<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/NCT03278483</url>
  </required_header>
  <id_info>
    <org_study_id>1341</org_study_id>
    <nct_id>NCT03278483</nct_id>
  </id_info>
  <brief_title>Efficacy, Security, Adherence, Tolerability and Cost Effectiveness of Latent TB Treatment in Patients With TB/DM2 (TBL)</brief_title>
  <acronym>TBL</acronym>
  <official_title>Efficacy, Security, Adherence, Tolerability and Cost Effectiveness of Latent TB Treatment in Patients With TB/DM2</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Instituto Nacional de Salud Publica, Mexico</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Instituto Nacional de Enfermedades Respiratorias</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Instituto Nacional de Ciencias Medicas y Nutrición</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Instituto Nacional de Salud Publica, Mexico</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>
      Researchers will evaluate the efficacy, toxicity, adherence and cost effectiveness of&#xD;
      treatment with isoniazid or rifampicin in patients with diabetes mellitus type two (DM2) and&#xD;
      latent TB (LTB).&#xD;
&#xD;
      This is a collaborative study with participation from three national institutes (Instituto&#xD;
      Nacional de Salud Pública (INSP), Instituto Nacional de Enfermedades Respiratorias (INER) and&#xD;
      the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubiran (INCMNSZ)).&#xD;
&#xD;
      The study will take place in the VII sanitary jurisdiction of Orizaba and the INCMNSZ that&#xD;
      has the necessary infrastructure and human resources. Researchers will evaluate 3000 patients&#xD;
      with diabetes using a standardized questionnaire and a tuberculin skin test (TST) test.&#xD;
      Eligible patients will be invited to participate and from those that agree to participate and&#xD;
      sign a written informed consent we will obtain clinical, epidemiological, nutritional and&#xD;
      metabolic information. Patients with altered liver function tests will be excluded.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study is a randomized control trial, with two parallel arms, fixed assignment, fixed&#xD;
      sample size and in two study sites. Participants will be assigned 1:1 to receive one of the&#xD;
      two treatment regimens: isoniazid for 6 months or rifampicin for 3 months. The assignment&#xD;
      will be fixed because the covariates that predict the clinical outcome and the accumulated&#xD;
      outcome of participants will not affect treatment assignment. In patients that the Michigan&#xD;
      evaluation identifies as having neuropathic changes researchers will perform an&#xD;
      electroneurography in order to identify the degree of neuropathy if any. This will be&#xD;
      performed in the neurophysiology lab of the INCMNSZ. An independent comity will monitor&#xD;
      adverse events.&#xD;
&#xD;
      Sample size It is necessary to include 193 participants, for each arm; this includes a 20%&#xD;
      increase to compensate loss during follow up. This will provide a power equal or higher than&#xD;
      80% considering an alpha of 0.05 (.25 at two tails) in order to answer to each one of the&#xD;
      following objectives.&#xD;
&#xD;
      Latent tuberculosis treatment with isoniazid is the gold standard and given its efficacy it&#xD;
      would not be ethical to propose a placebo group. Researchers hypothesize that treatment with&#xD;
      rifampicin will not be inferior in efficacy (measured using the response of biomarkers) and&#xD;
      will be equivalent in toxicity to that observed with isoniazid treatment.&#xD;
&#xD;
      Subjects will be asked to attend on the 15th and 30th of the month and then once a month till&#xD;
      the end of treatment. In case a patient does not assist, researchers will carry out a home&#xD;
      visit.&#xD;
&#xD;
      Clinical, microbiological and metabolic evaluation&#xD;
&#xD;
      Researchers will apply a validated questionnaire that explores sociodemographic,&#xD;
      epidemiological and clinical information as well as a questionnaire developed by the&#xD;
      researchers that captures information of DM2 long term complications. The Michigan&#xD;
      questionnaire will be applied using the NCI-CTC scale in version 3 for neuropathic symptoms&#xD;
      as well as an evaluation with a Semmes-Weinstein monofilament of 5.07/10gr in 4 points of the&#xD;
      sole of each foot:&#xD;
&#xD;
        -  Distal phalange of the 1st toe, base of the 1st metatarsal and base of the 3rd&#xD;
           metatarsal&#xD;
&#xD;
        -  Base of the 5th metatarsal In a subsample researchers will carry out an&#xD;
           electroneurography study in order to measure and document the level of likely damage as&#xD;
           an adverse event.&#xD;
&#xD;
      Tuberculin Skin Test (TST) In patients with DM2 researchers will apply TST using the Mantoux&#xD;
      technique. Reactivity will be measured with the diameter of the induration at 48 and 72&#xD;
      hours. Patients with a TST&gt;10mm will be randomized to the trail.&#xD;
&#xD;
      Chest X ray All patients with a positive TST will have a chest X ray taken which will be&#xD;
      evaluated by a pulmonologist in order to exclude millar TB.&#xD;
&#xD;
      All patients will be tested for hematic cytology, glucose, glycosylated hemoglobin, and&#xD;
      creatinine and liver tests. All lab tests will be carried out using standardized methods that&#xD;
      are commercially available.&#xD;
&#xD;
      All documentation of clinical evaluations will be included in the patient's medical chart.&#xD;
      These will be safeguarded by the main researcher and confidentiality will be protected at all&#xD;
      times.&#xD;
&#xD;
      TB tests During follow up respiratory symptoms will be evaluated. Patients with respiratory&#xD;
      symptoms of more than 2 weeks will be asked to give 3 sputum samples in order to analyze for&#xD;
      acid fast bacilli (AFB) and Mycobacterium tuberculosis (MTB) culture using standardized&#xD;
      methods.&#xD;
&#xD;
      All samples will be identified with a code that links the sample with clinical and&#xD;
      epidemiological data. Researchers have established a system that prevents unauthorized people&#xD;
      from accessing the samples and personal data.&#xD;
&#xD;
      Field work Personnel have been trained in the good clinical practice course which Works very&#xD;
      closely with the health centers. Activities are monitored by supervisors that have been&#xD;
      trained to insure the coordination of activities and quality control.&#xD;
&#xD;
      Independent comity for monitoring adverse events For this study researchers will integrate an&#xD;
      independent comity to monitor adverse events, which will revise all adverse events and will&#xD;
      give follow up.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 28, 2019</start_date>
  <completion_date type="Actual">February 28, 2019</completion_date>
  <primary_completion_date type="Actual">February 28, 2019</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Arm Isoniacid Diabetic patients with a positive TST of &gt;10mm, who wil be randomly assigned to receive treatment with isoniazid tablets 300mg daily plus pyridoxine 50mg daily&#xD;
Arm B Diabetic patients with a positive TST of &gt;10mm, who wil be randomly assigned to receive treatment with rifampin capsules 600mg daily</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Efficacy of treatment with rifampicin compared to efficacy of treatment with isoniazid</measure>
    <time_frame>Up to 18 months</time_frame>
    <description>Researchers will measure with ELISA in vitro production of interferon gamma of peripheric mononuclear cels as a response to stimuli by RV0849 and RV1737 antigens. The cut of value is of &gt;100pg/ml.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Toxicity (neuropathy)</measure>
    <time_frame>Up to 6 months</time_frame>
    <description>Neurological alterations will be assessed using the Michigan questionnaire and in a subsample they will evaluate neuropathy using electroneurography.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Adherence</measure>
    <time_frame>Up to 6 months</time_frame>
    <description>Counting the number of administered pills, adequate adherence is more than 80% of administered pills.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Toxicity (liver function)</measure>
    <time_frame>Up to 6 months</time_frame>
    <description>Liver function tests</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">396</enrollment>
  <condition>Diabetes Mellitus</condition>
  <condition>Tuberculin (Skin Test) Positive</condition>
  <arm_group>
    <arm_group_label>Isoniazid</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Diabetic patients with a positive TST of &gt;10mm, will be randomly assigned to receive treatment with isoniazid 300mg Oral Tablet daily plus pyridoxine 50mg daily for six months</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Rifampin</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Diabetic patients with a positive TST of &gt;10mm, who wil be randomly assigned to receive treatment with rifampin 600mg Oral Tablets daily for three months</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Isoniazid 300 mg Oral Tablet</intervention_name>
    <description>Isoniazid tablets 300mg daily plus pyridoxine 50mg daily</description>
    <arm_group_label>Isoniazid</arm_group_label>
    <other_name>Isonicotinic acid</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rifampin 600 mg Oral Tablet</intervention_name>
    <description>Rifampin capsules 600mg daily</description>
    <arm_group_label>Rifampin</arm_group_label>
    <other_name>Rifadin</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Type 2 diabetes mellitus (DM2) diagnosed based on the National Official Norm&#xD;
&#xD;
          2. respiratory symptoms&#xD;
&#xD;
          3. Tuberculin Skin Test (TST) &gt;10mm of induration&#xD;
&#xD;
          4. chest X ray without pleural, lung or mediastinal lesions&#xD;
&#xD;
          5. hemoglobin &lt; 8 gm/dl&#xD;
&#xD;
          6. platelets &gt; 60,000 per microliter&#xD;
&#xD;
          7. bilirubin &lt; 2.5 mg/dl&#xD;
&#xD;
          8. Aspartate aminotransferase (AST) , Glutamic oxalacetic transaminases (SGOT) and&#xD;
             alkaline phosphatase less than twice the normal value&#xD;
&#xD;
          9. negative pregnancy test&#xD;
&#xD;
         10. negative Human immunodeficiency virus infection test (HIV test)&#xD;
&#xD;
         11. signed written informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Attending selected cites&#xD;
&#xD;
          2. Respiratory symptoms defined as cough with or without sputum for more than 2 weeks&#xD;
&#xD;
          3. Evidence or clinical suspicion of active tuberculosis (TB)&#xD;
&#xD;
          4. Current treatment with antituberculous drugs&#xD;
&#xD;
          5. History of having received more than one month's treatment for latent Tuberculosis&#xD;
             (LTB) or antituberculous drugs&#xD;
&#xD;
          6. Hypersensitivity or intolerance to isoniazid or rifampicin&#xD;
&#xD;
          7. Active hepatopathy&#xD;
&#xD;
          8. Grade III or higher peripheral neuropathy&#xD;
&#xD;
          9. Chronic alcohol ingestion&#xD;
&#xD;
         10. Contacts of patients with isoniazid or rifampicin drug resistance&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jose JS Sifuentes -Osornio, Dr</last_name>
    <role>Principal Investigator</role>
    <affiliation>Instituto Nacional de Ciencias Médcias y Nutrición</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Martha MT Torres-Rojas, DCs</last_name>
    <role>Principal Investigator</role>
    <affiliation>Instituto Nacional de Enfermedades Respiratorias</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Instituto Nacional de Ciencias Medicas y Nutrición</name>
      <address>
        <city>Mexico City</city>
        <zip>14000</zip>
        <country>Mexico</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Mexico</country>
  </location_countries>
  <results_reference>
    <citation>Torres M, Garcia-Garcia L, Cruz-Hervert P, Guio H, Carranza C, Ferreyra-Reyes L, Canizales S, Molina S, Ferreira-Guerrero E, Tellez N, Montero-Campos R, Delgado-Sanchez G, Mongua-Rodriguez N, Sifuentes-Osornio J, Ponce-de Leon A, Sada E, Young DB, Wilkinson RJ. Effect of isoniazid on antigen-specific interferon-gamma secretion in latent tuberculosis. Eur Respir J. 2015 Feb;45(2):473-82. doi: 10.1183/09031936.00123314. Epub 2014 Oct 30.</citation>
    <PMID>25359354</PMID>
  </results_reference>
  <verification_date>April 2019</verification_date>
  <study_first_submitted>August 7, 2017</study_first_submitted>
  <study_first_submitted_qc>September 7, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 11, 2017</study_first_posted>
  <last_update_submitted>April 25, 2019</last_update_submitted>
  <last_update_submitted_qc>April 25, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">April 26, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Instituto Nacional de Salud Publica, Mexico</investigator_affiliation>
    <investigator_full_name>Ma. de Lourdes Garcia Garcia</investigator_full_name>
    <investigator_title>Director of prevention of infectious diseases</investigator_title>
  </responsible_party>
  <keyword>Latent tuberculosis, ,</keyword>
  <keyword>isoniazid, rifampin,</keyword>
  <keyword>rifampin,</keyword>
  <keyword>adverse,</keyword>
  <keyword>diabetes mellitus</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Diabetes Mellitus</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rifampin</mesh_term>
    <mesh_term>Isoniazid</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/NCT03278483
org study id: 1341
nct id: NCT03278483
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
Researchers will evaluate the efficacy, toxicity, adherence and cost effectiveness of
      treatment with isoniazid or rifampicin in patients with diabetes mellitus type two (DM2) and
      latent TB (LTB).

      This is a collaborative study with participation from three national institutes (Instituto
      Nacional de Salud Pública (INSP), Instituto Nacional de Enfermedades Respiratorias (INER) and
      the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubiran (INCMNSZ)).

      The study will take place in the VII sanitary jurisdiction of Orizaba and the INCMNSZ that
      has the necessary infrastructure and human resources. Researchers will evaluate 3000 patients
      with diabetes using a standardized questionnaire and a tuberculin skin test (TST) test.
      Eligible patients will be invited to participate and from those that agree to participate and
      sign a written informed consent we will obtain clinical, epidemiological, nutritional and
      metabolic information. Patients with altered liver function tests will be excluded.
This study is a randomized control trial, with two parallel arms, fixed assignment, fixed
      sample size and in two study sites. Participants will be assigned 1:1 to receive one of the
      two treatment regimens: isoniazid for 6 months or rifampicin for 3 months. The assignment
      will be fixed because the covariates that predict the clinical outcome and the accumulated
      outcome of participants will not affect treatment assignment. In patients that the Michigan
      evaluation identifies as having neuropathic changes researchers will perform an
      electroneurography in order to identify the degree of neuropathy if any. This will be
      performed in the neurophysiology lab of the INCMNSZ. An independent comity will monitor
      adverse events.

      Sample size It is necessary to include 193 participants, for each arm; this includes a 20%
      increase to compensate loss during follow up. This will provide a power equal or higher than
      80% considering an alpha of 0.05 (.25 at two tails) in order to answer to each one of the
      following objectives.

      Latent tuberculosis treatment with isoniazid is the gold standard and given its efficacy it
      would not be ethical to propose a placebo group. Researchers hypothesize that treatment with
      rifampicin will not be inferior in efficacy (measured using the response of biomarkers) and
      will be equivalent in toxicity to that observed with isoniazid treatment.

      Subjects will be asked to attend on the 15th and 30th of the month and then once a month till
      the end of treatment. In case a patient does not assist, researchers will carry out a home
      visit.

      Clinical, microbiological and metabolic evaluation

      Researchers will apply a validated questionnaire that explores sociodemographic,
      epidemiological and clinical information as well as a questionnaire developed by the
      researchers that captures information of DM2 long term complications. The Michigan
      questionnaire will be applied using the NCI-CTC scale in version 3 for neuropathic symptoms
      as well as an evaluation with a Semmes-Weinstein monofilament of 5.07/10gr in 4 points of the
      sole of each foot:

        -  Distal phalange of the 1st toe, base of the 1st metatarsal and base of the 3rd
           metatarsal

        -  Base of the 5th metatarsal In a subsample researchers will carry out an
           electroneurography study in order to measure and document the level of likely damage as
           an adverse event.

      Tuberculin Skin Test (TST) In patients with DM2 researchers will apply TST using the Mantoux
      technique. Reactivity will be measured with the diameter of the induration at 48 and 72
      hours. Patients with a TST>10mm will be randomized to the trail.

      Chest X ray All patients with a positive TST will have a chest X ray taken which will be
      evaluated by a pulmonologist in order to exclude millar TB.

      All patients will be tested for hematic cytology, glucose, glycosylated hemoglobin, and
      creatinine and liver tests. All lab tests will be carried out using standardized methods that
      are commercially available.

      All documentation of clinical evaluations will be included in the patient's medical chart.
      These will be safeguarded by the main researcher and confidentiality will be protected at all
      times.

      TB tests During follow up respiratory symptoms will be evaluated. Patients with respiratory
      symptoms of more than 2 weeks will be asked to give 3 sputum samples in order to analyze for
      acid fast bacilli (AFB) and Mycobacterium tuberculosis (MTB) culture using standardized
      methods.

      All samples will be identified with a code that links the sample with clinical and
      epidemiological data. Researchers have established a system that prevents unauthorized people
      from accessing the samples and personal data.

      Field work Personnel have been trained in the good clinical practice course which Works very
      closely with the health centers. Activities are monitored by supervisors that have been
      trained to insure the coordination of activities and quality control.

      Independent comity for monitoring adverse events For this study researchers will integrate an
      independent comity to monitor adverse events, which will revise all adverse events and will
      give follow up.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Arm Isoniacid Diabetic patients with a positive TST of >10mm, who wil be randomly assigned to receive treatment with isoniazid tablets 300mg daily plus pyridoxine 50mg daily
Arm B Diabetic patients with a positive TST of >10mm, who wil be randomly assigned to receive treatment with rifampin capsules 600mg daily
primary purpose: Treatment
masking: None (Open Label)
measure: Efficacy of treatment with rifampicin compared to efficacy of treatment with isoniazid
time frame: Up to 18 months
description: Researchers will measure with ELISA in vitro production of interferon gamma of peripheric mononuclear cels as a response to stimuli by RV0849 and RV1737 antigens. The cut of value is of >100pg/ml.
measure: Toxicity (neuropathy)
time frame: Up to 6 months
description: Neurological alterations will be assessed using the Michigan questionnaire and in a subsample they will evaluate neuropathy using electroneurography.
measure: Adherence
time frame: Up to 6 months
description: Counting the number of administered pills, adequate adherence is more than 80% of administered pills.
measure: Toxicity (liver function)
time frame: Up to 6 months
description: Liver function tests
arm group label: Isoniazid
arm group type: Active Comparator
description: Diabetic patients with a positive TST of >10mm, will be randomly assigned to receive treatment with isoniazid 300mg Oral Tablet daily plus pyridoxine 50mg daily for six months
arm group label: Rifampin
arm group type: Active Comparator
description: Diabetic patients with a positive TST of >10mm, who wil be randomly assigned to receive treatment with rifampin 600mg Oral Tablets daily for three months
intervention type: Drug
intervention name: Isoniazid 300 mg Oral Tablet
description: Isoniazid tablets 300mg daily plus pyridoxine 50mg daily
arm group label: Isoniazid
other name: Isonicotinic acid
intervention type: Drug
intervention name: Rifampin 600 mg Oral Tablet
description: Rifampin capsules 600mg daily
arm group label: Rifampin
other name: Rifadin
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Jose JS Sifuentes -Osornio, Dr
role: Principal Investigator
affiliation: Instituto Nacional de Ciencias Médcias y Nutrición
last name: Martha MT Torres-Rojas, DCs
role: Principal Investigator
affiliation: Instituto Nacional de Enfermedades Respiratorias
facility: 
country: Mexico
citation: Torres M, Garcia-Garcia L, Cruz-Hervert P, Guio H, Carranza C, Ferreyra-Reyes L, Canizales S, Molina S, Ferreira-Guerrero E, Tellez N, Montero-Campos R, Delgado-Sanchez G, Mongua-Rodriguez N, Sifuentes-Osornio J, Ponce-de Leon A, Sada E, Young DB, Wilkinson RJ. Effect of isoniazid on antigen-specific interferon-gamma secretion in latent tuberculosis. Eur Respir J. 2015 Feb;45(2):473-82. doi: 10.1183/09031936.00123314. Epub 2014 Oct 30.
PMID: 25359354
responsible party type: Principal Investigator
investigator affiliation: Instituto Nacional de Salud Publica, Mexico
investigator full name: Ma. de Lourdes Garcia Garcia
investigator title: Director of prevention of infectious diseases
mesh term: Diabetes Mellitus
mesh term: Rifampin
mesh term: Isoniazid