Isoniazid

Regimen Would Decrease Duration of Treatment from Nine to Six Months LOS ANGELES, Dec. 07, 2023 (GLOBE NEWSWIRE) -- ACTG, a global clinical trials network focused on HIV and other infectious diseases, today announced the opening of the IMAGINE-TBM study (Improved Management with Antimicrobial AGents Isoniazid rifampiciN LinEzolid for TBM, also known as A5384). IMAGINE-TBM is a phase 2, randomized, open-label trial comparing a six-month regimen of high-dose rifampicin, high-dose isoniazid, linezolid, and pyrazinamide to the nine-month standard-of-care regimen for the treatment of tuberculous meningitis. Tuberculous meningitis is a life-threatening infectious disease that causes inflammation of the membranes that surround the brain and spinal cord. It is the most severe form of tuberculosis and is universally fatal when untreated. Even with standard-of-care treatment, outcomes are poor, with high rates of mortality and chronic disability among those who survive. While the global burden of tuberculous meningitis is unclear (due in large part to limited diagnostics), it is estimated to affect at least 100,000 people worldwide each year. “ACTG is especially excited about IMAGINE-TBM because it is an important step in addressing the paucity of data evaluating the best treatment approach for this devastating illness,” said ACTG Chair Judith Currier, M.D., M.Sc., University of California, Los Angeles. “ACTG has designed this study with investigators from around the globe with the goal of evaluating the potential benefit of the new regimen in diverse settings.” This multi-center trial will enroll 330 participants aged 15 years and older who have definite, probable, or possible tuberculous meningitis, including people living with and without HIV. Participants will be randomized in equal proportions to receive either the six-month regimen being studied or the nine-month standard of care: Those in the six-month regimen arm will receive rifampicin 35 mg/kg, isoniazid 10-15 mg/kg, linezolid 1200 mg, and pyrazinamide 25 mg/kg for eight weeks followed by rifampicin 35 mg/kg and isoniazid 10 mg/kg for 16 weeks (for a total of 24 weeks of study treatment)Those in the nine-month standard-of-care regimen arm will receive rifampicin 10 mg/kg, isoniazid 5 mg/kg, ethambutol 20 mg/kg, and pyrazinamide 25 mg/kg for eight weeks, followed by rifampicin 10 mg/kg and isoniazid 5 mg/kg for 28 weeks (for a total of 36 weeks of study treatment). Up to 15 mg/kg or a maximum of 900 mg daily of oral rifampicin will be permitted at the clinician’s discretion. “IMAGINE-TBM is ACTG’s first tuberculous meningitis protocol and will take place in locations around the world that have a high tuberculosis burden,” said IMAGINE-TBM protocol Co-Chair Felicia Chow, M.D., M.A.S., University of California, San Francisco. “IMAGINE-TBM is a tremendous opportunity to leverage ACTG’s diverse international sites to test a novel intervention for this devastating form of TB.” IMAGINE-TB will take place at 17 sites in Peru, Tanzania, Thailand, Vietnam, Mexico, Philippines, India, Brazil, Zimbabwe, Kenya, Malawi, and South Africa. It is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (which also funds ACTG) under award numbers UM1 AI068636, UM1 AI107716, and UM1 AI068634. “Our hope is that this regimen will result in improved outcomes among individuals compared to the current standard of care, while significantly decreasing the required length of treatment,” said IMAGINE-TBM protocol Co-Chair Vidya Mave, M.D., M.P.H., Byramjee Jeejeebhoy Government Medical College-Johns Hopkins University Clinical Research Site and Johns Hopkins Center for Infectious Diseases in India. “One of the top priorities for tuberculous meningitis research is optimizing treatment, which could have a profound impact on a population who has historically experienced abysmal outcomes.” IMAGINE-TBM is led by Drs. Chow and Mave and Kelly Dooley, M.D., Ph.D., Vanderbilt University (Vice-Chair). ACTG is led by Dr. Currier and Joseph J. Eron, M.D., University of North Carolina (ACTG Vice-Chair). For more information about IMAGINE-TBM, please visit clinicaltrials.gov. About ACTG ACTG is the world’s largest and longest running clinical trials network focused on HIV and other infectious diseases and the people living with them. It is funded by NIAID and collaborating NIH Institutes. Founded in 1987, ACTG conducts research to improve the management of HIV and its comorbidities; develop a cure for HIV; and innovate treatments for tuberculosis, hepatitis B, and emerging infectious diseases. It comprises thousands of dedicated researchers, staff, and community members who are pursuing research into novel treatments and cures for infectious diseases at hundreds of locations across four continents, with the ultimate goal of advancing science that meaningfully impacts the lives of the people we serve. Disclaimer: This content is solely the responsibility of ACTG and does not necessarily represent the official views of the NIH. Media Contact:Jenna Conley, ACTGjenna@conleycommunications.net

Early results presented at the Union World Conference on Lung Health suggest promise of new compound to fight tuberculosis that will be tested as part of Phase 2 trial The first participant has been dosed in this partially double-blind study to evaluate the safety and efficacy of what has the potential to be a "universal regimen" to treat TB PARIS, Nov. 16, 2023 /PRNewswire/ -- TB Alliance launched a new Pan-Phase 2 clinical trial incorporating elements of Phase 2a, b and c, identified as NC-009, to evaluate the safety and efficacy of a combination of a new experimental compound, TBAJ-876, with pretomanid and linezolid, components of TB Alliance's BPaL regimen. This regimen has the potential to shorten and improve treatment for both drug-sensitive and drug-resistant tuberculosis (TB)—one of the world's deadliest infectious diseases. Results from preclinical and Phase 1 studies presented at the Union Conference showed that the new compound, when compared with bedaquiline (a TB medicine in the same drug class), eliminated TB bacteria faster and had a potentially safer profile. "A 'universal' TB medicine needs to be highly effective while causing very few adverse effects; initial Phase 1 trial results show that TBAJ-876 could possibly move the needle in this direction," said Dr. Mel Spigelman, President and CEO of TB Alliance. "If we can develop a regimen that is composed of novel compounds with minimal pre-existing resistance that is both highly potent and safe, it could blur the distinction between drug-sensitive and drug-resistant TB allowing for treatment of virtually all patients with active TB with the same regimen." The new trial, NC-009, will test different doses of TBAJ-876 in combination with pretomanid and linezolid against the current standard of care for drug-sensitive TB—isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE). Another arm of the trial will also test pretomanid and linezolid in combination with bedaquiline (BPaL), a regimen recommended by the World Health Organization to treat some forms of drug-resistant TB, against drug-sensitive TB. The study aims to enroll 300 participants with drug-sensitive TB at 21 clinical trial sites in five countries: Georgia, Philippines, South Africa, Tanzania, and Uganda. "To truly get ahead of the tuberculosis pandemic in all of its forms, we need to continually innovate," said Dr. Francesca Conradie, Principal Investigator for the NC-009 clinical trial in South Africa. "Recent innovations in drug-resistant TB therapy have been enormously important, but we need to continue to develop shorter, simpler, and more people-friendly cures, including in drug-sensitive TB where there hasn't been a new drug approved in more than 50 years." New Experimental Compound TBAJ-876 is a diarylquinoline, a category of antibiotic that targets a key enzyme of the tuberculosis bacteria involved in energy production. Bedaquiline, a TB drug approved for the treatment of drug-resistant TB by the US FDA in 2012, is in the same diarylquinoline drug class. At the Union Conference in Paris, data were presented—showing that the new experimental compound has the potential to become an important component in TB regimens moving forward: In in vitro studies, TBAJ-876 demonstrated anti-mycobacterial activity approximately 10-fold greater than bedaquiline. In mouse models of TB, TBAJ-876, together with pretomanid and linezolid, cured infections with shorter treatment durations than HRZE and BPaL regimens. TBAJ-876 also demonstrates greater activity against TB strains resistant to bedaquiline (Rv0678 mutants), suggesting it will also be more effective in treating these emerging strains. In preclinical studies, TBAJ-876 showed the potential to be safer than bedaquiline, including low potential for QT prolongation. In Phase 1 studies involving 165 healthy subjects, few, generally mild, adverse events were observed. About TB TB is a difficult infection to cure, requiring patients to take a combination of medicines for at least four to six months. Even after symptoms disappear, medicines still need to be taken so that all traces of the disease can be fully eradicated. The scope and intensity of TB globally is in large part fueled by antiquated and inadequate TB drugs. Novel drug regimens are urgently needed to bring the TB pandemic under control. About BPaL The BPaL regimen—which combines the antibiotics bedaquiline (B), pretomanid (Pa), and linezolid (L)—was first clinically studied by TB Alliance. Pretomanid, as part of the BPaL regimen, received its first regulatory approval in August 2019 for use against highly drug-resistant strains of TB. Previously, less than two-thirds of drug-resistant TB patients around the world had been successfully treated. Treatment options were limited, expensive, toxic, and lengthy – requiring patients to take more than 20 pills per day for 9-20 months. About TB Alliance TB Alliance is a not-for-profit organization dedicated to finding faster-acting and affordable drug regimens to fight TB. Through innovative science and with partners around the globe, we aim to ensure equitable access to faster, better TB cures that will advance global health and prosperity. TB Alliance operates with support from Australia's Department of Foreign Affairs and Trade, Bill & Melinda Gates Foundation, Foreign, Commonwealth and Development Office (United Kingdom), Cystic Fibrosis Foundation, Germany's Federal Ministry of Education and Research through KfW, Global Disease Eradication Fund (South Korea), Global Health Innovative Technology Fund, Irish Aid, Korea International Cooperation Agency, National Institute of Allergy and Infectious Diseases, South Korea's Ministry of Foreign Affairs, Unitaid, and the United States Agency for International Development. For more information, please visit: . Contact: Jess Wiggs, [email protected], +1 240 425 7117 SOURCE TB Alliance