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Safety and Efficacy Evaluation of 4-month Regimen of OPC-167832, Delamanid and Bedaquiline in Participants With Drug-Susceptible Pulmonary TB

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05221502
Recruitment Status : Recruiting
First Posted : February 3, 2022
Last Update Posted : July 5, 2022
Sponsor:
Collaborator:
Bill and Melinda Gates Foundation
Information provided by (Responsible Party):
Otsuka Pharmaceutical Development & Commercialization, Inc.

Brief Summary:
This trial will assess the safety and efficacy of OPC-167832 combined with Delamanid and Bedaquiline in subjects with DS-TB administered for 4 months compared to rifampin, isoniazid, ethambutol, pyrazinamide (RHEZ) administered for 6 months

Condition or disease Intervention/treatment Phase
Pulmonary TB Drug: Delamanid + Bedaquiline + OPC-167832 10 mg Drug: Delamanid + Bedaquiline + OPC-167832 30 mg Drug: Delamanid + Bedaquiline + OPC-167832 90 mg Drug: RHEZ Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 120 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Trial 323-201-00006 is a multicenter, phase 2b/c, open-label, randomized, dose-finding trial in subjects with DS-TB. Following a screening period of up to 14 days, eligible subjects will be randomized on

Day -1 or predose Day 1 in a ratio of 1:2:2:1 to one of the following treatment arms:

Arm 1: DLM (300 mg once daily [QD]) + BDQ (400 mg QD x 2 weeks, then 200 mg thrice-weekly [TIW]) + OPC-167832 (10 mg QD) for 17 weeks

Arm 2: DLM (300 mg QD) + BDQ (400 mg QD x 2 weeks, then 200 mg TIW) + OPC-167832 (30 mg QD) for 17 weeks

Arm 3: DLM (300 mg once daily [QD]) + BDQ (400 mg QD x 2 weeks, then 200 mg TIW) + OPC-167832 (90 mg QD) for 17 weeks

Arm 4: RHEZ for 8 weeks followed by 18 weeks of rifampin and isoniazid (for a total of 26 weeks)

Randomization will be stratified by HIV status (yes or no) and presence of bilateral cavitation on screening chest x-ray (yes or no). After the end of the treatment period, subjects will be followed until 12 months postrandomization.

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multicenter, Phase 2b/c, Open-label, Randomized, Dose-finding Trial to Evaluate the Safety and Efficacy of a 4 Month Regimen of OPC-167832 in Combination With Delamanid and Bedaquiline in Subjects With Drug-susceptible Pulmonary Tuberculosis in Comparison With Standard Treatment
Actual Study Start Date : April 12, 2022
Estimated Primary Completion Date : February 2024
Estimated Study Completion Date : February 2024

Resource links provided by the National Library of Medicine

Drug Information available for: Bedaquiline

Arm Intervention/treatment
Experimental: Arm 1
Delamanid + Bedaquiline + OPC-167832 10 mg
Drug: Delamanid + Bedaquiline + OPC-167832 10 mg
Delamanid (300 mg once daily [QD]) + Bedaquiline (400 mg QD x 2 weeks, then 200 mg thrice-weekly [TIW]) + OPC-167832 (10 mg QD) for 17 weeks

Experimental: Arm 2
Delamanid + Bedaquiline + OPC-167832 30 mg
Drug: Delamanid + Bedaquiline + OPC-167832 30 mg
Delamanid (300 mg once daily [QD]) + Bedaquiline (400 mg QD x 2 weeks, then 200 mg thrice-weekly [TIW]) + OPC-167832 (30 mg QD) for 17 weeks

Experimental: Arm 3
Delamanid + Bedaquiline + OPC-167832 90 mg
Drug: Delamanid + Bedaquiline + OPC-167832 90 mg
Delamanid (300 mg QD) + Bedaquiline (400 mg QD x 2 weeks, then 200 mg TIW) + OPC-167832 (90 mg QD) for 17 weeks

Active Comparator: Arm 4
RHEZ
Drug: RHEZ
RHEZ for 8 weeks followed by 18 weeks of rifampin and isoniazid (for a total of 26 weeks)




Primary Outcome Measures :
  1. Incidence of Treatment Emergent Adverse Events [ Time Frame: Baseline to 12 months post randomization ]
    Incidence of TEAEs: all TEAEs, TEAEs by severity, TEAEs potentially causally related to the IMP or trial medication, TEAEs with an outcome of death or trial medication, Serious TEAEs, TEAEs leading to discontinuation of the IMP or trial medication

  2. Incidence of potentially clinically significant changes of laboratory tests from baseline and abnormalities in the vital signs, physical examinations, electrocardiograms (ECGs) at each visit were assessed and at end of study. [ Time Frame: Baseline to 12 months post randomization ]

    Incidence of potentially clinically significant changes from baseline and abnormalities in the parameters below, at each visit were assessed and at end of study:

    Lab Tests: Hematology, Clinical Chemistry, CD4 Count, Urinalysis Vital Signs: systolic and diastolic blood pressure (mmHg), heart rate (beats/min), respiratory rate (breaths/min), body temperature (C), weight (kg) and body mass index (kg/m2)

    Physical exam include examination of the abdomen; extremities; head, eyes, ears, nose (HEENT); neurological; skin and mucosae; thorax; urogenital; audiometry assessment and visual assessment.

    ECGs:

    ECG PR interval (msec) ECG QTc interval (msec) ECG arrhythmia


  3. Number of participants with a grade 3 or higher AE [ Time Frame: Baseline to 12 months post randomization ]
    The proportion of subjects with a grade 3 or higher AE

  4. Number of all cause Treatment Discontinuation [ Time Frame: Baseline to 12 months post randomization ]
    Rate of All Cause Treatment Discontinuation

  5. Sputum culture conversion (SCC) in Mycobacteria Growth Indicator Tube® (MGIT) [ Time Frame: Baseline to End of Treatment Period - Week 17 and Week 26 ]
    The proportion of subjects achieving sputum culture conversion (SCC) in Mycobacteria Growth Indicator Tube® (MGIT) (Sputum culture conversion occurs when a subject has the first of 2 visits of at least 1 week apart (±4 days) with sputum cultures negative and without a positive sputum culture result in between).


Secondary Outcome Measures :
  1. Proportion of participants who achieve SCC in MGIT by 8 weeks of treatment [ Time Frame: Baseline to Week 8 ]
    Proportion of subjects who achieve SCC.

  2. Time to detection of MGIT cultures [ Time Frame: Baseline to 12 months post randomization ]
    Change in time to detection, in days, of MGIT liquid culture results

  3. Proportion of participants who convert sputum LAM to negative by 8 weeks of treatment and by end of treatment [ Time Frame: End of Treatment Period - Week 17 and Week 26 ]
    The proportion of subjects who convert sputum LAM concentrations from positive to negative by 8 weeks of treatment and by end of treatment

  4. Proportion of participants who develop drug resistance [ Time Frame: Baseline to 12 months post randomization ]
    Proportion of subjects whose sputum cultures test "resistant" to any drugs in the treatment regimens during the treatment period.

  5. Time to Sputum Culture Conversion (SCC) of each treatment group. [ Time Frame: Baseline to 12 months post randomization ]
    To compare time to SCC, in days, of each treatment group.


Other Outcome Measures:
  1. Assess the positron emission tomography/computerized axial tomography (PET/CT) imaging response over the course of treatment [ Time Frame: Baseline to Week 26 ]
    Positron emission tomography/computerized axial tomography (PET/CT) imaging changes over the course of treatment, using quantitative scan assessment.

  2. Evaluate the ribosomal ribonucleic acid synthesis ratio (RS ratio) decline in sputum [ Time Frame: Baseline to 12 months post randomization ]
    The decline of ribosomal ribonucleic acid synthesis ratio (RS ratio - a ratio of spacers between the mRNA) in sputum over the course of trial.

  3. Assess whole blood transcriptomic signatures previously associated with TB cure from serum [ Time Frame: Screening to 12 months post randomization ]
    The change in whole blood transcriptomic signatures over the course of treatment will be evaluated using ROC curves for association with microbiological and clinical response.

  4. The proportion of participants with favorable outcome at 12 months post randomization [ Time Frame: Baseline to 12 months post randomization ]
    The proportion of subjects with favorable outcome as compared to the 6 months post end of treatment and at 12 months post randomization.

  5. Number of participants with relapse at 12 months post randomization [ Time Frame: Baseline to 12 months post randomization ]
    Proportion of participants with relapse at 12 months post randomization.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Able to provide written, informed consent prior to initiation of any trial-related procedures or treatments, and able, in the opinion of the investigator, to comply with all the requirements of the trial.
  2. Male or female participants between 18 and 65 years of age (inclusive) at the screening visit.
  3. Body weight ≥ 35.0 kg at the screening visit.
  4. Newly diagnosed, rifampin and isoniazid susceptible (on the screening sample) pulmonary TB.
  5. Able to spontaneously produce sputum.
  6. Females of childbearing potential (FOCBP) must agree to use 2 different approved methods of birth control or remain abstinent throughout their participation in the trial and for 12 weeks after the last dose of IMP or dose of RHEZ.
  7. Male participants must agree to use 2 different approved methods of birth control or remain abstinent throughout their participation in the trial and for 12 weeks after the last dose of IMP or RHEZ.

Exclusion Criteria:

  1. Participants are known or suspected of having resistance to rifampin, isoniazid, ethambutol, pyrazinamide, DLM, or BDQ either confirmed by the laboratory, or based on epidemiological history, at screening.
  2. Evidence of clinically significant metabolic (for example, including ongoing or current hypokalemia [ie, potassium <3.5 mEq/dL at screening]), gastrointestinal, neurological, psychiatric, endocrine or liver (eg, hepatitis B and C) disease; malignancy; or other abnormalities (other than the indication being studied).
  3. History of, or current, clinically relevant cardiovascular disorder such as heart failure, coronary heart disease, uncontrolled hypertension, arrhythmia or symptom strongly suggestive of such a problem (for example, syncope or palpitations), tachyarrhythmia or status after myocardial infarction.
  4. Known bleeding disorders or family history of bleeding disorders.
  5. Any diseases or conditions in which the use of DLM, BDQ, OPC 167832, rifampin, isoniazid, pyrazinamide, or ethambutol is contraindicated.
  6. Any prior treatment for M tuberculosis within the past 2 years.
  7. Any treatment with a drug active against M tuberculosis (eg, quinolones) within the 3 months prior to screening.
  8. Clinical evidence of severe extrapulmonary TB (eg, miliary TB, abdominal TB, urogenital TB, osteoarthritic TB, TB meningitis).
  9. 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.
  10. Any renal impairment characterized by creatinine clearance/estimated glomerular filtration rate (eGFR) of < 60 mL/min/1.73 m2, or hepatic impairment characterized by alanine transaminase or aspartate transaminase > 2.0 × upper limit of normal of the clinical laboratory reference range or bilirubin > 2.0 × upper limit of normal of the clinical laboratory reference range, at screening.
  11. Screening glucose (nonfasting) ≥ 200 mg/dL or glycosylated hemoglobin (HbA1c) ≥ 6.5%.
  12. QTcF > 450 msec in male participants (> 470 msec in female participants), atrioventricular block II or III, bi-fasicular block, at screening or current or history of clinically significant ventricular arrhythmias. Other ECG abnormalities, if considered clinically significant by the investigator.
  13. Participants receiving any of the prohibited medications (see Section 6.5.1) within the specified periods or who would be likely to require prohibited concomitant therapy during the trial.
  14. 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.
  15. Current history of significant drug and/or alcohol abuse that is likely to result in poor adherence to trial requirements or that would pose a risk to the participant's well-being during the course of the trial.
  16. History of current hepatitis or carriers of hepatitis B surface antigen (HBsAg) and/or anti hepatitis C virus (HCV).
  17. Participants who test positive for cocaine or other drugs of abuse (excluding known prescription stimulants and other prescribed medications and marijuana) at screening are excluded. Detectable levels of alcohol, marijuana, barbiturates, or opiates in the drug screen are not exclusionary if, in the investigator's documented opinion, the participant does not meet Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for moderate to severe substance use disorder and the positive test does not signal a clinical condition that would impact the safety of the participant or interpretation of the trial results, and participation is agreed to by the medical monitor prior to treatment.
  18. History of having taken an investigational drug within 30 days preceding trial entry.
  19. A history of difficulty in donating blood.
  20. Donation of blood or plasma within 30 days prior to dosing.
  21. History of serious mental disorders that, in the opinion of the investigator, would exclude the participant from participating in this trial.
  22. Any known prior exposure to OPC-167832, DLM, or BDQ.
  23. Participants with significant medical comorbidities that in the opinion of the investigator, should not participate in the trial.
  24. Participants with Karnofsky score < 60 will be excluded from the trial.
  25. Participants testing positive for active severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection at screening.
  26. Participants with HIV co infection not on a stable anti-retroviral regimen consisting of tenofovir, emtricitabine/ lamivudine, dolutegravir (ie > 3 months), or who have a detectable viral load, or who have a CD4 count < 350 cells/mm3 will be excluded from the trial.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05221502


Contacts
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Contact: Jeffrey Hafkin, MD +1 240 683 3281 Jeffrey.Hafkin@otsuka-us.com

Locations
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South Africa
Aurum Institute - Tembisa Clinical Research Centre Recruiting
Tembisa, Gauteng, South Africa, 1632
Contact: Modulakgotla Sebe, MD    027 87 135 1645    msebe@auruminstitute.org   
Ndlovu Research Centre Not yet recruiting
Dennilton, Limpopo, South Africa, 0470
Contact: Rebone Maboa, MD       rmaboa@ndlovu.com   
TASK Delft Recruiting
Cape Town, South Africa, 7100
Contact: Thirumani Govender, MD       dr.thirumani@task.org.za   
University of CapeTown Lung Center Institute Recruiting
Cape Town, South Africa, 7700
Contact: Rodney Dawson, MD    +27(0) 21 406 6864    rodney.dawson@uct.ac.za   
Principal Investigator: Rodney Dawson, MD         
Masiphumelele Clinical Research Site Recruiting
Cape Town, South Africa, 7975
Contact: Mellissa Le Fevre, MD       mellissa.lefevre@hiv-research.org.za   
Themba Lethu Clinic Clinical HIV Research Unit (CHRU) Recruiting
Johannesburg, South Africa, 2092
Contact: Mohammed Rassool, MD       mrassool@witshealth.co.za   
Perinatal HIV Research Unit Tshepong Hospital Complex Recruiting
Klerksdorp, South Africa, 2574
Contact: Ebrahim Variava, MD       variava@worldonline.co.za   
Setshaba Research Center Recruiting
Pretoria, South Africa, 0152
Contact: Khatija Ahmed, MD       kahmed@setshaba.org.za   
Sponsors and Collaborators
Otsuka Pharmaceutical Development & Commercialization, Inc.
Bill and Melinda Gates Foundation
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Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
ClinicalTrials.gov Identifier: NCT05221502    
Other Study ID Numbers: 323-201-00006
First Posted: February 3, 2022    Key Record Dates
Last Update Posted: July 5, 2022
Last Verified: August 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Anonymized Individual participant data (IPD) that underlie the results of this study will be shared with researchers to achieve aims pre-specified in a methodologically sound research proposal. Small studies with less than 25 participants are excluded from data sharing.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Time Frame: Data will be available after marketing approval in global markets, or beginning 1-3 years following article publication. There is no end date to the availability of the data.
Access Criteria: Otsuka will share data on the Vivli data sharing platform which can be found here: https://vivli.org/ourmember/Otsuka/
URL: https://clinical-trials.otsuka.com

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Tuberculosis, Pulmonary
Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Bacterial Infections and Mycoses
Infections
Respiratory Tract Infections
Lung Diseases
Respiratory Tract Diseases
Bedaquiline
Diarylquinolines
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents