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A Trial to Evaluate the Male Reproductive Safety of Pretomanid in Adult Male Participants With Drug Resistant (DR-TB) Pulmonary TB Volunteers (PaSEM) (PaSEM)

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: NCT04179500
Recruitment Status : Recruiting
First Posted : November 27, 2019
Last Update Posted : October 11, 2021
Sponsor:
Information provided by (Responsible Party):
Global Alliance for TB Drug Development

Brief Summary:
Pretomanid is being used in an antimicrobial combination regimen(s) to treat patients with pulmonary tuberculosis. The primary purpose of the Male Reproductive Safety - "BPaMZ/SEM"- clinical study is to evaluate the potential effect of pretomanid on human testicular function whilst being used in a 26 weeks antimicrobial combination regimen consisting of bedaquiline (B) plus pretomanid (Pa) plus moxifloxacin (M) and pyrazinamide (Z) (BPaMZ).

Condition or disease Intervention/treatment Phase
Tuberculosis, Pulmonary Tuberculosis, Multidrug-Resistant Tuberculosis, MDR Tuberculosis Drug-Resistant Tuberculosis Drug: Pretomanid Drug: Bedaquiline Drug: moxifloxacin Drug: pyrazinamide Phase 2

Detailed Description:

The primary objective of this study is to assess the male reproductive safety of pretomanid in the regimen (BPaMZ) of bedaquiline 200mg (200mg daily for 8 weeks then 100 mg daily for 18 weeks), together with pretomanid 200 mg (1x daily) + moxifloxacin 400 mg (1x daily) + pyrazinamide 1500 mg (1 x daily) for 26 weeks in participants with Drug-resistant (DR) pulmonary TB.

The secondary objective of the study is to evaluate the TB treatment efficacy, safety and tolerability after 26 weeks of active treatment for TB and follow up until 45 weeks after start of the above described treatment regimen in participants with Drug-resistant (DR) pulmonary TB.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:

Phase 2 single arm multi-center, open-label clinical trial in DR-TB participants. Participants will receive bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks together with pretomanid 200 mg

+ moxifloxacin 400 mg + pyrazinamide 1500 mg once daily (BPaMZ) for 26 weeks.

Participants will be followed for 18 weeks after end of treatment

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-Label Phase 2 Trial to Evaluate the Male Reproductive Safety of a 6-Month Combination Treatment for Pulmonary TB of Bedaquiline Plus Pretomanid Plus Moxifloxacin Plus Pyrazinamide (BPaMZ) in Adult Male Participants With Drug Resistant (DR-TB) Pulmonary TB
Actual Study Start Date : September 16, 2021
Estimated Primary Completion Date : October 2022
Estimated Study Completion Date : April 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Medicines

Arm Intervention/treatment
Experimental: Study Participants
Participants will receive bedaquiline 200 mg once daily for 8 weeks then 100 mg once daily for 18 weeks together with pretomanid 200 mg + moxifloxacin 400 mg + pyrazinamide 1500 mg once daily (BPaMZ) for 26 weeks.
Drug: Pretomanid
pretomanid 200 mg (once daily) for 26 weeks (with meal)
Other Name: Pa-824

Drug: Bedaquiline
bedaquiline 200 mg (once daily) for 8 weeks (with meal), then bedaquiline 100mg (once daily) for 18 weeks (with meal)

Drug: moxifloxacin
moxifloxacin 400 mg (once daily) for 26 weeks (with meal)

Drug: pyrazinamide
pyrazinamide 1500 mg (once daily) for 26 weeks (with meal)




Primary Outcome Measures :
  1. Total Sperm Number - Week 26 [ Time Frame: Week 26 ]
    Change from baseline in total sperm number at 26 weeks of therapy.


Secondary Outcome Measures :
  1. Total Sperm Number - Week 13 and Week 18 [ Time Frame: Week 13 and Week 18 ]
    Change from baseline in total sperm number at 13 weeks of therapy and at 18 weeks post end of therapy.

  2. Change in Male Reproductive Hormones [ Time Frame: Up to Week 44 ]
    The change from baseline in male reproductive hormones at Week 2, 4, 8,12,16, 26, 44 and at early withdrawal. Reproductive hormones: luteinizing hormone (LH), follicle-stimulating hormone (FSH), Inhibin B and testosterone)

  3. Efficacy: Bacteriologic Failure or relapse or clinical failure [ Time Frame: 18 weeks after end of therapy ]
    Incidence of bacteriologic failure or relapse or clinical failure 18 weeks after end of therapy.

  4. Efficacy: Sputum culture conversion to negative status in liquid culture [ Time Frame: Up to Week 44 ]
    Proportion of participants with sputum culture conversion to negative status in liquid culture (MGIT) at Week 4, 8, 12, 16, 22, 26 and 44

  5. Safety and Tolerability: Weight [ Time Frame: Week 26 ]
    Change in weight from baseline at 26 weeks of therapy.

  6. Safety and Tolerability: Treatment Emergent Adverse Events (TEAEs) [ Time Frame: Week 26 ]
    Incidence of Treatment Emergent Adverse Events (TEAEs) presented by incidence, severity, drug relatedness, seriousness, leading to early withdrawal, and leading to death. at 26 weeks of therapy.

  7. Safety and Tolerability: Clinical safety laboratory measurements - full blood count [ Time Frame: Week 26 ]
    Quantitative and qualitative clinical safety laboratory measurements (full blood count: hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, platelet count), including observed and change from baseline at 26 weeks of therapy

  8. Safety and Tolerability: Clinical safety laboratory measurements - clinical chemistry [ Time Frame: Week 26 ]
    Quantitative and qualitative clinical safety laboratory measurements (clinical chemistry: albumin, urea, creatinine, direct, indirect and total bilirubin, uric acid, total protein, alkaline phosphatase [ALP], aspartate aminotransferase [AST], alanine aminotransferase [ALT], lipase, phosphate, sodium, potassium, calcium (corrected for albumin), chloride, magnesium, glucose, bicarbonate/carbon dioxide [CO2], creatine phosphokinase [CPK]), including observed and change from baseline at 26 weeks of therapy.

  9. Safety and Tolerability: Clinical safety laboratory measurements - clinical chemistry [ Time Frame: Week 26 ]
    Quantitative and qualitative clinical safety laboratory measurements (Urinalysis: pH, specific gravity, protein, glucose, micro-albumin, ketones, bilirubin, creatinine, nitrite, sodium, urobilinogen, blood, leukocytes), including observed and change from baseline at 26 weeks of therapy.

  10. Safety and Tolerability: ECG results [ Time Frame: Week 26 ]
    Quantitative and qualitative electrocardiogram (ECG) results (heart rate, RR interval, PR interval, QRS interval, QT interval and QTc interval, including observed QT/QTc intervals and change from baseline) will be categorized at 26 weeks of therapy.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Gender Based Eligibility:   Yes
Gender Eligibility Description:   males 18 years of age or older
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Participants are required to meet all the following inclusion criteria during the screening period to be enrolled. Patients must abstain from ejaculation for at least 2 days prior to screening clinic visit.

  1. Understands study procedures and voluntarily provides written informed consent prior to the start of any study-specific procedures.
  2. Male gender 18 years or over
  3. Body weight (in light clothing and no shoes) ≥ 45kg.
  4. A positive molecular test for tuberculosis in sputum either at screening or within one month prior to enrolment.

Exclusion criteria- Participants will be excluded from participation if they meet any of the following criteria.

Medical History and Concurrent Conditions:

1. Resistant to fluoroquinolones by rapid molecular test 2. History of male infertility or vasectomy 3. Unable to produce semen sample 4. Evidence at screening of azoospermia 5. Known erectile dysfunction that would prevent ejaculation. 6. Historical or active disease process of the male reproductive tract that would compromise sperm production. e.g. tuberculous epididymitis. 5. Disease Characteristics:

  • Participants must have been diagnosed with TB prior to or at screening
  • Participants' TB should be resistant to rifampicin and/or isoniazid, and susceptible to fluoroquinolones by rapid sputum-based tests.
  • Participants who have had previous treatment for DR-TB for more than 28 days at start of screening should be discussed with the medical monitor. 6. A chest x-ray, within 26 weeks prior to or at the screening visit, which in the opinion of the Investigator is compatible with pulmonary TB 7. History of any illness that, in the opinion of the Investigator, might confound the results of the study or poses an additional risk to the participant by their Participation in the study.

    8. Abuse of alcohol or illegal drugs that in the opinion of the Investigator would compromise the participants' safety or ability to follow through with all protocol-specified restrictions, visits, and evaluations. 9. Being, or about to be, treated for malaria. 10. Is critically ill and, in the judgment of the Investigator, has a diagnosis likely to result in death during the trial or the follow-up period. 11. TB meningitis or other forms of extrapulmonary tuberculosis with high risk of a poor outcome, or likely to require a longer course of therapy (such as TB of the bone or joint), as judged by the Investigator. 12. History of allergy or hypersensitivity to any of the trial IMP or related substances, including known allergy to any fluoroquinolone antibiotic, history of tendinopathy associated with quinolones. 13. For HIV infected participants any of the following:

    1. CD4+ count <100 cells/μL
    2. Received intravenous antifungal medication within the last 90 days
    3. WHO Clinical Stage 4 HIV disease (Appendix 3) 14. Participants who recently started or expected to need to start ART within 1 month after randomization. Participants who have been on ARTs for more than 30 days prior to start of the Screening visit or expected to start ART greater than 30 days after enrolment may be included. 15. Participants with any of the following at the Screening visit (per measurements and reading done by ECG):
    1. QTcF interval on ECG >500 msec. Participants with QTcF > 450 must be discussed with the Sponsor Medical Monitor before enrolment.
    2. Heart failure
    3. A personal or family history of congenital QT prolongation
    4. A history of or known, untreated, ongoing hypothyroidism
    5. A history of or ongoing bradyarrhythmia
    6. A history of Torsade de Pointe 16. Unstable Diabetes Mellitus which required hospitalization for hyper- or hypo-glycaemia within the past year prior to start of screening. 17. Receiving any form of hormone or hormone-like (nutraceuticals) therapy. 18. Received pretomanid and/or delamanid to treat TB 19. Known chronic hepatitis B or C 20. Use of any drug within 30 days prior to randomisation known to prolong QTc interval (including, but not limited to, amiodarone, amitriptyline, bepridil, chloroquine, chlorpromazine, cisapride, clarithromycin, disopyramide dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, levomethadyl, mesoridazine, methadone, pentamidine, pimozide, procainamide, quinacrine, quinidine, sotalol, sparfloxacin, thioridazine). 21. For HIV infected participants:
    1. The following antiretroviral therapy (ART) should not be used:

      1. Stavudine
      2. Zidovudine
      3. Didanosine
      4. Triple NRTI regimen is not considered optimal for HIV treatment (poor efficacy)
    2. A standard NRTI backbone may be combined with the following:

      1. Rilpivirine
      2. Dolutegravir
      3. Raltegravir
      4. Nevirapine
      5. Lopinavir/r
      6. Participants who are on efavirenz, atazanavir/r or darunavir/r at the time of screening and have an undetectable viral load, should have their ART switched to one of the agents listed above (1-5). It would be preferable to switch to another permissible ARV within the same class accompanied by the same nucleoside backbone.
    3. ART regimen choice should be discussed with the Sponsor Medical Monitors if there are any concerns.

Confirmed plans to use Isoniazid prophylaxis for HIV positive participants during the treatment and follow up period is not permitted.


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): NCT04179500


Contacts
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Contact: Joanna Moreira 1 (646) 616-8621 Joanna.Moreira@tballiance.org
Contact: Paul Bruinenberg, MD, MBA +1 646-616-8629 Paul.Bruinenberg@tballiance.org

Locations
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South Africa
CHRU, Sizwe Tropical Diseases Hospital Recruiting
Johannesburg, South Africa
Contact: Pauline Howell, MD         
Isango Lethemba TB Research Unit Empilweni TB Hospital Recruiting
Port Elizabeth, South Africa
Contact: Veronique Bailey, MD         
The Aurum Institute: Rustenburg Clinical Research Centre Recruiting
Rustenburg, South Africa
Contact: William Brumskine, MD         
Sponsors and Collaborators
Global Alliance for TB Drug Development
Investigators
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Study Chair: Paul Bruinenberg, MD, MBA Global Alliance for TB Drug Development
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Responsible Party: Global Alliance for TB Drug Development
ClinicalTrials.gov Identifier: NCT04179500    
Other Study ID Numbers: Pa-824-CL-012
First Posted: November 27, 2019    Key Record Dates
Last Update Posted: October 11, 2021
Last Verified: October 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Global Alliance for TB Drug Development:
tuberculosis
TB
DR-TB
pretomanid (PA)
PA-824
XDR TB
Pa
Additional relevant MeSH terms:
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Tuberculosis
Tuberculosis, Multidrug-Resistant
Tuberculosis, Pulmonary
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Bacterial Infections and Mycoses
Infections
Respiratory Tract Infections
Lung Diseases
Respiratory Tract Diseases
Moxifloxacin
Pyrazinamide
Bedaquiline
Anti-Bacterial Agents
Anti-Infective Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antitubercular Agents