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

Study Overview
=================
Brief Summary
-----------------
Pretomanid is being used in an antimicrobial combination regimen(s) to treat patients with pulmonary tuberculosis (TB). 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).

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 pulmonary tuberculosis (DR-TB). The secondary objective of the study is to evaluate the tuberculosis (TB) treatment efficacy, safety and tolerability after 26 weeks of active treatment for TB and follow up until 52 weeks after end of the above-described treatment regimen in participants with DR-TB.

Official Title
-----------------
An Open-Label Phase 2 Trial to Evaluate the Male Reproductive Safety of a 6-Month Combination Treatment for Pulmonary Tuberculosis (TB) of Bedaquiline Plus Pretomanid Plus Moxifloxacin Plus Pyrazinamide (BPaMZ) in Adult Male Participants With Drug Resistant Pulmonary TB

Conditions
-----------------
Tuberculosis, Pulmonary, Tuberculosis, Multidrug-Resistant, Tuberculosis, MDR, Tuberculosis, Drug-Resistant Tuberculosis

Intervention / Treatment
-----------------
* Drug: Pretomanid
* Drug: Bedaquiline
* Drug: moxifloxacin
* Drug: pyrazinamide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Understands study procedures and voluntarily provides written informed consent prior to the start of any study-specific procedures. Male gender 18 years or over Body weight (in light clothing and no shoes) ≥ 45kg. A positive molecular test for tuberculosis in sputum either at screening or within one month prior to enrolment. 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. 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 Exclusion criteria: Resistant to fluoroquinolones by rapid molecular test History of male infertility or vasectomy Unable to produce semen sample Evidence at screening of azoospermia Known erectile dysfunction that would prevent ejaculation. Historical or active disease process of the male reproductive tract that would compromise sperm production. e.g. tuberculous epididymitis. 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. For HIV infected participants any of the following: CD4+ count <100 cells/μL Received intravenous antifungal medication within the last 90 days 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. Received pretomanid and/or delamanid to treat TB Known chronic hepatitis B or C For HIV infected participants: 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) 13. 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: Platelets <75,000/mm3 Creatinine >1.5 times upper limit of normal (ULN) eGFR ≤ 60 mL/min Haemoglobin <8.0 g/dL Serum potassium less than the lower limit of normal for the laboratory. This may be repeated once 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 ALT: ≥3.0 x ULN to be excluded greater than ULN must be discussed with and approved by the Sponsor Medical Monitor 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 Total bilirubin: >1.5 x ULN to be excluded Greater than ULN must be discussed with and approved by the Sponsor Medical Monitor Direct bilirubin: • greater than 1x ULN to be excluded Positive hepatitis B surface Ag, or hepatitis C antibody

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional 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 52 weeks after end of treatment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study Participants<br>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<br>* pretomanid 200 mg (once daily) for 26 weeks (with meal)<br>* Other names: Pa-824;Drug: Bedaquiline<br>* bedaquiline 200 mg (once daily) for 8 weeks (with meal), then bedaquiline 100mg (once daily) for 18 weeks (with meal)<br>Drug: moxifloxacin<br>* moxifloxacin 400 mg (once daily) for 26 weeks (with meal)<br>Drug: pyrazinamide<br>* pyrazinamide 1500 mg (once daily) for 26 weeks (with meal)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Sperm Number - Week 26 | Change from baseline in total sperm number at 26 weeks of therapy. | Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Sperm Number - Week 13 and Week 44 | Change from baseline in total sperm number at 13 weeks of therapy and at 18 weeks post end of therapy. | Week 13 to Week 44 | 
| Change in Male Reproductive Hormones | The change from baseline in Male reproductive hormones at Week 2, 4, 8, 12, 16, 35, 44, 52, 65, 78 and at early withdrawal. Reproductive hormones: luteinizing hormone (LH), follicle-stimulating hormone (FSH), Inhibin B and Testosterone. | Up to Week 78 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
TB, tuberculosis, DR-TB, pretomanid (PA), PA-824, XDR TB, Pa