<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/NCT02216331</url>
  </required_header>
  <id_info>
    <org_study_id>TMC207-CL002</org_study_id>
    <nct_id>NCT02216331</nct_id>
  </id_info>
  <brief_title>PK Interaction Between Rifapentine or Rifampicin and a Single Dose of TMC207 in Healthy Subjects (TMC207-CL002)</brief_title>
  <official_title>A Phase I Open-label Trial to Investigate the Pharmacokinetic Interaction Between Rifapentine or Rifampicin and a Single Dose of TMC207 in Healthy Subjects</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Global Alliance for TB Drug Development</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Global Alliance for TB Drug Development</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a open-label study, 2-treatment, 2-period, single sequence design. Period 1 will&#xD;
      examine the pharmacokinetics of TMC207 in the absence of rifapentine or rifampicin. Subjects&#xD;
      will receive a single 400-mg dose of TMC207 administered alone on Study Day 1. Period 2 will&#xD;
      examine the effects of repeated doses of either rifapentine or rifampicin on TMC207&#xD;
      pharmacokinetics and will begin on Study Day 20. During Period 2, subjects will receive 22&#xD;
      daily doses of either 600 mg rifapentine or rifampicin from Study Day 20 through Study Day&#xD;
      41. A single 400-mg dose of TMC207 will be administered on Study Day 29. Subjects will be&#xD;
      confined to the clinic from Study Day-1 to Study Day 2 in the morning of Period 1, and Study&#xD;
      Day 19 to Study Day 30 in the morning of Period 2. The study hypothesis is to determine&#xD;
      whether Rifapentine affects the pharmacokinetics of TMC207 as measured by effects on Cmax and&#xD;
      AUC(0-t) to a lesser degree than rifampicin.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>March 2010</start_date>
  <completion_date type="Actual">May 2010</completion_date>
  <primary_completion_date type="Actual">May 2010</primary_completion_date>
  <phase>Phase 1</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>Maximum observed TMC207 concentration in ng/mL [Cmax] between Groups 1 and 2</measure>
    <time_frame>through 336 hours post dosing in Period 1 and Period 2</time_frame>
    <description>To evaluate the relative effect of rifapentine and rifampicin on Cmax of TMC207, the Cmax of TMC207 was compared between Group 1 (rifapentine) and Group 2 (rifampicin) using analysis of variance model (ANOVA).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Area under the TMC207 concentration-time curve in ng*hr/mL [AUC0-t] between Groups 1 and 2</measure>
    <time_frame>through 336 hours post dosing in Period 1 and Period 2</time_frame>
    <description>To evaluate the relative effect of rifapentine and rifampicin on AUC0-t of TMC207, the AUC0-t of TMC207 was compared between Group 1 (rifapentine) and Group 2 (rifampicin) using analysis of variance model (ANOVA).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Area under the TMC207 concentration cuve from time zero to infinity in ng*hr/mL [AUC0-inf] between Groups 1 and 2</measure>
    <time_frame>through 336 hours post dosing in Period 1 and Period 2</time_frame>
    <description>To evaluate the relative effect of rifapentine and rifampicin on AUC0-inf of TMC207, the AUC0-inf of TMC207 was compared between Group 1 (rifapentine) and Group 2 (rifampicin) using analysis of variance model (ANOVA).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Maximum observed TMC207 concentration in ng/mL [Cmax] within treatment groups between Periods 1 and 2</measure>
    <time_frame>through 336 hours post dosing in Period 1 and Period 2</time_frame>
    <description>To evaluate the relative effect of rifapentine and rifampicin on Cmax of TMC207, the Cmax of TMC207 was compared between the TMC207 + rifapentine treatment (Group 1) or rifampicin (Group 2) and TMC207 alone using analysis of variance model (ANOVA).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the TMC207 concentration-time curve in ng*hr/mL [AUC0-t] within treatment groups between Periods 1 and 2</measure>
    <time_frame>through 336 hours post dosing in Period 1 and Period 2</time_frame>
    <description>To evaluate the relative effect of rifapentine and rifampicin on AUC0-t of TMC207, the AUC0-t of TMC207 was compared between the TMC207 + rifapentine treatment (Group 1) or rifampicin (Group 2) and TMC207 alone using analysis of variance model (ANOVA).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the TMC207 concentration cuve from time zero to infinity in ng*hr/mL [AUC0-inf] within treatment groups between Periods 1 and 2</measure>
    <time_frame>through 336 hours post dosing in Period 1 and Period 2</time_frame>
    <description>To evaluate the relative effect of rifapentine and rifampicin on AUC0-inf of TMC207, the AUC0-inf of TMC207 was compared between the TMC207 + rifapentine treatment (Group 1) or rifampicin (Group 2) and TMC207 alone using analysis of variance model (ANOVA).</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Number of participants with adverse events</measure>
    <time_frame>through study day 57</time_frame>
    <description>To compare the safety and tolerability as measured by the number of participants with adverse events.</description>
  </other_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">32</enrollment>
  <condition>Tuberculosis</condition>
  <arm_group>
    <arm_group_label>Group 1 TMC207 alone</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>A single 400 mg dose of TMC207 will be administered as 4 tablets of 100 mg per tablet on Study Day 1.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group 1 TMC207 and rifapentine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>A single 400 mg dose of TMC207 will be administered as 4 tablets of 100 mg per tablet on Study Day 29 and 600 mg of rifapentine administered as 4 tablets of 150 mg per tablet on each of Study Days 20-41.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group 2 TMC207 alone</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>A single 400 mg dose of TMC207 will be administered as 4 tablets of 100 mg per tablet on Study Day 1.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group 2 TMC207 and rifampicin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>A single 400 mg dose of TMC207 will be administered as 4 tablets of 100 mg per tablet on Study Day 29 and 600 mg of rifampicin administered as 4 capsules of 150 mg per capsule on each of Study Days 20-41.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>TMC207</intervention_name>
    <description>This is a two group, 2 period study design with both groups in the first period receiving TMC207 alone, followed by one group in the second period receiving TMC207 in the presence of dosing with rifapentine and the other group receiving TMC207 in the presence of dosing with rifampicin. All treatments details specified under &quot;Arms&quot; description.</description>
    <arm_group_label>Group 1 TMC207 alone</arm_group_label>
    <arm_group_label>Group 1 TMC207 and rifapentine</arm_group_label>
    <arm_group_label>Group 2 TMC207 alone</arm_group_label>
    <arm_group_label>Group 2 TMC207 and rifampicin</arm_group_label>
    <other_name>bedaquiline</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>rifapentine</intervention_name>
    <arm_group_label>Group 1 TMC207 and rifapentine</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>rifampicin</intervention_name>
    <arm_group_label>Group 2 TMC207 and rifampicin</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Aged between 19 and 55 years, extremes included.&#xD;
&#xD;
          -  Non tobacco/nicotine using (at least 3 months prior to screening).&#xD;
&#xD;
          -  Body Mass Index (BMI, weight in kg divided by the square of height in meters) of 18.0&#xD;
             to 32.0 kg/m2, inclusive.&#xD;
&#xD;
          -  Informed Consent Form (ICF) signed voluntarily before the first trial-related&#xD;
             activity.&#xD;
&#xD;
          -  Able to comply with protocol requirements.&#xD;
&#xD;
          -  Healthy on the basis of a medical evaluation or history that reveals the absence of&#xD;
             any clinically relevant abnormality and includes a physical examination, medical&#xD;
             history, electrocardiogram (ECG), vital signs, and the results of blood biochemistry,&#xD;
             and hematology tests and a urinalysis carried out at screening (See Section 6.1).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Female, except if postmenopausal since more than 2 years, or post-hysterectomy, or&#xD;
             post surgical sterilization, i.e., tubal ligation (without reversal operation) or&#xD;
             total hysterectomy.&#xD;
&#xD;
          -  History or evidence of current use of alcohol, barbiturate, amphetamine, recreational&#xD;
             or narcotic drug use, which in the investigator's opinion would compromise subject's&#xD;
             safety and/or compliance with the trial procedures.&#xD;
&#xD;
          -  Any clinically significant (as deemed by the Principle Investigator) history acute&#xD;
             illness (resolved within 4 weeks of screening), or presence of cardiovascular,&#xD;
             pulmonary, hepatic, renal, hematologic, gastrointestinal (including eating disorders),&#xD;
             endocrine, metabolic, immunologic, dermatologic, neurologic, psychological, or&#xD;
             psychiatric disease.&#xD;
&#xD;
          -  Currently significant diarrhea, gastric stasis, or constipation that in the&#xD;
             investigator's opinion could influence drug absorption or bioavailability.&#xD;
&#xD;
          -  Any history of significant skin disease such as, but not limited to, rash or&#xD;
             eruptions, drug allergies, food allergy, dermatitis, eczema, psoriasis, or urticaria.&#xD;
             Subjects with a history of skin disease may be enrolled into the study after&#xD;
             consultation with the Sponsor Medical Monitor.&#xD;
&#xD;
          -  Previously demonstrated clinically significant allergy or hypersensitivity to any of&#xD;
             the excipients of the investigational medication administered in this trial (i.e.&#xD;
             rifapentine, rifampicin, and TMC207).&#xD;
&#xD;
          -  Subjects with QTcF [Fredericia correction] interval &gt; 450 msec (based on the average&#xD;
             of the triplicate ECGs) at screening (and confirmed by repeat ECG).&#xD;
&#xD;
          -  Subjects with any other clinically significant ECG abnormality at screening, such as&#xD;
             arrhythmia, ischemia, or evidence of heart failure or with a family history of Long QT&#xD;
             Syndrome.&#xD;
&#xD;
          -  Use of concomitant medication, including over-the-counter products and dietary&#xD;
             supplements, except for ibuprofen and paracetamol up to 7 days before the first dose&#xD;
             of trial medication and all prescribed medication must have been discontinued at least&#xD;
             14 days before first intake of trial medication.&#xD;
&#xD;
          -  Participation in an investigational drug trial within 60 days prior to the first&#xD;
             intake of trial medication.&#xD;
&#xD;
          -  Donation of blood or significant loss of blood within 56 days or plasma donation&#xD;
             within 7 days preceding the first intake of trial medication.&#xD;
&#xD;
          -  Having received TMC207 in a previous trial.&#xD;
&#xD;
          -  Positive HIV-1 or HIV-2 test at screening&#xD;
&#xD;
          -  Hepatitis A, B, or C infection (confirmed by hepatitis A antibody IgM, hepatitis B&#xD;
             surface antigen, or hepatitis C virus antibody, respectively) at screening.&#xD;
&#xD;
          -  A positive urine drug test at screening. Urine will be tested to check the current use&#xD;
             of alcohol, amphetamines, benzodiazepines, cocaine, cannabinoids, and opioids.&#xD;
&#xD;
          -  Subjects with the following laboratory abnormalities at screening as defined by the&#xD;
             NIH, NIAID, Division of Microbiology and Infectious Diseases (DMID) Adult Toxicity&#xD;
             Table and in accordance with the normal ranges of the clinical laboratory: Serum&#xD;
             creatinine grade 1 or greater (&gt; 1.0 x ULN); Pancreatic lipase grade 1 or greater (&gt;&#xD;
             1.0 x ULN); Hemoglobin grade 1 or greater (≤ 10.5 g/dL); Platelet count grade 1 or&#xD;
             greater (≤ 99000/mm3); Absolute neutrophil count grade 1 or greater (≤ 1500/mm3);&#xD;
             Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) grade 1 or greater&#xD;
             (&gt; 1.0 x ULN); Total bilirubin grade 1 or greater (&gt; 1.0 x ULN); Any other toxicity&#xD;
             grade 2 or above, including: proteinuria (spot urine) &gt; 1+ and gross hematuria.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>19 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Scott Rasmussen, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Celerion (MDS Pharma Services)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Celerion (MDS Pharma Services)</name>
      <address>
        <city>Lincoln</city>
        <state>Nebraska</state>
        <zip>68502</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.tballiance.org</url>
    <description>Global Alliance for TB Drug Development website</description>
  </link>
  <verification_date>September 2019</verification_date>
  <study_first_submitted>August 12, 2014</study_first_submitted>
  <study_first_submitted_qc>August 12, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 13, 2014</study_first_posted>
  <last_update_submitted>September 4, 2019</last_update_submitted>
  <last_update_submitted_qc>September 4, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">September 6, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>tuberculosis</keyword>
  <keyword>PK</keyword>
  <keyword>TMC207</keyword>
  <keyword>bedaquiline</keyword>
  <keyword>rifapentine</keyword>
  <keyword>rifampicin</keyword>
  <keyword>drug drug interaction</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tuberculosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rifampin</mesh_term>
    <mesh_term>Rifapentine</mesh_term>
    <mesh_term>Bedaquiline</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/NCT02216331
org study id: TMC207-CL002
nct id: NCT02216331
lead sponsor: 
has dmc: No
This is a open-label study, 2-treatment, 2-period, single sequence design. Period 1 will
      examine the pharmacokinetics of TMC207 in the absence of rifapentine or rifampicin. Subjects
      will receive a single 400-mg dose of TMC207 administered alone on Study Day 1. Period 2 will
      examine the effects of repeated doses of either rifapentine or rifampicin on TMC207
      pharmacokinetics and will begin on Study Day 20. During Period 2, subjects will receive 22
      daily doses of either 600 mg rifapentine or rifampicin from Study Day 20 through Study Day
      41. A single 400-mg dose of TMC207 will be administered on Study Day 29. Subjects will be
      confined to the clinic from Study Day-1 to Study Day 2 in the morning of Period 1, and Study
      Day 19 to Study Day 30 in the morning of Period 2. The study hypothesis is to determine
      whether Rifapentine affects the pharmacokinetics of TMC207 as measured by effects on Cmax and
      AUC(0-t) to a lesser degree than rifampicin.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum observed TMC207 concentration in ng/mL [Cmax] between Groups 1 and 2
time frame: through 336 hours post dosing in Period 1 and Period 2
description: To evaluate the relative effect of rifapentine and rifampicin on Cmax of TMC207, the Cmax of TMC207 was compared between Group 1 (rifapentine) and Group 2 (rifampicin) using analysis of variance model (ANOVA).
measure: Area under the TMC207 concentration-time curve in ng*hr/mL [AUC0-t] between Groups 1 and 2
time frame: through 336 hours post dosing in Period 1 and Period 2
description: To evaluate the relative effect of rifapentine and rifampicin on AUC0-t of TMC207, the AUC0-t of TMC207 was compared between Group 1 (rifapentine) and Group 2 (rifampicin) using analysis of variance model (ANOVA).
measure: Area under the TMC207 concentration cuve from time zero to infinity in ng*hr/mL [AUC0-inf] between Groups 1 and 2
time frame: through 336 hours post dosing in Period 1 and Period 2
description: To evaluate the relative effect of rifapentine and rifampicin on AUC0-inf of TMC207, the AUC0-inf of TMC207 was compared between Group 1 (rifapentine) and Group 2 (rifampicin) using analysis of variance model (ANOVA).
measure: Maximum observed TMC207 concentration in ng/mL [Cmax] within treatment groups between Periods 1 and 2
time frame: through 336 hours post dosing in Period 1 and Period 2
description: To evaluate the relative effect of rifapentine and rifampicin on Cmax of TMC207, the Cmax of TMC207 was compared between the TMC207 + rifapentine treatment (Group 1) or rifampicin (Group 2) and TMC207 alone using analysis of variance model (ANOVA).
measure: Area under the TMC207 concentration-time curve in ng*hr/mL [AUC0-t] within treatment groups between Periods 1 and 2
time frame: through 336 hours post dosing in Period 1 and Period 2
description: To evaluate the relative effect of rifapentine and rifampicin on AUC0-t of TMC207, the AUC0-t of TMC207 was compared between the TMC207 + rifapentine treatment (Group 1) or rifampicin (Group 2) and TMC207 alone using analysis of variance model (ANOVA).
measure: Area under the TMC207 concentration cuve from time zero to infinity in ng*hr/mL [AUC0-inf] within treatment groups between Periods 1 and 2
time frame: through 336 hours post dosing in Period 1 and Period 2
description: To evaluate the relative effect of rifapentine and rifampicin on AUC0-inf of TMC207, the AUC0-inf of TMC207 was compared between the TMC207 + rifapentine treatment (Group 1) or rifampicin (Group 2) and TMC207 alone using analysis of variance model (ANOVA).
measure: Number of participants with adverse events
time frame: through study day 57
description: To compare the safety and tolerability as measured by the number of participants with adverse events.
arm group label: Group 1 TMC207 alone
arm group type: Experimental
description: A single 400 mg dose of TMC207 will be administered as 4 tablets of 100 mg per tablet on Study Day 1.
arm group label: Group 1 TMC207 and rifapentine
arm group type: Experimental
description: A single 400 mg dose of TMC207 will be administered as 4 tablets of 100 mg per tablet on Study Day 29 and 600 mg of rifapentine administered as 4 tablets of 150 mg per tablet on each of Study Days 20-41.
arm group label: Group 2 TMC207 alone
arm group type: Experimental
description: A single 400 mg dose of TMC207 will be administered as 4 tablets of 100 mg per tablet on Study Day 1.
arm group label: Group 2 TMC207 and rifampicin
arm group type: Experimental
description: A single 400 mg dose of TMC207 will be administered as 4 tablets of 100 mg per tablet on Study Day 29 and 600 mg of rifampicin administered as 4 capsules of 150 mg per capsule on each of Study Days 20-41.
intervention type: Drug
intervention name: TMC207
description: This is a two group, 2 period study design with both groups in the first period receiving TMC207 alone, followed by one group in the second period receiving TMC207 in the presence of dosing with rifapentine and the other group receiving TMC207 in the presence of dosing with rifampicin. All treatments details specified under "Arms" description.
arm group label: Group 1 TMC207 alone
arm group label: Group 1 TMC207 and rifapentine
arm group label: Group 2 TMC207 alone
arm group label: Group 2 TMC207 and rifampicin
other name: bedaquiline
intervention type: Drug
intervention name: rifapentine
arm group label: Group 1 TMC207 and rifapentine
intervention type: Drug
intervention name: rifampicin
arm group label: Group 2 TMC207 and rifampicin
criteria: 
gender: All
minimum age: 19 Years
maximum age: 55 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Scott Rasmussen, MD
role: Principal Investigator
affiliation: Celerion (MDS Pharma Services)
facility: 
country: United States
url: http://www.tballiance.org
description: Global Alliance for TB Drug Development website
responsible party type: Sponsor
mesh term: Tuberculosis
mesh term: Rifampin
mesh term: Rifapentine
mesh term: Bedaquiline