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A Phase 1/2 Trial of Multiple Oral Doses of OPC-167832 for Uncomplicated Pulmonary Tuberculosis

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ClinicalTrials.gov Identifier: NCT03678688
Recruitment Status : Recruiting
First Posted : September 20, 2018
Last Update Posted : August 20, 2021
Sponsor:
Collaborator:
Bill and Melinda Gates Foundation
Information provided by (Responsible Party):
Otsuka Pharmaceutical Development & Commercialization, Inc.

Tracking Information
First Submitted Date  ICMJE September 18, 2018
First Posted Date  ICMJE September 20, 2018
Last Update Posted Date August 20, 2021
Actual Study Start Date  ICMJE October 25, 2018
Estimated Primary Completion Date November 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 27, 2021)
  • Change in TB bacterial load in sputum [ Time Frame: baseline to Day 14 ]
    Stage 1: The change in TB bacterial load in sputum as a measure of early bactericidal activity (EBA) and measured by colony-forming unit (CFU) counts on solid media cultures. The EBA will be measured as the slope of the change in log-CFU from baseline (ie, the mean of the values from Day -2 and Day -1) to Day 14.
  • Plasma drug levels of OPC-167832 and/or delamanid and/or Bedaquiline (BDQ) at specified pre-dose and post-dose time points [ Time Frame: up to Day 14-20 ]
    Stage 1: PK parameters will be determined for plasma OPC-167832 Stage 2: PK parameters will be determined for plasma OPC-167832, Delamanid, and BDQ
  • Incidence of adverse events (AEs) [ Time Frame: Up to follow-up visit, an average of 28 days ]
    Stage 1 and Stage 2: The incidence of AEs and the incidence of abnormal laboratory findings in clinical laboratory tests (serum chemistry, hematology, urinalysis, and coagulation), physical examinations, vital signs, and electrocardiograms will be assessed.
Original Primary Outcome Measures  ICMJE
 (submitted: September 19, 2018)
  • Change in TB bacterial load in sputum [ Time Frame: baseline to Day 14 ]
    The change in TB bacterial load in sputum as a measure of early bactericidal activity (EBA) and measured by colony-forming unit (CFU) counts on solid media cultures. The EBA will be measured as the slope of the change in log-CFU from baseline to Day 14.
  • Plasma drug levels of OPC-167832 with and without delamanid at specified pre-dose and post-dose time points [ Time Frame: up to Day 14-20 ]
  • Incidence of adverse events (AEs) [ Time Frame: Up to follow-up visit, an average of 28 days ]
    The incidence of AEs and the incidence of abnormal laboratory findings in clinical laboratory tests (serum chemistry, hematology, urinalysis, and coagulation), physical examinations, vital signs, and electrocardiograms will be assessed.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 27, 2021)
  • Changes in sputum lipoarabinomannan (LAM) concentration and time to detection (TTD) in the Mycobacteria Growth Indicator Tube® (MGIT) system [ Time Frame: baseline to Day 14 ]
    Stage 1: The slope of the change in log-LAM values of OPC-167832 and the change in TTD in the Mycobacteria Growth Indicator Tube® (MGIT) system. Stage 2: The change in TB bacterial load in sputum as a measure of early bactericidal activity (EBA) and measured by colony-forming unit (CFU) counts on solid media cultures. The EBA will be measured as the slope of the change in log-CFU from baseline (ie, the mean of the values from Day -2 and Day -1) to Day 14.
  • Plasma concentrations of rifampin and isoniazid at specified post-dose time points [ Time Frame: Day 14 ]
    Stage 1 and Stage 2 Plasma concentrations of rifampin and isoniazid at 2 and 6 hours post-dose will be determined for compliance.
  • Plasma concentrations of DM-6705 (metabolite of delamanid) and M2 (metabolite of BDQ) at specified pre-dose and post-dose time points [ Time Frame: Day 1, 2, and 12-20 ]
  • Correlation of QT interval and plasma concentrations of OPC-167832 and/or delamanid and/or Bedaquiline [ Time Frame: Day 1 and Day 14 ]
    Stage 1 and 2 The maximum effect and EC80 for OPC-167832, regardless of dose level, will be determined from an exposure-response analysis of the results from the Otsuka TB ELISA LAM. The relationship between QT interval and plasma concentrations of OPC-167832 (stage 1) and OPC-167832 when administered with delamanid and/or BDQ (stage 2) will be evaluated.
  • Incidence of AEs of OPC-167832 with delamanid and or Bedaquiline [ Time Frame: Up to follow-up visit, an average of 28 days ]
    Stage 1 and 2: Incidence of AEs and the incidence of abnormal laboratory findings in clinical laboratory tests (serum chemistry, hematology, urinalysis, and coagulation), physical examinations, vital signs, and electrocardiograms of OPC-167832 when administered with delamanid and/or BDQ (data derived from stage 2) will be compared with the administration of OPC-167832 alone (data derived from stage 1).
Original Secondary Outcome Measures  ICMJE
 (submitted: September 19, 2018)
  • Changes in sputum lipoarabinomannan (LAM) concentration and time to detection (TTD) in the Mycobacteria Growth Indicator Tube® (MGIT) system [ Time Frame: baseline to Day 14 ]
    The slope of the change in log-LAM values of OPC-167832 with and without delamanid.
  • Plasma concentrations of rifampin and isoniazid at specified post-dose time points [ Time Frame: Day 14 ]
  • Plasma concentrations of DM-6705 at specified pre-dose and post-dose time points [ Time Frame: Day 1, 2, and 14-20 ]
  • Correlation of corrected interval using Fridericia's method (QTcF) and plasma concentrations of OPC-167832 with and without delamanid [ Time Frame: Day 1 and Day 14 ]
  • Incidence of AEs of OPC-167832 with delamanid [ Time Frame: Up to follow-up visit, an average of 28 days ]
    Incidence of AEs and the incidence of abnormal laboratory findings in clinical laboratory tests (serum chemistry, hematology, urinalysis, and coagulation), physical examinations, vital signs, and electrocardiograms of OPC-167832 when administered with delamanid (data derived in Stage 2) will be compared with the administration of OPC-167832 alone (data derived from Stage 1).
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Phase 1/2 Trial of Multiple Oral Doses of OPC-167832 for Uncomplicated Pulmonary Tuberculosis
Official Title  ICMJE A Phase 1/2, Active-controlled, Randomized, Open-label Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of Multiple Oral Doses of OPC-167832 Tablets in Subjects With Uncomplicated, Smear-positive, Drug-susceptible Pulmonary Tuberculosis
Brief Summary This trial will evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of multiple oral doses of OPC-167832 in subjects with uncomplicated, smear-positive, drug-susceptible pulmonary tuberculosis (TB).
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

This will be a multiple-dose trial of OPC-167832 with 2 stages.

Stage 1 is a multiple ascending dose trial planned to be conducted in 4 sequential cohorts of 18 participants each. There will be 2 arms (OPC-167832, RHEZ) in each cohort.

Stage 2 will be a parallel group comparison of 4 treatment regimens: 1) OPC-167832 plus Delamanid 2) OPC-167832 plus Bedaquiline 3) OPC-167832 plus Delamanid plus Bedaquiline 4) RHEZ.

Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Pulmonary TB
Intervention  ICMJE
  • Drug: 10 mg OPC-167832
    Once daily oral dose of 10 mg OPC-167832 from Day 1 through Day 14.
  • Drug: 30 mg OPC-167832
    Once daily oral dose of 30 mg OPC-167832 from Day 1 through Day 14.
  • Drug: 90 mg OPC-167832
    Once daily oral dose of 90 mg OPC-167832 from Day 1 through Day 14.
  • Drug: 3 mg OPC-167832
    Once daily oral dose of 3 mg OPC-167832 from Day 1 through Day 14.
  • Drug: RHEZ

    RHEZ will be used in both Stage 1 and Stage 2. Each tablet contains 150 mg rifampicin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol. Participants will receive a single-dose from Day 1 through Day 20. The total number of tablets per day will be based on the pretreatment body weight:

    • Participants weighing 30 to 37 kg will receive 2 tablets per day
    • Participants weighing 38 to 54 kg will receive 3 tablets per day
    • Participants weighing 55 to 70 kg will receive 4 tablets per day
    • Participants weighing > 70 kg will receive 5 tablets per day
  • Drug: 30 mg OPC-167832 plus 300 mg delamanid
    Once daily oral dose of 30 mg OPC-167832 plus 300 mg delamanid from Day 1 through Day 14.
  • Drug: 30 mg OPC-167832 plus 400 mg Bedaquiline (BDQ)
    Once daily oral dose of 30 mg OPC-167832 plus 400 mg BDQ from Day 1 through Day 14. Subjects will receive a loading dose of 700 mg BDQ on Day 1 and 500 mg on Day 2. The dose of BDQ will be 400 mg QD for Days 3 to 14.
  • Drug: 30 mg OPC-167832 plus 300 mg delamanid plus 400 mg Bedaquiline (BDQ)
    Once daily oral dose of 30 mg OPC-167832 plus 300 mg delamanid plus 400 mg BDQ from Day 1 through Day 14. Subjects will receive a loading dose of 700 mg BDQ on Day 1 and 500 mg on Day 2. The dose of BDQ will be 400 mg QD for Days 3 to 14.
Study Arms  ICMJE
  • Active Comparator: Stage 1 and Stage 2: RHEZ
    Intervention: Drug: RHEZ
  • Experimental: Stage 1 Cohort 1
    Intervention: Drug: 10 mg OPC-167832
  • Experimental: Stage 1 Cohort 2
    Intervention: Drug: 30 mg OPC-167832
  • Experimental: Stage 1 Cohort 3
    Intervention: Drug: 90 mg OPC-167832
  • Experimental: Stage 1 Cohort 4
    Intervention: Drug: 3 mg OPC-167832
  • Experimental: Stage 2: OPC-167832/Delamanid
    Intervention: Drug: 30 mg OPC-167832 plus 300 mg delamanid
  • Experimental: Stage 2: OPC-167832/Bedaquiline
    Intervention: Drug: 30 mg OPC-167832 plus 400 mg Bedaquiline (BDQ)
  • Experimental: Stage 2: OPC-167832/Delamanid/Bedaquiline
    Intervention: Drug: 30 mg OPC-167832 plus 300 mg delamanid plus 400 mg Bedaquiline (BDQ)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 27, 2021)
118
Original Estimated Enrollment  ICMJE
 (submitted: September 19, 2018)
125
Estimated Study Completion Date  ICMJE November 2021
Estimated Primary Completion Date November 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Able to provide written, informed consent prior to initiation of any trial-related procedures, and able, in the opinion of the investigator, to comply with all the requirements of the trial.
  • Male or female participants between 18 and 64 years of age (inclusive) at the screening visit.
  • Body mass index ≥ 16.0 and ≤ 32.0 kg/m^2 (inclusive) at the screening visit.
  • Newly diagnosed, uncomplicated, drug-susceptible pulmonary TB.
  • Microscopy performed on a sputum smear at screening indicates presence of acid-fast bacilli (at least 1+).
  • Able to produce an adequate volume of sputum (approximately 10 mL or more estimated overnight production).
  • Female participants of childbearing potential must agree to use 2 different approved methods of birth control or remain abstinent throughout the participation in the trial and for 12 weeks after the last dose of trial treatment (IMP or RHEZ).
  • Male participants must agree to use 2 different approved methods of birth control or remain abstinent throughout the participation in the trial and for 12 weeks after the last dose of trial treatment (IMP or RHEZ).

Exclusion Criteria:

  • Participants are known or suspected of having resistance to rifampicin, isoniazid, ethambutol, or pyrazinamide using any combination of Xpert MTB/RIF, line probe assay, culture, and/or epidemiologic history at screening.
  • Poor general condition where no delay in treatment can be tolerated or where immediate hospital admission is warranted.
  • Evidence of clinically significant metabolic (including ongoing or current hypokalemia), gastrointestinal, neurological, psychiatric, endocrine or liver (e.g., hepatitis B and C) disease; malignancy; or other abnormalities (other than the indication being studied).
  • History of or current clinically relevant cardiovascular disorder such as heart failure, coronary heart disease, hypertension, arrhythmia or symptom strongly suggestive of such a problem (for example, syncope or palpitations), tachyarrhythmia or status after myocardial infarction.
  • Known bleeding disorders or family history of bleeding disorders.
  • Any diseases or conditions in which the use of delamanid, rifampicin, isoniazid, pyrazinamide, ethambutol, or Bedaquiline is contraindicated.
  • Any prior treatment for M. tuberculosis within the past 3 years.
  • Any treatment with a drug active against M. tuberculosis (e.g., quinolones) within the 3 months prior to screening.
  • Clinical evidence of severe extrapulmonary TB (e.g., miliary TB, abdominal TB, urogenital TB, osteoarthritic TB, TB meningitis).
  • Evidence of pulmonary silicosis, lung fibrosis, or other lung condition considered as severe by the investigator (other than TB). In particular any underlying condition that could interfere with the assessment of x-ray images, sputum collection, or interpretation of sputum findings, or otherwise compromise the subject's participation in the trial.
  • Any renal impairment characterized by serum creatinine clearance of <60 mL/min, or hepatic impairment characterized by alanine transaminase, aspartate transaminase, or total bilirubin >1.5 x upper limit of normal of the clinical laboratory reference range at screening.
  • For Stage 1, participants who are HIV positive are excluded. For Stage 2, participants with HIV co-infection who are on antiretroviral drugs during screening or with CD4 cell count <500/mm^3 are excluded.
  • Changes in the ECG such as QTcF >450 msec, atrioventricular block II or III, bi-fasicular block, at screening or current history of clinically significant ventricular arrhythmias. Other ECG changes if considered clinically significant by the investigator.
  • Participants receiving any of the prohibited medications within the specified periods or who would be likely to require prohibited concomitant therapy during the trial.
  • Female participants who are breast-feeding or who have a positive pregnancy test result prior to receiving the first dose of IMP or RHEZ on Day 1.
  • History of significant drug and/or alcohol abuse within 2 years prior to screening.
  • History of or current hepatitis or carriers of HBsAg and/or anti-HCV.
  • Positive urine or blood alcohol test and/or urine drug screen for substance abuse at screening (not including cannabinoids).
  • History of having taken an investigational drug within 30 days preceding trial entry (ie, prior to screening).
  • A history of difficulty in donating blood.
  • Donation of blood or plasma within 30 days prior to dosing.
  • Consumption of alcohol and/or grapefruit, grapefruit juice, Seville oranges, or Seville orange juice and related products within 72 hours prior to the first dose of IMP or RHEZ on Day 1.
  • History of serious mental disorders that, in the opinion of the investigator, would exclude the subject from participating in this trial.
  • Any known prior exposure to OPC-167832, delamanid or Bedaquiline.
  • Participants with significant medical comorbidities that in the opinion of the investigator, should not participate in the trial.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 64 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Global Clinical Development 609 524 6788 mailto:clinicaltransparency@otsuka-us.com
Listed Location Countries  ICMJE South Africa
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03678688
Other Study ID Numbers  ICMJE 323-201-00003
OPP1178898 ( Other Grant/Funding Number: Bill and Melinda Gates Foundation )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Otsuka Pharmaceutical Development & Commercialization, Inc.
Study Sponsor  ICMJE Otsuka Pharmaceutical Development & Commercialization, Inc.
Collaborators  ICMJE Bill and Melinda Gates Foundation
Investigators  ICMJE
Principal Investigator: Veronique R de Jager, MD TASK Clinical Research Centre
Principal Investigator: Prof. Rodney Dawson, MD University of Cape Town (Pty) Ltd.
PRS Account Otsuka Pharmaceutical Development & Commercialization, Inc.
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP