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More follow-up data on phase 2 trial of bedaquiline (TMC-207)

Author: Richard Lessells - 2012-03-15


Bedaquiline (TMC-207), a diarylquinolone, is an anti-TB drug based on a novel mode of action (inhibition of ATP synthase). Initial results from a phase 2 randomised, double blind, placebo-controlled trial were reported in the New England Journal of Medicine in 2009. A new article published ahead of print in Antimicrobial Agents and Chemotherapy provides longer term follow-up data on efficacy and safety up to 104 weeks.


This was a multicentre trial within South Africa, enrolling individuals with pulmonary MDR-TB, most of whom were HIV negative (87%). All were treated with an individualised background drug regimen consisting at least of kanamycin, ethionamide, ofloxacin (all except one patient), in combination with other selected second-line TB drugs. Patients were randomised to the inclusion of bedaquiline or placebo in the regimen, administered only for the first eight weeks of therapy. Participants then continued on the background regimen and were followed up for two years (104 weeks).

In total 47 patients were included in the trial (23 treated with bedaquiline, 24 with placebo). Two patients with XDR-TB at baseline were excluded from the efficacy analysis as was one patient with negative pre-treatment culture.

The key findings were:

- Time to 50% sputum conversion was 78 days in the bedaquiline arm vs 129 days in the placebo arm

- At 24 weeks, 81.0% in the bedaquiline arm had culture conversion vs 65.2% in the placebo arm

- Treatment success at 104 weeks was not substantially different between the two groups (52.4% for bedaquiline vs 47.8% for placebo). The precise definition of this outcome is not stated in the paper but it is presumed to represent standard WHO definitions, i.e. cure or completion

Rates of discontinuation in the study were very high, with 49% of all study subjects discontinuing, over half of those within the first 24 weeks. It should be noted that many of these were discontinuation from study follow-up rather than necessarily discontinuation of treatment and that many study subjects were culture negative at the time of discontinuation.

There was evidence that the accumulation of additional drug resistance was more frequent in the placebo arm (6 patients developed additional resistance vs one subject in the bedaquiline arm). Of particular concern was the emergence of fluoroquinolone resistance in four patients in the placebo arm.

In the safety analysis, there was excess nausea in the bedaquiline arm (26.1% vs nil) but no other significant difference between the two arms. This is of concern given that nausea is a symptom that might affect adherence to therapy, especially outside the trial setting with less rigorous monitoring and follow-up. Having said that it is surprising that no nausea was reported in the placebo arm given the drug regimens used in this group and the frequency of this symptom in routine practice. It will be important to assess the frequency, severity, and effect on adherence of nausea in the continuing trials of bedaquiline.

The second stage of the phase 2 trial (an open label trial comparing 24 weeks of bedaquiline vs placebo in combination with a background regimen for MDR-TB patients) has now completed recruitment and the results are awaited with much interest. It is expected that regulatory approval will be sought on the basis of these results. Furthermore, a phase 3 trial is planned, evaluating the use of bedaquiline as part of a 9-month treatment regimen for MDR-TB.

References

Diacon AH, Pym A, Grobusch M, et al. The diarylquinolone TBC207 for multidrug-resistant tuberculosis. N Engl J Med 2009; 360: 2397-2405

Diacon AH, Donald PR, Pym A, et al. Randomised pilot trial of 8 weeks of bedaquiline (TMC207) for MDR-TB: long-term outcome, tolerability and effect on emergence of drug resistance. Antimicrob Agents Chemother 2012 (published ahead of print)

http://clinicaltrials.gov/ct2/show/NCT00910871?term=tmc207&rank=3

http://www.resisttb.org/uploads/TMC-207_Phase_III_MDR-TB_Trial_Oct_29_2011.pdf

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