Another negative result in the quest for a shorter TB treatment course

Results from a Phase III trial that attempted to shorten the treatment duration for drug-sensitive pulmonary TB from four to six months, by using gatifloxacin instead of ethambutol, showed that the shortened treatment duration was inferior when compared to the standard treatment course. Results from the OFLOTUB trial were presented earlier this month at the 44th World Conference on Lung Health in Paris.

A previous study, RIFAQUIN, found that it was not possible to shorten the TB treatment regimen from 6 months to 4 months by use of moxifloxacin and rifapentine twice weekly in place of rifampicin and isonazid in the continuation phase of TB treatment.

The non-inferiority, blinded, randomised control trial was conducted in Benin, Guinea, Senegal, Kenya, and South Africa. In the control arm of the study, 919 people were given the World Health Organization-recommended six-month course of TB treatment, whereas 917 people in the test arm received 400mg of gatifloxacin, six days a week, in place of ethambutol for two months, followed by two months of treatment with gatifloxacin, rifampicin and isoniazid.

Glossary

control group

A group of participants in a trial who receive standard treatment, or no treatment at all, rather than the experimental treatment which is being tested. Also known as a control arm.

treatment failure

Inability of a medical therapy to achieve the desired results. 

loss to follow up

In a research study, participants who drop out before the end of the study. In routine clinical care, patients who do not attend medical appointments and who cannot be contacted.

generic

In relation to medicines, a drug manufactured and sold without a brand name, in situations where the original manufacturer’s patent has expired or is not enforced. Generic drugs contain the same active ingredients as branded drugs, and have comparable strength, safety, efficacy and quality.

relapse

The return of signs and symptoms of a disease after a patient has been free of those signs and symptoms. 

The median age for participants in the study was 31 years, 27% were female, and 18% had HIV. All participants were adults with new TB diagnoses.

The study used a 6% non-inferiority margin, and considered patients’ “unfavourable” outcomes as a composite endpoint at two months, end of treatment, 18 months, and 24 months, with the primary outcome being at 24 months. Researchers considered participants who died, were lost to follow-up during treatment, experienced treatment failure, or experienced TB re-occurrence (a category that included relapse and re-infection), as experiencing unfavourable outcomes. 

At two months and end of treatment, those in the intervention arm fared better. However, 24 months after completion of treatment, a larger proportion of people in the gatifloxacin-containing arm had unfavourable outcomes (20.9 vs 16.8%). This difference was driven by a higher frequency of tuberculosis recurrence in the gatifloxacin arm (14.6 vs 6.9% of participants were diagnosed with TB again). The intent-to-treat analysis showed a difference of 3.8% favouring the control arm, with a confidence interval that exceeded the non-inferiority margin (-0.03%, +8%). As a consequence the gatifloxacin-containing regimen was found to be inferior to standard TB treatment.

Importantly, the gatifloxacin-containing regimen was considered safe and well-tolerated: participants taking it were less likely to experience a QT prolongation in the test arm than the control arm, with a risk difference of -0.1% in the test arm (95% confidence interval -0.2, 0.1). "This is very important because almost all the [new] drugs in the pipeline have QT prolongation issues," says clinical investigator Corinna Merle, who presented the findings. "When it comes to mixing new TB drugs, you might not want to mix two drugs with QT prolongation." The risk of hyperglycemia was "almost the same in both arms", she says.

Interestingly, different countries demonstrated different outcomes: people fared better in the intervention arm in Benin, Guinea, and Kenya than those in Senegal and South Africa. Noting that countries where participants had lower BMIs when they began treatment – such as Benin and Guinea – did better on treatment than those with higher initial BMIs – such as Senegal and South Africa – Merle wonders whether the regimen's effectiveness could be increased with better dosing. (Patients in Kenya and Senegal, however, had similar BMIs at baseline, yet Kenyan patients did better in the intervention arm than Senegalese patients.) All patients, regardless of body weight, were given 400mg a day.

A pharmacokinetic study is currently being conducted in South Africa to help determine appropriate dosing. Results are expected within the next six months. Merle also suggests that giving treatment every day of the week, instead of six days out of seven, may be important when attempting to use a shortened regimen (the team decided to treat six out of seven days as many participating countries did not have healthcare centres open on Sunday). Participants who were living with HIV also did better in the intervention arm than those who did not have HIV.

Merle says that the intricacies found in the OFLOTUB trial suggest that more research should be conducted, and that gatifloxacin shouldn't be discounted as a potential TB regimen yet. "In the control arm we had  more patients lost to follow-up," Merle says. "And then more treatment failure in the control arm, but what you have more of in the [intervention arm] is re-occurrences.” Merle notes that poorer outcomes in the intervention arm at 24 months may simply be because patients who had taken gatifloxacin were followed-up for longer than those on standard treatment, as they were taking two months' less treatment. “We need to look at the dynamics in more detail to explain all of this, and why patients in some countries did better than others. We also need to look more at dosing, and at gatifloxacin treatment in HIV-positive patients."

Merle also notes that gatifloxacin is a generic drug, whereas moxifloxicin – being considered for use in a shortened TB treatment regimen as part of the REMox trial – is not. Given that both OFLOTUB and REMox are attempting to shorten TB treatment periods, Merle says "lets see [the REMox] results. If they have very good results, there's no reason to have two types of regimens. But if they have results similar to ours, then there could be a discussion…I really think that [gatifloxacin] should not be buried…For the moment we will wait."

References

Merle C et al. A randomised controlled trial of a 4-month gatifloxacin-containing regimen vs standard 6-month regimen for treating drug-susceptible pulmonary tuberculosis: main efficacy and safety results of the OFLOTUB trial. 44th Union World Conference on Lung Health, Paris, session 39 (late breaker), 2013.

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