Tuberculosis (TB) is a leading cause of infectious disease death, especially in HIV-prevalent regions, and the emergence of highly resistant TB further threatens global TB control. There is a need for highly potent TB treatments that can cure disease in substantially fewer than the six months currently required. PA-824, an investigational nitroimidazole with bactericidal and sterilizing activity against M. tuberculosis, has significant potential as a treatment-shortening drug when used as part of multidrug TB therapy. The nitroimidazoles are of particular interest because of their activity against "persisters," those bacteria that are hard to kill and lead to relapse when TB is not treated for a long enough duration. In an experimental murine model of TB, PA-824 was shown to have bactericidal activity during the early phase of TB treatment and sterilizing activity during the continuation phase of TB therapy when given as monotherapy. In subsequent murine studies, using PA-824 in combination with a multidrug regimen containing rifampin and pyrazinamide reduced the treatment time required for cure from 6 months to 4 months. Phase I and early Phase II studies suggest that PA-824 is well tolerated and has measurable, dose-dependent early bactericidal activity, significantly reducing sputum colony counts of M. tuberculosis over two weeks of once-daily dosing. The main objective of the proposed Phase II clinical trial is to evaluate the antimicrobial activity of PA-824 when added to standard-dose TB treatment over the first 12 weeks of TB treatment. Patients with sputum smear-positive pulmonary TB in Cape Town, South Africa, will all receive standard doses of isoniazid, rifampin, and pyrazinamide and will be randomized to receive PA-824 200 mg once daily for 8 weeks (Arm 1), PA-824 200 mg once daily for 12 weeks (Arm 2), or ethambutol at standard doses for 8 weeks (control arm). The primary efficacy endpoint will be time to stable sputum culture conversion in liquid media, defined as the time from the start of treatment until the first of at least two negative sputum cultures, over 12 weeks. The primary safety endpoint is grade 3 or higher adverse events. Pharmacokinetics, solid culture results after 8 weeks of treatment, change in time to sputum culture positivity in liquid culture, and quantitative change in extent of disease on computed tomography will also be assessed. Results will determine the antimicrobial activity of daily PA-824 and inform further development of PA-824, a highly promising drug for TB treatment shortening.

Public Health Relevance

Tuberculosis (TB) is a leading cause of infectious disease death worldwide, and new drugs are needed to shorten treatment from the current six months to four months or less. PA-824 has demonstrated impressive activity against TB in preclinical studies and is of particular interest because of its activity against persisters, those bacteria that are hard to kill and lead to relapse when TB is not treated for a long enough duration. The goal of this project is assess the antimicrobial activity of PA-824 when used with other standard TB medicines during the first 12 weeks of treatment for pulmonary TB.

Agency
National Institute of Health (NIH)
Institute
Food and Drug Administration (FDA)
Type
Research Project (R01)
Project #
1R01FD004794-01
Application #
8615391
Study Section
Special Emphasis Panel (ZFD1-OPD-N (S1))
Project Start
2014-08-15
Project End
2018-07-31
Budget Start
2014-08-15
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218