Short TB Therapies Fail in Larger, Longer Trials

Veronica Hackethal, MD

October 24, 2014

Shorter regimens for the treatment of tuberculosis (TB) are not as good as standard 6-month therapy, according to results of three phase 3 trials published in the October 23 issue of the New England Journal of Medicine.

All three trials looked at whether substituting one of the standard drugs with a fluoroquinolone could shorten treatment. The current regimen for drug-susceptible TB, in use for more than 3 decades, consists of a 2-month intensive phase using rifampin, isoniazid, pyrazinamide, and ethambutol, followed by 4 months of isoniazid and rifampin.

Researchers want to shorten the length of therapy because it could decrease costs and increase adherence, but they can only do so if they find a regimen as effective as the existing standard. And these newly reported trials indicate that that hurdle has not been overcome, write Digby Warner, PhD, and Valerie Mizrahi, PhD, both from the University of Capetown, South Africa, in an accompanying editorial. They note that these three trials reveal key challenges in the area of TB drug development.

Remarkably, the results from the shorter phase 2 trials for these regimens looked promising and showed rapid culture conversion at 2 months with fluoroquinolones. The results had suggested this drug class could potentially decrease the length of standard therapy for newly diagnosed TB and might even be better.

However, as sometimes happens, the longer, more rigorous phase 3 trials show that 2-month results may not be adequate predictors of relapse. Improved methodology in study design and drug selection is needed, Dr Warner and Dr Mizrahi suggest.

"The disconnect between the phase 2 data that motivated these trials and the phase 3 results reinforces the idea that small sample sizes limit the utility of short trials in predicting the success of future treatment-shortening regimens," they write.

Moreover, all three trials were based on evidence from mouse models, in which TB may behave differently. Notably, key TB lesions found in humans and thought to be the cause of relapse may be absent in mice. Future research will need to look at the ability of TB drugs to penetrate such lesions. Other animal models, such as rabbits and nonhuman primates, may better approximate human disease, they suggest.

"[A]lthough the urgency of the medical need may justify additional clinical trials of experimental [TB] drugs and drug regimens, there must be a considerable increase in investment in fundamental research if we are to develop and validate correlates of durable cure," the editorialists conclude. "As these three trials have confirmed, our understanding of the science underlying positive clinical outcomes remains rudimentary. It's time to go back to basics."

Overview of the Three Trials

The open-label Multicentre, Randomised, Control Trial of Ofloxacin-Containing, Short-Course Regimen for the Treatment of Pulmonary Tuberculosis (OFLOTUB)/Gatifloxacin for TB project included 1836 patients in five sub-Saharan African countries. Researchers replaced ethambutol with gatifloxacin in the intensive phase and maintained it in combination with rifampin and isoniazid in the 2-month continuation phase.

Results of the trial show:

  • 21.0% of patients in the experimental group had unfavorable outcomes compared with 17.2% of the patients in the control group in a modified intention-to-treat analysis.

  • The adjusted difference (3.5 percentage points; 95% confidence interval, −0.7 to 7.7) did not meet the noninferiority margin of 6 percentage points.

  • Early culture conversion was consistent with phase 2 results.

  • Recurrences were higher in the experimental group (14.6%) compared with standard therapy (7.1%).

The International Multicentre Controlled Clinical Trial to Evaluate High Dose Rifapentine and a Quinolone in the Treatment of Pulmonary Tuberculosis (RIFAQUIN) trial took place in 4 countries in Africa. Researchers randomly assigned 827 participants to receive either the standard regimen or one of two experimental regimens: a 4-month regimen in which moxifloxacin daily replaced isoniazid for 2 months, followed by moxifloxacin and rifapentine twice weekly for 2 months; or a 6-month regimen in which moxifloxacin daily replaced isoniazid for 2 months, followed by a weekly dose of moxifloxacin plus rifapentine for 4 months. Twenty-eight percent of participants had HIV. Key results of the trial include:

  • unfavorable responses in 18.2% of patients in the 4-month moxifloxacin group, 3.2% of patients in the 6-month moxifloxacin group, and 4.9% of the patients in the standard therapy group in an intent-to-treat analysis.

  • In the modified intent-to-treat analysis, 26.9% of patients in the 4-month group had unfavorable responses, as did 13.7% of those in the 6-month group and 14.4% of those in the control group.

  • Although the 6-month regimen proved as effective as standard therapy, the 4-month regimen was worse and had a significantly higher relapse rate than controls.

  • Participants receiving intermittent regimens did not appear to develop resistance, but the authors note the numbers may have been too small to reach definitive conclusions.

As previously reported by Medscape Medical News, the Rapid Evaluation of Moxifloxacin in Tuberculosis (REMoxTB) trial was one of the largest phase 3 TB randomized controlled trials in history and included 1931 patients in nine countries on three continents (Africa, Asia, and the Americas). The trial looked at replacing ethambutol or isoniazid with moxifloxacin, which would have shortened standard treatment to 4 months.

Results showed:

  • Bacterial load initially declined more rapidly with the two moxifloxacin-containing regimens, but longer-term outcomes were not as good as standard therapy.

  • Favorable outcomes occurred in the 85% of the isoniazid group, 80% of the ethambutol group, and 92% of control patients.

  • Unfavorable outcomes mostly occurred because of relapse.

"Instead of relying on the results of 2-month phase 2 trials to select candidate regimens for phase 3 studies, investigators might find that the most efficient approach is to conduct phase 3 trials as quickly as possible while establishing more feasible and less costly approaches to performing these studies," Stephen Gillespie, MD, DSc, from the School of Medicine, University of St. Andrews, United Kingdom, and colleagues write. "Possible improvements could include larger noninferiority margins, permitting smaller sample sizes, and building multiple treatment durations into each study."

Dr Mizrahi reports receiving grant support from the Foundation of the NIH National Institutes of Health through a sub-award from the Bill & Melinda Gates Foundation, the European Community's Seventh Framework Programme, and the South African Medical Research Council, outside the submitted work. She also directs a research institute at the University of Cape Town, which receives significant funding from the European and Developing Countries Clinical Trials Partnership, the Bill & Melinda Gates Foundation, the Wellcome Trust, and the US Agency for International Development for research led by members of the institute. She is also a member of the Scientific Advisory Committee of the Global Alliance for TB Drug Development. Dr Warner reports receiving grant support from the South African Medical Research Council and the National Research Foundation South Africa, as well as personal fees from the Wellcome Trust outside the submitted work. The OFLOTUB/Gatifloxacin trial was supported by the Special Program for Research and Training in Tropical Diseases, a cosponsored program of the United Nations Children's Fund, the United Nations Development Program, the World Bank, and the World Health Organization, and in part by the European Commission (International Cooperation with Developing Countries program). Specific support was also provided by the US Agency for International Development, the government of Japan, the Global Alliance for TB Drug Development, and the Li Ka Shing Foundation Global Health Programme at the University of Oxford. Lupin Pharmaceuticals, India, provided study drugs. The RIFAQUIN trial was supported by the European and Developing Countries Clinical Trials Partnership and the Wellcome Trust. The REMoxTB study was sponsored by the Global Alliance for TB Drug Development with support from the Bill & Melinda Gates Foundation, the European and Developing Countries Clinical Trials Partnership, the US Agency for International Development, the UK Department for International Development, the Directorate General for International Cooperation of the Netherlands, Irish Aid, the Australia Department of Foreign Affairs and Trade, and the National Institutes of Health, AIDS Clinical Trial Group. Moxifloxacin was donated by Bayer Healthcare AG, and rifampicin was donated by Sanofi.

N Engl J Med. 2014;371:1577-1608,1642-1643. Gatifloxacin trial full text, Rifapentine trial full text, Moxifloxacin trial full text, Editorial full text

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