· REMoxTB confirmed the safety of moxifloxacin and its effect in killing TB; results pave way for further study of moxifloxacin in novel drug regimens
· Substituting moxifloxacin alone in the standard TB drug regimen did not shorten treatment time from six to four months
[WASHINGTON, DC, September 7, 2014] The results of a Phase 3 clinical trial called REMoxTB has found that replacing one of the drugs with the antibiotic moxifloxacin in the standard six-month treatment regimen did not allow the treatment time for tuberculosis (TB) patients to be shortened to four months. The results were presented today at the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) and published in the New England Journal of Medicine.
The trial, however, confirmed the safety of daily moxifloxacin over four months of therapy. Researchers concluded that the safety of moxifloxacin, combined with its activity against TB, supports the continued clinical testing of moxifloxacin as a component of other novel regimens.
“Shorter and simpler TB cures are urgently needed—the present first-line treatment is nearly 50 years old, too complicated and interacts with common HIV medications,” said Mel Spigelman, MD, president and CEO of TB Alliance, the sponsor of the trial. “REMoxTB paved the way for future progress by showing us that effective, markedly shorter and safer treatments will most likely require developing novel regimens that combine multiple novel agents.”
The trial enrolled 1,931 patients at 50 sites in nine countries: Kenya, Mexico, Tanzania, South Africa, China, India, Thailand, Malaysia and Zambia. The three-arm study substituted moxifloxacin for either isoniazid or ethambutol in the first-line treatment for drug-sensitive TB (first-line treatment consists of isoniazid, rifampicin, pyrazinamide and ethambutol). The study found that, while the experimental regimens initially killed more TB bacteria than the standard regimen, patients receiving those shortened regimens were more likely to relapse than those taking the standard treatment.
“The REMox trial was among the most rigorous TB drug trials ever conducted in the modern era of TB treatment and among the largest ever conducted for a new TB treatment. Although the regimen we studied wasn’t quite sufficient to reduce TB treatment time by our two month target, the trial brought us a significant step closer,” said Professor Stephen Gillespie, the Sir James Black Chair of Medicine at the University of St. Andrews and the REMox study’s chief investigator.
“REMoxTB succeeded in showing that high-quality clinical trials with clear, unequivocal results can be conducted in resource-poor regions where TB is endemic and also in paving the way for future TB trials, especially those that might include moxifloxacin as part of the regimen,” Gillespie continued.
TB killed 1.3 million people in 2012—one person every 25 seconds. The current treatment for the nearly nine million people newly diagnosed with TB each year is highly inadequate and requires a minimum of six months of therapy, which often has significant side effects. The length of today’s TB treatment makes it difficult for many patients to complete therapy. Failure to complete treatment is a major driver of the emergence of multi-drug resistant TB (MDR-TB), which requires substantially longer, more complicated and expensive treatment.
The REMoxTB study was a collaboration between the TB Alliance, Bayer HealthCare AG, the University College London (UCL) Centre for Clinical Microbiology, the Medical Research Council Clinical Trials Unit at UCL and the University of St. Andrews.
Other Impacts: Future Trials Shorter, Less Expensive
“The REMox trial has helped develop new research sites in developing countries that can conduct high quality research in the future to evaluate new regimens,” said Gillespie. “The quality and amount of the data from this trial will advance the entire TB research field, and improve future trials by allowing them to enroll fewer patients, making them shorter and less expensive to conduct.”
“This study has been critical in improving our understanding of how to analyze and interpret the results of trials aimed at shortening treatment for TB,” said Andrew Nunn, professor of epidemiology and medical statistics at the Medical Research Council Clinical Trials Unit at UCL.
“Bayer Healthcare AG was proud to participate in the REMoxTB study as part of its larger social responsibility commitment,” said Martin Springsklee, MD, head, global medical affairs, anti-infectives, at Bayer Healthcare AG. “The study will have a long-term impact, not only in verifying the safety of moxifloxacin for the four month administration period of the study, but also in building the clinical capacity to conduct large-scale TB registration trials. Future TB research can now be conducted in a much more efficient and effective manner because of the groundwork laid through this trial.”
The results of the trial also showed that there is no evidence that populations in different regions of the world respond differently to TB therapy. It has previously been suggested that Asian patients have a more chronic form of disease with a different clinical course than African patients, but the investigators did not see any evidence of variation in treatment outcome in different geographic regions.
“Our rigorous approach to conducting the trial and standardizing the laboratory methods are firsts for such a broad global study,” said Tim McHugh, professor of medical microbiology and director of the UCL Centre for Clinical Microbiology. “We found minimal variation in the results between 50 trial sites on three different continents.”
The study provided a wealth of data that gives researchers insights into how smaller, shorter studies can be used to predict results of later, larger and more expensive studies, how to identify and distinguish between patient relapses and re-infections, how the severity of infection correlates with treatment outcome, and how to develop universal standards for microbiology testing in TB clinical trials around the world. It also brought community engagement (CE) programs around clinical trial sites to scale, establishing CE as a best practice in TB R&D.
Moxifloxacin is currently approved to treat acute respiratory infections (and other infections) and is included in World Health Organization guidelines to treat drug-resistant TB in combination with other drugs, even though it has never been approved by regulatory authorities for TB treatment.
The manner in which moxifloxacin works against bacteria like Mycobacterium tuberculosis differs from the medicines currently used to treat TB. Moxifloxacin inhibits a bacterial enzyme called DNA gyrase, which is essential for bacterial survival. Moxifloxacin does not interact with antiretroviral (ARV) therapies used to treat HIV patients
The trial was funded by the Australian Department of Foreign Affairs (DFAT), Bill & Melinda Gates Foundation (BMGF), the Directorate General for International Cooperation of the Netherlands (DGIS), the European and Developing Countries Clinical Trials Partnership (EDCTP), Irish Aid, the UK Department for International Development (DFID), the US Agency for International Development (USAID), and the US National Institutes of Health AIDS Clinical Trial Group (ACTG).
About Bayer HealthCare
The Bayer Group is a global enterprise with core competencies in the fields of health care, agriculture and high-tech materials. Bayer HealthCare, a subgroup of Bayer AG with annual sales of EUR 17.2 billion (2011), is one of the world’s leading, innovative companies in the healthcare and medical products industry and is based in Leverkusen, Germany. The company combines the global activities of the Animal Health, Consumer Care, Medical Care and Pharmaceuticals divisions. Bayer HealthCare’s aim is to discover, develop, manufacture and market products that will improve human and animal health worldwide. Bayer HealthCare has a global workforce of 55,700 employees (Dec 31, 2011) and is represented in more than 100 countries. More information at www.healthcare.bayer.com.
About the TB Alliance
The Global Alliance for TB Drug Development (TB Alliance) is a not-for-profit organization dedicated to finding faster-acting and affordable drug regimens to fight tuberculosis. 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. The TB Alliance operates with funding from Australia Department of Foreign Affairs and Trade, Bill & Melinda Gates Foundation, European Commission, Global Health Innovative Technology Fund, Irish Aid, National Institute of Allergy and Infectious Disease, UNITAID, United Kingdom Department for International Development, United States Agency for International Development, and the United States Food and Drug Administration. For more information please visit tballiance.org.
About UCL (University College London)
Founded in 1826, UCL was the first English university established after Oxford and Cambridge, the first to admit students regardless of race, class, religion or gender, and the first to provide systematic teaching of law, architecture and medicine. We are among the world's top universities, as reflected by performance in a range of international rankings and tables. UCL currently has almost 29,000 students from 150 countries and in the region of 10,000 employees. Our annual income is more than £900 million.
About University of St Andrews
The University of St Andrews is Scotland’s first university and is the third oldest in the English speaking world, founded in 1413. It is ranked 4th in the Good University Guide 2015, 3rd in the Guardian University Guide 2015 and is The Times and Sunday Times Scottish University of the Year 2014/15. It is ranked first equal amongst UK universities for student satisfaction.