Tropical Diseases will be randomized to receive either human (3000 IU) or equine (21,000 units) intramuscular antitoxin. Second, participants will be randomized to receive the addition of 500 IU intrathecal human antitoxin.
arm group label: Human tetanus immunoglobulin
arm group label: Intramuscular antitoxin
other name: Human tetanus immunoglobulin (Tetagam-P)
intervention type: Procedure
intervention name: Intramuscular antitoxin
description: First, adults admitted to ICU at Hospital for Tropical Diseases will be randomized to receive either human (3000 IU) or equine (21,000 units) intramuscular antitoxin including a 0.05ml test dose (ie 75 units equine antitoxin or 12.5 IU human antitoxin). Second, participants will be randomized with sham procedure
arm group label: Intramuscular antitoxin
criteria: 
gender: All
minimum age: 16 Years
maximum age: N/A
healthy volunteers: No
last name: Minh Yen Lam, MD
role: Principal Investigator
affiliation: Oxford University Clinical Research Unit
facility: 
country: Vietnam
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citation: Ahmad A, Qaisar I, Naeem M, Mazhar AU, Ashfaq M. Intrathecal anti-tetanus human immunoglobulin in the treatment of neonatal tetanus. J Coll Physicians Surg Pak. 2011 Sep;21(9):539-41.
PMID: 21914410
citation: Mongi PS, Mbise RL, Msengi AE, Do Amsi DM. Tetanus neonatorum--experience with intrathecal serotherapy at Muhimbili Medical Centre, Dar es Salaam, Tanzania. Ann Trop Paediatr. 1987 Mar;7(1):27-31. doi: 10.1080/02724936.1987.11748469.
PMID: 2439000
citation: Rowbotham MC. Pain's policy on the spinal administration of drugs. Pain. 2010 Jun;149(3):415-416. doi: 10.1016/j.pain.2010.02.027. Epub 2010 Mar 3. No abstract available.
PMID: 20202752
citation: Eisenach JC, Shafer SL, Yaksh T. The need for a journal policy on intrathecal, epidural, and perineural administration of non-approved drugs. Pain. 2010 Jun;149(3):417-419. doi: 10.1016/j.pain.2010.02.028. Epub 2010 Mar 15. No abstract available.
PMID: 20227830
citation: Geeta MG, Krishnakumar P, Mathews L. Intrathecal tetanus immunoglobulins in the management of tetanus. Indian J Pediatr. 2007 Jan;74(1):43-5. doi: 10.1007/s12098-007-0025-y.
PMID: 17264452
citation: Turillazzi E, Neri M, Pomara C, Riezzo I, Fineschi V. An immunohistochemical study on a tetanus fatal case using toxin fragment C (TTC). Should it be a useful diagnostic tool? Neuropathology. 2009 Feb;29(1):68-71. doi: 10.1111/j.1440-1789.2008.00912.x. Epub 2008 Apr 15.
PMID: 18422910
responsible party type: Sponsor
mesh term: Tetanus
mesh term: Tetany
mesh term: Immunoglobulins
mesh term: Immunoglobulins, Intravenous
mesh term: Antibodies
mesh term: Antitoxins
sharing ipd: Undecided