Kate Johnson

September 07, 2014

WASHINGTON — Hopes for a new, moxifloxacin-containing tuberculosis (TB) treatment that might have shortened therapy from 6 to 4 months suffered a setback today with the results of REMoxTB study, one of the largest phase 3 TB trials in history.

But findings from the study are not all disappointing, according to lead investigator Stephen Gillespie, MD, from the University of St. Andrews Medical School, in Scotland.

"While the results are not what we had hoped for, the trial will dramatically improve knowledge in the field and also pave the way for future TB trials ― especially those that might include moxifloxacin as part of the regimen," Dr. Gillespie told Medscape Medical News.

The results were reported here at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) and published simultaneously in the New England Journal of Medicine.

Failure to Show Noninferiority

The REMoxTB (Rapid Evaluation of Moxifloxacin in Tuberculosis) trial investigated whether replacing 1 of the first-line TB drugs (isoniazid, rifampicin, pyrazinamide, or ethambutol) with a shorter course of moxifloxacin was noninferior to standard treatment.

The trial randomly assigned 1931 patients with drug-sensitive TB to a control group, which received isoniazid, rifampin, pyrazinamide, and ethambutol (Myambutol, STI Pharma LLC) for 8 weeks, followed by 18 weeks of isoniazid and rifampin, or to 2 separate moxifloxacin-containing arms: 1 that replaced ethambutol with moxifloxacin for 17 weeks, followed by 9 weeks of placebo (INH arm), and one that replaced isoniazid with moxifloxacin for 17 weeks, followed by 9 weeks of placebo (ETH arm).

The primary end point of the noninferiority trial was treatment failure or relapse within 18 months after randomization.

The study failed to show noninferiority of the moxifloxacin regimens compared with the control regimen. Treatment failure or relapse occurred in 8% of patients in the control arm compared with 15% and 20% of the INH and ETH arms, respectively.

"Among patients receiving the 2 moxifloxacin-containing regimens, a small number had treatment failures, but a larger number had a relapse after the end of active treatment," reported Dr. Gillespie and coauthors.

However, compared with control patients, those in both moxifloxacin arms had a quicker initial response to treatment, producing conversion to culture-negative sputum sooner.

Additionally, compared with the control regimen, both moxifloxacin-containing regimens were safe, with no difference in the incidence of grade 3 and 4 adverse events (19% in both the control and INH arms and 17% in the ETH arm).

Study investigators report that they found no evidence of hypoglycemia or hyperglycemia or tendinopathies, which have been associated with fluoroquinolones, nor evidence of increased hepatic dysfunction, a potential concern in regimens containing moxifloxacin or lacking isoniazid. They also state that there was no clinical evidence of cardiac toxicity, although electrocardiography was not performed systematically.

"There is much that is encouraging about the results," said Dr. Gillespie. "The trial showed that moxifloxacin is effective against TB; however, it may not be effective enough as part of a single drug substitution model to shorten treatment to 4 months. The trial is also the first regulatory study to confirm the safety of daily moxifloxacin over 4 months of therapy. The safety of moxifloxacin, combined with its activity against TB, supports the continued clinical testing of moxifloxacin as a component of other, novel regimens."

Results Are "Encouraging"

David Aronoff, MD, director of the Division of Infectious Diseases at Vanderbilt University Medical Center in Nashville, Tennessee, who was not involved in the trial, called the results "encouraging."

"A faster time to negative respiratory cultures for TB could translate into reduced transmission of this dangerous pathogen. It is also notable that the safety profile of the moxifloxacin-based treatments appeared to be similar to the traditional, 6-month regimen," he told Medscape Medical News.

"It can also be seen as a success that this large and complicated phase 3 clinical trial helped establish a major global research infrastructure for conducting large trials in TB-endemic areas. This will greatly accelerate future efforts to study the efficacy of new treatment regimens in TB-infected populations," said Dr. Aronoff.

Indeed, before the REMoxTB trial, "there was little, if any, capacity to conduct registration-grade clinical trials for new TB treatments in countries where TB was a major problem," Dr. Gillespie told Medscape Medical News. "REMoxTB was a pioneering trial that has shown that a large-scale trial can be run efficiently in resource-poor settings with a high TB burden, adhere to the highest standards of good clinical trial practices, and deliver a clear, unequivocal result."

He added that the current results "are just the tip of the iceberg of the learning from this trial. The quality and amount of the data that will be analyzed from this trial are expected to advance the entire field. We have already seen how the clinical capacity and learnings from REMox are improving future trials by making them shorter and less expensive to conduct — in this way, the impact of the REMox trial will be felt for many years to come. It will also report new insights that will be useful to anyone making a diagnosis of tuberculosis or monitoring the treatment response."

The REMoxTB study was sponsored by the Global Alliance for TB Drug Development (TB Alliance) with support from the Bill & Melinda Gates Foundation, the European and Developing Countries Clinical Trials Partnership (EDCTP), the US Agency for International Development (USAID), the UK Department for International Development (DFID), the Directorate General for International Cooperation of the Netherlands (DGIS), Irish Aid, the Australia Department of Foreign Affairs and Trade (DFAT), and the US National Institutes of Health, AIDS Clinical Trial Group (ACTG). Moxifloxacin was donated by Bayer Healthcare AG, and rifampicin was donated by Sanofi. Dr. Gillespie and Dr. Aronoff have disclosed no relevant financial relationships.

54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC): Abstract L-1062. Presented September 7, 2014.

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