<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/NCT03281226</url>
  </required_header>
  <id_info>
    <org_study_id>CAAE: 60219916.5.0000.0005</org_study_id>
    <nct_id>NCT03281226</nct_id>
  </id_info>
  <brief_title>RIPE vs RIPE Plus N-acetylcysteine in Patients With HIV/TB Co-infection</brief_title>
  <acronym>RIPENACTB</acronym>
  <official_title>An Open Label Randomized Phase 2 Clinical Trial to Assess Safety and Tolerability of RIPE vs RIPE Plus N-acetylcysteine in Patients With HIV/Aids and Pulmonary Tuberculosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Fundação de Medicina Tropical Dr. Heitor Vieira Dourado</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Fundação de Medicina Tropical Dr. Heitor Vieira Dourado</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>
      Although tuberculosis is a treatable disease, it is currently the infectious disease with the&#xD;
      highest mortality in the world. It is estimated that one-third of the world's population is&#xD;
      infected. HIV is the main predisposing factor for TB development. The Brazilian Ministry of&#xD;
      Health and the World Health Organization recommends that patients should initially be treated&#xD;
      orally with RIPE - rifampicin (R), isoniazid (I), pyrazinamide (P) and ethambutol (E). The&#xD;
      N-acetylcysteine (NAC) first benefit was reported during the 1960s, when it proved to be an&#xD;
      effective mucolytic agent in individuals with cystic fibrosis. Later, a new role arose when&#xD;
      investigating its therapeutic potential in acetaminophen intoxication. Cleavage of the acetyl&#xD;
      group makes cysteine available for later incorporation into glutathione synthesis, decreased&#xD;
      in hepatic injury caused by acetaminophen. This mechanism causes NAC to have an indirect&#xD;
      antioxidant effect, which aroused an interest in studying the effect in diseases that occur&#xD;
      with oxidative stress. TB and HIV/Aids are also diseases with chronic inflammation. The&#xD;
      present study aims to evaluate the effects of NAC as a adjuvant therapy in the treatment of&#xD;
      TB. This is a phase II randomized clinical trial in which the safety and tolerability of NAC&#xD;
      as adjunctive therapy for TB treatment will be assessed. Fifty-six patients will be&#xD;
      randomized into two groups. The first group will receive the standard tuberculosis treatment&#xD;
      as recommended by the Brazilian Ministry of Health (RIPE); the second will receive in&#xD;
      addition to this treatment 1200mg of NAC per day for two months. In this way, microscopy and&#xD;
      culture conversion rate to mycobacteria at 8 weeks, levels of glutathione and biomarkers of&#xD;
      immune activation and inflammation in case of TB with or without NAC will be monitored.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      TB and AIDS are also diseases that occur with a chronic inflammatory stimulus, with constant&#xD;
      formation of excessive free radicals, leading to cellular and systemic oxidative stress. The&#xD;
      effects of NAC in both populations are studied. A study demonstrated that HIV-positive&#xD;
      individuals have low levels of glutathione in CD4+ T lymphocytes when compared to healthy&#xD;
      controls, these levels being restored after in vivo supplementation with NAC, favoring the&#xD;
      production of cytokines involved in Th1 response. They also observed that glutathione&#xD;
      depletion in lymphocytes was correlated with increased levels of tumor necrosis factor and&#xD;
      free radicals. Some authors suggested that the immune system's inability of HIV-positive&#xD;
      individuals (or not) in containing Mycobaterium tuberculosis (Mtb) may be a consequence of&#xD;
      low levels of glutathione in macrophages. The same occurred in a model of animals infected&#xD;
      with Mtb, suggesting that oxidative stress was partly due to the poor antioxidant defense of&#xD;
      the host. NAC supplementation decreases the bacterial load on the spleen and the severity of&#xD;
      necrosis in the lung. The balance between oxidative and antioxidant substances plays a&#xD;
      critical role in the induction of IL-12 production involved in the Th1 response and suggests&#xD;
      that the use of NAC may be useful for better immune control of TB. Additional benefits of NAC&#xD;
      in individuals with TB are related to the possible protective effect of hepatic to&#xD;
      tuberculostatic drugs and to the direct antimicrobial effect demonstrated in vitro. Some&#xD;
      authors suggest that the restoration of glutathione levels reversed the loss of innate&#xD;
      immunity functions, pointing to a new mechanism of control of Mtb and a possible complement&#xD;
      to antiretroviral treatment. This clinical trial will be undertaken in the Amazonas State&#xD;
      (Western Brazilian Amazon), in Manaus, at Fundação de Medicina Tropical Dr. Heitor Vieira&#xD;
      Dourado. It is a prospective, open-label, 2-arm, randomized clinical trial. Twenty-five&#xD;
      patients will be enrolled in each treatment arm. A total number of 50 patients should be&#xD;
      enrolled. Patients hospitalized in the ICU, in the wards or emergency room of the tertiary&#xD;
      unit care will be invited to participate in this study. The assessment schedule will be done&#xD;
      in days 1, 7, 14, 28, 42, 56, 120 and 180 (in addition, patient will be asked to come back to&#xD;
      the health centre if symptoms occurs at any time). Sputum and blood collection and medical&#xD;
      evaluation will be performed.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">December 7, 2016</start_date>
  <completion_date type="Anticipated">December 2019</completion_date>
  <primary_completion_date type="Anticipated">June 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>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of participants with any biological intolerability or adverse event</measure>
    <time_frame>6 months</time_frame>
    <description>This evaluation will be done by the physician along all the follow-up of the study</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of patients in the NAC treatment arm with shorter sputum smear conversion time and culture</measure>
    <time_frame>Until week 8</time_frame>
    <description>This outcome will be monitored by culture of solid (Löwenstein Jensen) and liquid (MGIT) sputum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients presenting tuberculostatic drug-related hepatotoxicity</measure>
    <time_frame>6 months</time_frame>
    <description>This outcome will be monitored by hepatic transaminases and bilirubins levels</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Dosage of inflammatory cytokines</measure>
    <time_frame>6 months</time_frame>
    <description>This outcome will be evaluate immunological assays in the two groups</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">50</enrollment>
  <condition>Tuberculosis, Pulmonary</condition>
  <condition>HIV/AIDS</condition>
  <arm_group>
    <arm_group_label>RIPE (2m) and RI (4m)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>The patients enrolled in this arm will receive a treatment regimen with an intensive phase lasting two months of rifampicin 150mg + isoniazid 75mg + pyrazinamide 400mg + ethambutol 275mg (combined fixed dose tablet according to the weight) and a continuation with rifampicin 150mg and isoniazid 75mg (combined fixed dose tablet according to the weight) for 4 months.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>RIPE+NAC (2m) and RI (4m)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The patients enrolled in this arm will receive a treatment regimen with an intensive phase lasting two months of rifampicin 150 mg + isoniazid 75 mg + pyrazinamide 400 mg + ethambutol 275mg (combined fixed dose tablet according to the weight) plus N-acetylcysteine (NAC) and a continuation with rifampicin 150mg and isoniazid 75mg (combined fixed dose tablet according to the weight) for 4 months. The NAC is administered by means of effervescent tablet 1200 mg (two sachets of 600 mg) to be diluted in 200ml of water and administered in a 12-hour interval.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>RIPE (2m) and RI (4m)</intervention_name>
    <description>Rifampicin 150mg + isoniazid 75mg + pyrazinamide 400mg + ethambutol 275mg (oral combined fixed dose tablet according to the weight) for 2 months and a continuation with rifampicin 150mg and isoniazid 75mg (oral combined fixed dose tablet according to the weight) for 4 months</description>
    <arm_group_label>RIPE (2m) and RI (4m)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>RIPE+NAC (2m) and RI (4m)</intervention_name>
    <description>Rifampicin 150 mg + isoniazid 75 mg + pyrazinamide 400 mg + ethambutol 275mg (oral combined fixed dose tablet according to the weight) plus oral N-acetylcysteine (NAC) 1200 mg (600mg twice daily) for 2 months and a continuation with rifampicin 150mg and isoniazid 75mg (oral combined fixed dose tablet according to the weight) for 4 months</description>
    <arm_group_label>RIPE+NAC (2m) and RI (4m)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age greater than or equal to 18 years;&#xD;
&#xD;
          -  Acceptance of the HIV test;&#xD;
&#xD;
          -  Forecast of hospital stay of more than twenty-four hours;&#xD;
&#xD;
          -  Clinical and laboratory indication of RIPE;&#xD;
&#xD;
          -  Conditions for puncture of venous access;&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Brazilian indigenous people;&#xD;
&#xD;
          -  People the refuse to perform HIV test;&#xD;
&#xD;
          -  Pregnant women, nursing mothers or pregnant women,&#xD;
&#xD;
          -  Extra pulmonary TB, without pulmonary involvement;&#xD;
&#xD;
          -  Not be able to perform the collection of sputum or tracheal aspirate for&#xD;
             microbiological confirmation;&#xD;
&#xD;
          -  No MGIT® positive for Mtb;&#xD;
&#xD;
          -  Resistance to Mtb, detected by professional sensitivity;&#xD;
&#xD;
          -  Individuals under treatment for bronchospasm secondary to bronchial asthma, according&#xD;
             to the decision of the assistant team or researcher of the study;&#xD;
&#xD;
          -  Clinical suspicion of gastric or duodenal ulcer, as decided by the assistant team or&#xD;
             study investigator; or evidence by upper digestive endoscopy;&#xD;
&#xD;
          -  Alanine aminotransferase (ALT) greater than three times normal;&#xD;
&#xD;
          -  Need to suspend the RIPE treatment, according to the decision of the assistant team or&#xD;
             researcher of the study;&#xD;
&#xD;
          -  Lack of adherence to the proposed treatment for more than seven consecutive days.&#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>Marcelo C dos Santos, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Fundação de Medicina Tropical Dr. Heitor Vieira Dourado</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Bruno B Andrade, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Fundação Osvaldo Cruz Bahia</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Izabella P Safe, MD</last_name>
    <phone>(+55 92) 2127 3498</phone>
    <email>izabellasafe@gmail.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Marcelo C dos Santos, MD, PhD</last_name>
    <phone>(+55 92) 2127 3498</phone>
    <email>marcelocordeiro.br@gmail.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Fundação de Medicina Tropical Dr. Heitor Vieira Dourado</name>
      <address>
        <city>Manaus</city>
        <state>Amazonas</state>
        <zip>69040000</zip>
        <country>Brazil</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Izabella P Safe, MD</last_name>
      <phone>(+55 92) 2127 3498</phone>
      <email>izabellasafe@gmail.com</email>
    </contact>
    <investigator>
      <last_name>Marcelo C dos Santos, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Brazil</country>
  </location_countries>
  <verification_date>February 2019</verification_date>
  <study_first_submitted>September 11, 2017</study_first_submitted>
  <study_first_submitted_qc>September 11, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 13, 2017</study_first_posted>
  <last_update_submitted>February 12, 2019</last_update_submitted>
  <last_update_submitted_qc>February 12, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">February 15, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Pulmonary tuberculosis</keyword>
  <keyword>HIV/AIDS</keyword>
  <keyword>Glutathione</keyword>
  <keyword>N-acetylcysteine</keyword>
  <keyword>Oxidative stress</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tuberculosis</mesh_term>
    <mesh_term>Acquired Immunodeficiency Syndrome</mesh_term>
    <mesh_term>HIV Infections</mesh_term>
    <mesh_term>Tuberculosis, Pulmonary</mesh_term>
  </condition_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/NCT03281226
org study id: CAAE: 60219916.5.0000.0005
nct id: NCT03281226
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Although tuberculosis is a treatable disease, it is currently the infectious disease with the
      highest mortality in the world. It is estimated that one-third of the world's population is
      infected. HIV is the main predisposing factor for TB development. The Brazilian Ministry of
      Health and the World Health Organization recommends that patients should initially be treated
      orally with RIPE - rifampicin (R), isoniazid (I), pyrazinamide (P) and ethambutol (E). The
      N-acetylcysteine (NAC) first benefit was reported during the 1960s, when it proved to be an
      effective mucolytic agent in individuals with cystic fibrosis. Later, a new role arose when
      investigating its therapeutic potential in acetaminophen intoxication. Cleavage of the acetyl
      group makes cysteine available for later incorporation into glutathione synthesis, decreased
      in hepatic injury caused by acetaminophen. This mechanism causes NAC to have an indirect
      antioxidant effect, which aroused an interest in studying the effect in diseases that occur
      with oxidative stress. TB and HIV/Aids are also diseases with chronic inflammation. The
      present study aims to evaluate the effects of NAC as a adjuvant therapy in the treatment of
      TB. This is a phase II randomized clinical trial in which the safety and tolerability of NAC
      as adjunctive therapy for TB treatment will be assessed. Fifty-six patients will be
      randomized into two groups. The first group will receive the standard tuberculosis treatment
      as recommended by the Brazilian Ministry of Health (RIPE); the second will receive in
      addition to this treatment 1200mg of NAC per day for two months. In this way, microscopy and
      culture conversion rate to mycobacteria at 8 weeks, levels of glutathione and biomarkers of
      immune activation and inflammation in case of TB with or without NAC will be monitored.
TB and AIDS are also diseases that occur with a chronic inflammatory stimulus, with constant
      formation of excessive free radicals, leading to cellular and systemic oxidative stress. The
      effects of NAC in both populations are studied. A study demonstrated that HIV-positive
      individuals have low levels of glutathione in CD4+ T lymphocytes when compared to healthy
      controls, these levels being restored after in vivo supplementation with NAC, favoring the
      production of cytokines involved in Th1 response. They also observed that glutathione
      depletion in lymphocytes was correlated with increased levels of tumor necrosis factor and
      free radicals. Some authors suggested that the immune system's inability of HIV-positive
      individuals (or not) in containing Mycobaterium tuberculosis (Mtb) may be a consequence of
      low levels of glutathione in macrophages. The same occurred in a model of animals infected
      with Mtb, suggesting that oxidative stress was partly due to the poor antioxidant defense of
      the host. NAC supplementation decreases the bacterial load on the spleen and the severity of
      necrosis in the lung. The balance between oxidative and antioxidant substances plays a
      critical role in the induction of IL-12 production involved in the Th1 response and suggests
      that the use of NAC may be useful for better immune control of TB. Additional benefits of NAC
      in individuals with TB are related to the possible protective effect of hepatic to
      tuberculostatic drugs and to the direct antimicrobial effect demonstrated in vitro. Some
      authors suggest that the restoration of glutathione levels reversed the loss of innate
      immunity functions, pointing to a new mechanism of control of Mtb and a possible complement
      to antiretroviral treatment. This clinical trial will be undertaken in the Amazonas State
      (Western Brazilian Amazon), in Manaus, at Fundação de Medicina Tropical Dr. Heitor Vieira
      Dourado. It is a prospective, open-label, 2-arm, randomized clinical trial. Twenty-five
      patients will be enrolled in each treatment arm. A total number of 50 patients should be
      enrolled. Patients hospitalized in the ICU, in the wards or emergency room of the tertiary
      unit care will be invited to participate in this study. The assessment schedule will be done
      in days 1, 7, 14, 28, 42, 56, 120 and 180 (in addition, patient will be asked to come back to
      the health centre if symptoms occurs at any time). Sputum and blood collection and medical
      evaluation will be performed.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of participants with any biological intolerability or adverse event
time frame: 6 months
description: This evaluation will be done by the physician along all the follow-up of the study
measure: Number of patients in the NAC treatment arm with shorter sputum smear conversion time and culture
time frame: Until week 8
description: This outcome will be monitored by culture of solid (Löwenstein Jensen) and liquid (MGIT) sputum
measure: Number of patients presenting tuberculostatic drug-related hepatotoxicity
time frame: 6 months
description: This outcome will be monitored by hepatic transaminases and bilirubins levels
measure: Dosage of inflammatory cytokines
time frame: 6 months
description: This outcome will be evaluate immunological assays in the two groups
arm group label: RIPE (2m) and RI (4m)
arm group type: Active Comparator
description: The patients enrolled in this arm will receive a treatment regimen with an intensive phase lasting two months of rifampicin 150mg + isoniazid 75mg + pyrazinamide 400mg + ethambutol 275mg (combined fixed dose tablet according to the weight) and a continuation with rifampicin 150mg and isoniazid 75mg (combined fixed dose tablet according to the weight) for 4 months.
arm group label: RIPE+NAC (2m) and RI (4m)
arm group type: Experimental
description: The patients enrolled in this arm will receive a treatment regimen with an intensive phase lasting two months of rifampicin 150 mg + isoniazid 75 mg + pyrazinamide 400 mg + ethambutol 275mg (combined fixed dose tablet according to the weight) plus N-acetylcysteine (NAC) and a continuation with rifampicin 150mg and isoniazid 75mg (combined fixed dose tablet according to the weight) for 4 months. The NAC is administered by means of effervescent tablet 1200 mg (two sachets of 600 mg) to be diluted in 200ml of water and administered in a 12-hour interval.
intervention type: Drug
intervention name: RIPE (2m) and RI (4m)
description: Rifampicin 150mg + isoniazid 75mg + pyrazinamide 400mg + ethambutol 275mg (oral combined fixed dose tablet according to the weight) for 2 months and a continuation with rifampicin 150mg and isoniazid 75mg (oral combined fixed dose tablet according to the weight) for 4 months
arm group label: RIPE (2m) and RI (4m)
intervention type: Drug
intervention name: RIPE+NAC (2m) and RI (4m)
description: Rifampicin 150 mg + isoniazid 75 mg + pyrazinamide 400 mg + ethambutol 275mg (oral combined fixed dose tablet according to the weight) plus oral N-acetylcysteine (NAC) 1200 mg (600mg twice daily) for 2 months and a continuation with rifampicin 150mg and isoniazid 75mg (oral combined fixed dose tablet according to the weight) for 4 months
arm group label: RIPE+NAC (2m) and RI (4m)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Marcelo C dos Santos, MD, PhD
role: Principal Investigator
affiliation: Fundação de Medicina Tropical Dr. Heitor Vieira Dourado
last name: Bruno B Andrade, MD, PhD
role: Principal Investigator
affiliation: Fundação Osvaldo Cruz Bahia
last name: Izabella P Safe, MD
phone: (+55 92) 2127 3498
email: izabellasafe@gmail.com
last name: Marcelo C dos Santos, MD, PhD
phone: (+55 92) 2127 3498
email: marcelocordeiro.br@gmail.com
facility: 
status: Recruiting
contact: 
investigator: 
country: Brazil
responsible party type: Sponsor
mesh term: Tuberculosis
mesh term: Acquired Immunodeficiency Syndrome
mesh term: HIV Infections
mesh term: Tuberculosis, Pulmonary
sharing ipd: No