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

This is an interventional treatment trial for Tuberculosis, Pulmonary focused on measuring tuberculosis, TB, DR-TB, pretomanid (PA), PA-824, XDR TB, Pa Read More

Inclusion Criteria:

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.

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 3 months 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. Participants will be required to use a double contraceptive method during the whole treatment duration and 18 weeks post dose.
8. Can comply with the protocol and the assessments therein, including all restrictions.

Exclusion criteria:

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.
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
14. Participants with newly diagnosed tuberculosis and HIV that require initiation of appropriate HIV therapy before participants has received at least 2 weeks of an antituberculosis regimen.

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, except for well treated 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, except for well treated hypothyroidism.
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)

b. 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.

   c. ART regimen choice should be discussed with the Sponsor Medical Monitors if there are any concerns.

22. Participants with the following toxicities at screening as defined by the enhanced Division of Microbiology and Infectious Disease (DMID) adult toxicity table (Draft November 2007) where applicable:

1. Platelets <75,000/mm3
2. Creatinine >1.5 times upper limit of normal (ULN)
3. eGFR ≤ 60 mL/min
4. Haemoglobin <8.0 g/dL
5. Serum potassium less than the lower limit of normal for the laboratory. This may be repeated once

6. AST:

   • ≥3.0 x ULN to be excluded
   • results between 1.5 x ULN and 3 x ULN must be discussed with and approved by the Sponsor Medical Monitor

7. ALT:

   • ≥3.0 x ULN to be excluded
   • greater than ULN must be discussed with and approved by the Sponsor Medical Monitor

8. ALP:

   • ≥3.0 x ULN to be excluded
   • 2.0 - <3.0 x ULN must be discussed with and approved by the Sponsor Medical Monitor

9. Total bilirubin:

   • >1.5 x ULN to be excluded
   • Greater than ULN must be discussed with and approved by the Sponsor Medical Monitor

10. Direct bilirubin:

    • greater than 1x ULN to be excluded

11. Positive hepatitis B surface Ag, or hepatitis C antibody