<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/NCT03776500</url>
  </required_header>
  <id_info>
    <org_study_id>IM-006-13</org_study_id>
    <nct_id>NCT03776500</nct_id>
  </id_info>
  <brief_title>Study to Evaluate the Safety, Tolerability and Pharmacokinetics of PBTZ169 in Multiple Dosing</brief_title>
  <official_title>Safety, Tolerability and Pharmacokinetic Profile of PBTZ169 Formulated as Native Crystal Powder: Multiple Ascending Doses, Randomized, Placebo- Controlled, Parallel-group, Sequential Phase Ib Trial in Healthy Volunteers</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Innovative Medicines for Tuberculosis</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bill and Melinda Gates Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Innovative Medicines for Tuberculosis</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>
      This is a randomized, double-blind, placebo-controlled, multiple ascending dose study&#xD;
      conducted at one study center in Switzerland.&#xD;
&#xD;
      Four (4) panels (A, B, C and D) of 8 male subjects (6 active and 2 placebo) each receiving&#xD;
      multiple doses of PBTZ169 or a matching placebo, at increasing dose levels, once or twice&#xD;
      daily.&#xD;
&#xD;
      Subjects will participate in only one panel. Blocks of 4 subjects (3 under active treatment,&#xD;
      1 under placebo) will be investigated in parallel. Panels will start sequentially.&#xD;
&#xD;
      Safety will be assessed throughout the study; serial ECGs and serial blood samples will be&#xD;
      collected for the safety and PK assessment of PBTZ169.&#xD;
&#xD;
      Dose escalation will be allowed once the Trial Safety Board has determined that adequate&#xD;
      safety and tolerability after each panel completion has been demonstrated to permit&#xD;
      proceeding to the next panel.&#xD;
&#xD;
      In addition, a preliminary assessment of the drug interaction potential of PBTZ169 will be&#xD;
      done by the measurement of inhibition or induction of human cytochromes through the&#xD;
      metabolism of microdoses of standard probe substrates&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 21, 2019</start_date>
  <completion_date type="Actual">March 20, 2020</completion_date>
  <primary_completion_date type="Actual">March 20, 2020</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>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safety and tolerability of increasing multiple oral doses of PBTZ169 in healthy male adult subjects evaluated by Treatment Emergent Adverse Events (TEAEs).</measure>
    <time_frame>Days 0-17</time_frame>
    <description>Evaluation by thorough monitoring of Treatment Emergent Adverse Events (TEAEs) following doses of PBTZ169 crystalline or placebo</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Relative oral bioavailability assessment of PBTZ169 in healthy male subjects after multiple dosing</measure>
    <time_frame>Days 0-17</time_frame>
    <description>Estimation from the ratio of area under plasma concentration curves (AUCs) determined after the administration of PBTZ169</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics (PK) of multiple oral doses of PBTZ169 using Cmax</measure>
    <time_frame>Days 0-17</time_frame>
    <description>Determination of non-compartmental PK parameter Maximum Plasma Concentration [Cmax] after determination of the amount of the parent compound and its known metabolites in plasma samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics (PK) of multiple oral doses of PBTZ169 using Tmax</measure>
    <time_frame>Days 0-17</time_frame>
    <description>Determination of non-compartmental PK parameter Time of maximum observed Plasma Concentration [Tmax] after determination of the amount of the parent compound and its known metabolites in plasma samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Metabolism interaction of multiple oral doses of PBTZ169 by measuring ratios of 7 probe substrates before the first and and after the last dose</measure>
    <time_frame>Days -1 to 14</time_frame>
    <description>Measurement of the ratios of 7 probe of known substrates of human Cytochome P-450 enzyme family before the first and and after the last dose</description>
  </secondary_outcome>
  <number_of_arms>8</number_of_arms>
  <enrollment type="Actual">32</enrollment>
  <condition>Tuberculosis, Pulmonary</condition>
  <arm_group>
    <arm_group_label>Panel A - Active</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>N = 6, 150 mg twice daily of PBTZ169</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Panel A - Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>N = 2, 150 mg twice daily of PBTZ169 matching placebo</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Panel B - Active</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>N = 6, 300 mg twice daily of PBTZ169</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Panel B - Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>N = 2, 300 mg twice daily of PBTZ169 matching placebo</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Panel C - Active</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>N = 6, 600 mg once daily of PBTZ169</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Panel C - Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>N = 2, 600 mg once daily of PBTZ169 matching placebo</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Panel D - Active</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>N = 6, 600 mg twice daily of PBTZ169</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Panel D - Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>N = 2, 600 mg twice daily of PBTZ169 matching placebo</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>PBTZ169</intervention_name>
    <description>PBTZ169 crystalline supplied as powder for oral solution</description>
    <arm_group_label>Panel A - Active</arm_group_label>
    <arm_group_label>Panel B - Active</arm_group_label>
    <arm_group_label>Panel C - Active</arm_group_label>
    <arm_group_label>Panel D - Active</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>matching placebo supplied as powder for oral solution</description>
    <arm_group_label>Panel A - Placebo</arm_group_label>
    <arm_group_label>Panel B - Placebo</arm_group_label>
    <arm_group_label>Panel C - Placebo</arm_group_label>
    <arm_group_label>Panel D - Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Healthy male subjects aged between 18 and 48 years&#xD;
&#xD;
          -  Body weight (BW) ranging between 55 and 95 kg, providing body mass index (BMI) is&#xD;
             between 18 and 28 kg/m2&#xD;
&#xD;
          -  Absence of significant findings in the medical history and physical examination as&#xD;
             judged by the Investigator, especially for cardiovascular, pulmonary, haematological&#xD;
             and nervous systems&#xD;
&#xD;
          -  Absence of significant laboratory abnormalities as judged by the Investigator.&#xD;
             Gilbert's syndrome (increased total and unconjugated bilirubin when fasting) will be&#xD;
             accepted if mild. Moderate creatine kinase increases (up to 600 IU/L) without clinical&#xD;
             abnormalities, commonly found in physically active young males.&#xD;
&#xD;
          -  Absence of clinically significant abnormalities on 12-lead ECG&#xD;
&#xD;
          -  Negative urine drug screen (amphetamines, benzodiazepines, cannabis, cocaine, opiates)&#xD;
&#xD;
          -  Commitment to refrain from travel outside Europe over the whole study duration&#xD;
&#xD;
          -  Ability to understand the procedures, agreement to participate and willingness to give&#xD;
             written informed consent&#xD;
&#xD;
          -  Co-operative attitude and availability for scheduled visits over the entire study&#xD;
             period&#xD;
&#xD;
          -  Commitment to refrain from alcohol and tobacco consumption over the whole study&#xD;
             period.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of major cardiovascular, pulmonary, hepatic, immunological, renal,&#xD;
             haematological, gastrointestinal, genitourinary, neurological, or rheumatologic&#xD;
             disorders&#xD;
&#xD;
          -  Active diseases of any type, including inflammatory disorders and infections. Mild&#xD;
             acne is permissible providing no systemic or local treatment is provided or planned&#xD;
             (except for cleaning lotions)&#xD;
&#xD;
          -  History of significant allergy or asthma. Allergic rhinitis or conjunctivitis is&#xD;
             acceptable if non-symptomatic when starting the study and if symptoms are not&#xD;
             anticipated to occur during the study to a point that would require corticosteroid&#xD;
             therapy (e.g. in case of annual use)&#xD;
&#xD;
          -  History of cardiovascular dysfunction if considered as clinically relevant (conduction&#xD;
             abnormality, arrhythmia, bradycardia, angina pectoris, cardiac hypertrophy unless&#xD;
             elicited by training, pulmonary embolism)&#xD;
&#xD;
          -  Hypertension defined as supine blood pressure &gt;150/90 mmHg or recurrent hypotensive&#xD;
             events considered as clinically relevant or documented orthostatic hypotension&#xD;
&#xD;
          -  Sick sinus syndrome, known long QT syndrome, reproducible observation of corrected QT&#xD;
             interval QTc ≥440 msec or of pronounced sinus bradycardia (&lt;40 bpm/min)&#xD;
&#xD;
          -  Intense sport activities. Moderate sport is acceptable and activities should remain&#xD;
             fairly constant throughout the study&#xD;
&#xD;
          -  Any clinically significant laboratory values on screening that are not within normal&#xD;
             range on single repeat (Gilbert's syndrome or CK elevations usually acceptable if&#xD;
             moderate)&#xD;
&#xD;
          -  Positive hepatitis B and C antigen screen&#xD;
&#xD;
          -  Positive HIV antibody screen or screen not performed&#xD;
&#xD;
          -  Any recent acute illness or sequelae thereof which could expose the subject to a&#xD;
             higher risk or might confound the results of the study, according to the evaluation of&#xD;
             the investigator&#xD;
&#xD;
          -  Treatment in the previous three months with any drug known to have well-defined&#xD;
             potential for toxicity to a major organ&#xD;
&#xD;
          -  History of hypersensitivity to any drug if considered as serious&#xD;
&#xD;
          -  Use of any medication the week prior to study or as based on the 5 plasma half-life&#xD;
             rule and throughout study, including aspirin or other over-the-counter (OTC)&#xD;
             preparations. Paracetamol is permissible before and during the study as a rescue&#xD;
             medication but only with Investigator's permission&#xD;
&#xD;
          -  Participation in a clinical investigation or blood donation of 500 ml within the past&#xD;
             3 months&#xD;
&#xD;
          -  History of relevant alcohol or drug abuse&#xD;
&#xD;
          -  Usual smoking during the last month before participation in the study. Consumption of&#xD;
             ≤5 cigarettes/day or equivalent is acceptable providing the subject can totally&#xD;
             refrain from smoking from one week before and during the whole study duration&#xD;
&#xD;
          -  Usual consumption of a large quantity of coffee, tea, chocolate (more than 4 cups/day)&#xD;
             or equivalent (Cola drinks), during the last month before participation in the study&#xD;
&#xD;
          -  Current regular (i.e. 3 times per week or more) consumption of large quantities of&#xD;
             alcohol or wine (&gt;0.5 L wine/day) or equivalent (i.e. more than 50 g ethanol per day),&#xD;
             during the last month before participation in the study. Alcohol is not allowed during&#xD;
             the whole study period&#xD;
&#xD;
          -  Project to conceive a child during the study period (by principle of precaution, while&#xD;
             no indication exists for a definite reproductive risk following paternal exposure)&#xD;
&#xD;
          -  Psychological status which could impact on the subject's ability to give informed&#xD;
             consent&#xD;
&#xD;
          -  Any feature of the subject's medical history or present condition which, in the&#xD;
             Investigator's opinion, could confound the results of the study, complicate its&#xD;
             interpretation, or represent a potential risk for the subject.&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>48 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Stewart T Cole, Prof</last_name>
    <role>Study Chair</role>
    <affiliation>innovative Medicines for Tuberculosis (iM4TB)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Division of Clinical Pharmacology, Centre Hospitalier Universitaire Vaudois (CHUV)</name>
      <address>
        <city>Lausanne</city>
        <state>Vaud</state>
        <zip>1011</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Switzerland</country>
  </location_countries>
  <verification_date>October 2020</verification_date>
  <study_first_submitted>December 13, 2018</study_first_submitted>
  <study_first_submitted_qc>December 13, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 14, 2018</study_first_posted>
  <last_update_submitted>October 20, 2020</last_update_submitted>
  <last_update_submitted_qc>October 20, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">October 22, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tuberculosis</mesh_term>
    <mesh_term>Tuberculosis, Pulmonary</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Macozinone</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/NCT03776500
org study id: IM-006-13
nct id: NCT03776500
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This is a randomized, double-blind, placebo-controlled, multiple ascending dose study
      conducted at one study center in Switzerland.

      Four (4) panels (A, B, C and D) of 8 male subjects (6 active and 2 placebo) each receiving
      multiple doses of PBTZ169 or a matching placebo, at increasing dose levels, once or twice
      daily.

      Subjects will participate in only one panel. Blocks of 4 subjects (3 under active treatment,
      1 under placebo) will be investigated in parallel. Panels will start sequentially.

      Safety will be assessed throughout the study; serial ECGs and serial blood samples will be
      collected for the safety and PK assessment of PBTZ169.

      Dose escalation will be allowed once the Trial Safety Board has determined that adequate
      safety and tolerability after each panel completion has been demonstrated to permit
      proceeding to the next panel.

      In addition, a preliminary assessment of the drug interaction potential of PBTZ169 will be
      done by the measurement of inhibition or induction of human cytochromes through the
      metabolism of microdoses of standard probe substrates
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: Safety and tolerability of increasing multiple oral doses of PBTZ169 in healthy male adult subjects evaluated by Treatment Emergent Adverse Events (TEAEs).
time frame: Days 0-17
description: Evaluation by thorough monitoring of Treatment Emergent Adverse Events (TEAEs) following doses of PBTZ169 crystalline or placebo
measure: Relative oral bioavailability assessment of PBTZ169 in healthy male subjects after multiple dosing
time frame: Days 0-17
description: Estimation from the ratio of area under plasma concentration curves (AUCs) determined after the administration of PBTZ169
measure: Pharmacokinetics (PK) of multiple oral doses of PBTZ169 using Cmax
time frame: Days 0-17
description: Determination of non-compartmental PK parameter Maximum Plasma Concentration [Cmax] after determination of the amount of the parent compound and its known metabolites in plasma samples
measure: Pharmacokinetics (PK) of multiple oral doses of PBTZ169 using Tmax
time frame: Days 0-17
description: Determination of non-compartmental PK parameter Time of maximum observed Plasma Concentration [Tmax] after determination of the amount of the parent compound and its known metabolites in plasma samples
measure: Metabolism interaction of multiple oral doses of PBTZ169 by measuring ratios of 7 probe substrates before the first and and after the last dose
time frame: Days -1 to 14
description: Measurement of the ratios of 7 probe of known substrates of human Cytochome P-450 enzyme family before the first and and after the last dose
arm group label: Panel A - Active
arm group type: Experimental
description: N = 6, 150 mg twice daily of PBTZ169
arm group label: Panel A - Placebo
arm group type: Placebo Comparator
description: N = 2, 150 mg twice daily of PBTZ169 matching placebo
arm group label: Panel B - Active
arm group type: Experimental
description: N = 6, 300 mg twice daily of PBTZ169
arm group label: Panel B - Placebo
arm group type: Placebo Comparator
description: N = 2, 300 mg twice daily of PBTZ169 matching placebo
arm group label: Panel C - Active
arm group type: Experimental
description: N = 6, 600 mg once daily of PBTZ169
arm group label: Panel C - Placebo
arm group type: Placebo Comparator
description: N = 2, 600 mg once daily of PBTZ169 matching placebo
arm group label: Panel D - Active
arm group type: Experimental
description: N = 6, 600 mg twice daily of PBTZ169
arm group label: Panel D - Placebo
arm group type: Placebo Comparator
description: N = 2, 600 mg twice daily of PBTZ169 matching placebo
intervention type: Drug
intervention name: PBTZ169
description: PBTZ169 crystalline supplied as powder for oral solution
arm group label: Panel A - Active
arm group label: Panel B - Active
arm group label: Panel C - Active
arm group label: Panel D - Active
intervention type: Drug
intervention name: Placebo
description: matching placebo supplied as powder for oral solution
arm group label: Panel A - Placebo
arm group label: Panel B - Placebo
arm group label: Panel C - Placebo
arm group label: Panel D - Placebo
criteria: 
gender: Male
minimum age: 18 Years
maximum age: 48 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Stewart T Cole, Prof
role: Study Chair
affiliation: innovative Medicines for Tuberculosis (iM4TB)
facility: 
country: Switzerland
responsible party type: Sponsor
mesh term: Tuberculosis
mesh term: Tuberculosis, Pulmonary
mesh term: Macozinone