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

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

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Tuberculosis; Tuberculosis, Pulmonary; Tuberculosis, Multidrug-Resistant; Tuberculosis, MDR; Drug-Resistant Tuberculosis
• Intervention / Treatment: Drug: Pretomanid; Drug: Bedaquiline; Drug: moxifloxacin; Drug: pyrazinamide

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.

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Joanna Moreira; Phone Number: 1 (646) 616-8621; Email: Joanna.Moreira@tballiance.org
• Study Contact Backup: Name: Paul Bruinenberg, MD, MBA; Phone Number: +1 646-616-8629; Email: Paul.Bruinenberg@tballiance.org

Study Locations

• Georgia
  • Tbilisi, Georgia
    • National Center for Tuberculosis and Lung Diseases
• South Africa
  • Johannesburg, South Africa
    • CHRU, Sizwe Tropical Diseases Hospital
  • Port Elizabeth, South Africa
    • Isango Lethemba TB Research Unit Empilweni TB Hospital
  • Rustenburg, South Africa
    • The Aurum Institute: Rustenburg Clinical Research Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

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. For HIV infected participants any of the following:

   1. CD4+ count <100 cells/μL
   2. Received intravenous antifungal medication within the last 90 days
9. 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.
10. Received pretomanid and/or delamanid to treat TB
11. Known chronic hepatitis B or C

12. 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)

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:

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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 Names: 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)

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

Collaborators and Investigators

• Sponsor: Global Alliance for TB Drug Development
• Investigators: Study Chair: Antonio Lombardi, MD, Global Alliance for TB Drug Development

Study record dates

Study Major Dates

• Study Start (Actual): September 16, 2021
• Primary Completion (Actual): June 19, 2023
• Study Completion (Estimated): August 30, 2024

Study Registration Dates

• First Submitted: November 25, 2019
• First Submitted That Met QC Criteria: November 25, 2019
• First Posted (Actual): November 27, 2019

Study Record Updates

• Last Update Posted (Actual): September 13, 2023
• Last Update Submitted That Met QC Criteria: September 12, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: TB; tuberculosis; PA-824; DR-TB; pretomanid (PA); XDR TB; Pa
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Pulmonary; Tuberculosis, Multidrug-Resistant; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Antitubercular Agents; Moxifloxacin; Bedaquiline; Pyrazinamide
• Other Study ID Numbers: Pa-824-CL-012

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No