Early-stage studies attempting to shorten tuberculosis treatment regimens in African countries from 6 months to 4 months by including a fluoroquinolone failed to show noninferiority, according to 3 published reports and an editorial that appeared in the New England Journal of Medicine on Oct. 23.
Phase 2 clinical trials have suggested that fluoroquinolone-containing regimens may lead to negative culture results earlier than conventional therapy and might make shorter treatment regimens possible. The current trials were performed to determine whether shortened regimens containing a fluoroquinolone are noninferior to current standard therapy for tuberculosis. Noninferiority trials are intended to show that a treatment is not significantly worse than another treatment and are used in situations in which there is an established treatment for a disease and comparison to a placebo group is not possible.
In the first study, a randomized, double-blind, placebo-controlled, phase 3 trial found that moxifloxacin-containing regimens could provide a 4-month treatment for uncomplicated pulmonary tuberculosis.
The control group received isoniazid, rifampin, pyrazinamide, and ethambutol for 8 weeks, followed by 18 weeks of isoniazid and rifampin. The second group received moxifloxacin instead of ethambutol for 17 weeks, followed by 9 weeks of placebo. The third group received moxifloxacin instead of isoniazid for 17 weeks, followed by 9 weeks of placebo.
Of the 1,931 patients, a favorable outcome was reported in more patients in the control group (92%) than in the group in which isoniazid was replaced with moxifloxacin (85%) or the group in which ethambutol was replaced with moxifloxacin (80%). The difference between the control group and the isoniazid group was 6.1 percentage points (97.5% CI, 1.7 to 10.5 percentage points). The difference between the control group and the group in which ethambutol was replaced with moxifloxacin was 11.4 percentage points (97.5% CI, 6.7 to 16.1 percentage points). The hazard ratios for the time to culture negativity were shorter, with the lower bounds of the 95% CIs exceeding 1.00 in all cases.
The researchers wrote, “The two moxifloxacin-containing regimens produced a more rapid initial decline in bacterial load, as compared with the control group. However, noninferiority for these regimens was not shown, which indicates that shortening treatment to 4 months was not effective in this setting.”
In the second study, a 4-month regimen using gatifloxacin for treating rifampin-sensitive pulmonary tuberculosis did not show noninferiority to the standard regimen for the unfavorable outcomes of treatment failure, recurrence, or death or study dropout during treatment.
In the trial of 1,836 patients, the control group was treated with a standard 6-month regimen that included ethambutol during the 2-month intensive phase, compared to a 4-month regimen in which gatifloxacin, 400 mg/d, was substituted for ethambutol during the intensive phase and was continued, along with rifampin and isoniazid, during the continuation phase. The adjusted difference in the risk of an unfavorable outcome between the experimental group and the control group in the modified intention-to-treat population of 1,356 patients 24 months after stopping treatment was 3.5 percentage points (95% CI, −0.7 to 7.7 percentage points). The standard regimen, as compared with the 4-month regimen, was associated with a higher dropout rate during treatment (5.0% vs. 2.7%) and more treatment failures (2.4% vs. 1.7%) but fewer recurrences (7.1% vs. 14.6%).
“The expectations raised by the phase 2 study were not borne out in this phase 3 trial,” the researchers wrote, later continuing, “More robust phase 2 surrogate markers of treatment efficacy are needed to select suitable regimens for shortening tuberculosis treatment that can be further assessed in phase 3 studies.”
A third trial concluded that a 6-month regimen of weekly administration of high-dose rifapentine and moxifloxacin was as effective as the control regimen, while a 4-month regimen did not show noninferiority.
Researchers randomly assigned 827 patients to 1 of 3 regimens:
- the control regimen of 2 months of ethambutol, isoniazid, rifampicin, and pyrazinamide administered daily followed by 4 months of daily isoniazid and rifampicin;
- a 4-month regimen in which the isoniazid in the control regimen was replaced by moxifloxacin administered daily for 2 months followed by moxifloxacin and 900 mg of rifapentine administered twice weekly for 2 months; or
- a 6-month regimen in which isoniazid was replaced by daily moxifloxacin for 2 months followed by 1 weekly dose of both moxifloxacin and 1,200 mg of rifapentine for 4 months.
The proportion of patients with an unfavorable response was 4.9% in the control group in the per protocol analysis. The proportion of unfavorable responses was 3.2% in the 6-month group, for an adjusted difference from the control group of −1.8 percentage points (90% CI, −6.1 to 2.4 percentage points), and was 18.2% in the 4-month group, for an adjusted difference from the control group of 13.6 percentage points (90% CI, 8.1 to 19.1 percentage points). In the modified intention-to-treat analysis, the proportion of patients with an unfavorable response was 14.4% in the control group. The proportion was 13.7% in the 6-month group, for an adjusted difference from the control group of 0.4 percentage points (90% CI, −4.7 to 5.6 percentage points), and 26.9% in the 4-month control group, for an adjusted difference from control of 13.1 percentage points (90% CI, 6.8 to 19.4 percentage points).
An editorial noted that, while observed culture conversion rates at 2 months showed that fluoroquinolone regimens might be superior, this did not reliably predict sterilizing activity and risk of relapse. Also, small sample sizes in phase 2 studies limit the utility of short trials in predicting the success of treatment-shortening regimens. Finally, better animal models in early research might better mimic the pharmacokinetic-pharmacodynamic properties that might influence drug efficacy in humans.
The editorialists wrote, “In summary, although the urgency of the medical need may justify additional clinical trials of experimental tuberculosis 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. As these 3 trials have confirmed, our understanding of the science underlying positive clinical outcomes remains rudimentary. It's time to go back to basics.”