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

• Status: Recruiting
• Trial end date: 2023-04-01
• Target enrollment: 0
• Participant gender: Male

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).

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Global Alliance for TB Drug Development
• Treatments: Bedaquiline; Moxifloxacin; Pyrazinamide

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.