Dataset Information

A Moxifloxacin-based Regimen for the Treatment of Recurrent, Drug-sensitive Pulmonary Tuberculosis: An Open-label, Randomized, Controlled Trial.

ABSTRACT:

Background

The substitution of moxifloxacin for ethambutol produced promising results for improved tuberculosis treatment outcomes.

Methods

We conducted an open-label, randomized trial to test whether a moxifloxacin-containing treatment regimen was superior to the standard regimen for the treatment of recurrent tuberculosis. The primary and secondary outcomes were the sputum culture conversion rate at the end of 8 weeks and the proportion of participants with a favorable outcome, respectively.

Results

We enrolled 196 participants; 69.9% were male and 70.4% were co-infected with human immunodeficiency virus (HIV). There was no significant difference between the study groups in the proportion of patients achieving culture conversion at the end of 8 weeks (83.0% [moxifloxacin] vs 78.5% [control]; P = .463); however, the median time to culture conversion was significantly shorter (6.0 weeks, interquartile range [IQR] 4.0-8.3) in the moxifloxacin group than the control group (7.9 weeks, IQR 4.0- 11.4; P = .018). A favorable end-of-treatment outcome was reported in 86 participants (87.8%) in the moxifloxacin group and 93 participants (94.9%) in the control group, for an adjusted absolute risk difference of -5.5 (95% confidence interval -13.8 to 2.8; P = .193) percentage points. There were significantly higher proportions of participants with Grade 3 or 4 adverse events (43.9% [43/98] vs 25.5% [25/98]; P = .01) and serious adverse events (27.6% [27/98] vs 12.2% [12/98]; P = .012) in the moxifloxacin group.

Conclusions

The replacement of ethambutol with moxifloxacin did not significantly improve either culture conversion rates at the end of 8 weeks or treatment success, and was associated with a higher incidence of adverse events.

Clinical trials registration

NCT02114684.

SUBMITTER: Perumal R

PROVIDER: S-EPMC10686245 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Publications

A Moxifloxacin-based Regimen for the Treatment of Recurrent, Drug-sensitive Pulmonary Tuberculosis: An Open-label, Randomized, Controlled Trial.

Perumal Rubeshan R Padayatchi Nesri N Yende-Zuma Nonhlanhla N Naidoo Anushka A Govender Dhineshree D Naidoo Kogieleum K

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20200101 1

<h4>Background</h4>The substitution of moxifloxacin for ethambutol produced promising results for improved tuberculosis treatment outcomes.<h4>Methods</h4>We conducted an open-label, randomized trial to test whether a moxifloxacin-containing treatment regimen was superior to the standard regimen for the treatment of recurrent tuberculosis. The primary and secondary outcomes were the sputum culture conversion rate at the end of 8 weeks and the proportion of participants with a favorable outcome, ...[more]

PMID: 30809633

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Project description:BackgroundEarly-phase and preclinical studies suggest that moxifloxacin-containing regimens could allow for effective 4-month treatment of uncomplicated, smear-positive pulmonary tuberculosis.MethodsWe conducted a randomized, double-blind, placebo-controlled, phase 3 trial to test the noninferiority of two moxifloxacin-containing regimens as compared with a control regimen. One group of patients received isoniazid, rifampin, pyrazinamide, and ethambutol for 8 weeks, followed by 18 weeks of isoniazid and rifampin (control group). In the second group, we replaced ethambutol with moxifloxacin for 17 weeks, followed by 9 weeks of placebo (isoniazid group), and in the third group, we replaced isoniazid with moxifloxacin for 17 weeks, followed by 9 weeks of placebo (ethambutol group). The primary end point was treatment failure or relapse within 18 months after randomization.ResultsOf the 1931 patients who underwent randomization, in the per-protocol analysis, a favorable outcome was reported in fewer patients in the isoniazid group (85%) and the ethambutol group (80%) than in the control group (92%), for a difference favoring the control group of 6.1 percentage points (97.5% confidence interval [CI], 1.7 to 10.5) versus the isoniazid group and 11.4 percentage points (97.5% CI, 6.7 to 16.1) versus the ethambutol group. Results were consistent in the modified intention-to-treat analysis and all sensitivity analyses. The hazard ratios for the time to culture negativity in both solid and liquid mediums for the isoniazid and ethambutol groups, as compared with the control group, ranged from 1.17 to 1.25, indicating a shorter duration, with the lower bounds of the 95% confidence intervals exceeding 1.00 in all cases. There was no significant difference in the incidence of grade 3 or 4 adverse events, with events reported in 127 patients (19%) in the isoniazid group, 111 (17%) in the ethambutol group, and 123 (19%) in the control group.ConclusionsThe 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. (Funded by the Global Alliance for TB Drug Development and others; REMoxTB ClinicalTrials.gov number, NCT00864383.).

Project description:BackgroundThe combination of rifapentine and moxifloxacin administered daily with other anti-tuberculosis drugs is highly active in mouse models of tuberculosis chemotherapy. The objective of this phase 2 clinical trial was to determine the bactericidal activity, safety, and tolerability of a regimen comprised of rifapentine, moxifloxacin, isoniazid, and pyrazinamide administered daily during the first 8 weeks of pulmonary tuberculosis treatment.MethodsAdults with sputum smear-positive pulmonary tuberculosis were randomized to receive either rifapentine (approximately 7.5 mg/kg) plus moxifloxacin (investigational arm), or rifampin (approximately 10 mg/kg) plus ethambutol (control) daily for 8 weeks, along with isoniazid and pyrazinamide. The primary endpoint was sputum culture status at completion of 8 weeks of treatment.Results121 participants (56% of accrual target) were enrolled. At completion of 8 weeks of treatment, negative cultures using Löwenstein-Jensen (LJ) medium occurred in 47/60 (78%) participants in the investigational arm vs. 43/51 (84%, p = 0.47) in the control arm; negative cultures using liquid medium occurred in 37/47 (79%) in the investigational arm vs. 27/41 (66%, p = 0.23) in the control arm. Time to stable culture conversion was shorter for the investigational arm vs. the control arm using liquid culture medium (p = 0.03), but there was no difference using LJ medium. Median rifapentine area under the concentration-time curve (AUC0-24) was 313 mcg*h/mL, similar to recent studies of rifapentine dosed at 450-600 mg daily. Median moxifloxacin AUC0-24 was 28.0 mcg*h/mL, much lower than in trials where rifapentine was given only intermittently with moxifloxacin. The proportion of participants discontinuing assigned treatment for reasons other than microbiological ineligibility was higher in the investigational arm vs. the control arm (11/62 [18%] vs. 3/59 [5%], p = 0.04) although the proportions of grade 3 or higher adverse events were similar (5/62 [8%] in the investigational arm vs. 6/59 [10%, p = 0.76] in the control arm).ConclusionFor intensive phase daily tuberculosis treatment in combination with isoniazid and pyrazinamide, a regimen containing moxifloxacin plus low dose rifapentine was at least as bactericidal as the control regimen containing ethambutol plus standard dose rifampin.Trial registrationwww.ClinicalTrials.gov NCT00728507.

Project description:BackgroundLinezolid is an effective, but toxic anti-tuberculosis drug that is currently recommended for the treatment of drug-resistant tuberculosis. Improved oxazolidinones should have a better safety profile, while preserving efficacy. Delpazolid is a novel oxazolidinone developed by LegoChem Biosciences Inc. that has been evaluated up to phase 2a clinical trials. Since oxazolidinone toxicity can occur late in treatment, LegoChem Biosciences Inc. and the PanACEA Consortium designed DECODE to be an innovative dose-ranging study with long-term follow-up for determining the exposure-response and exposure-toxicity relationship of delpazolid to support dose selection for later studies. Delpazolid is administered in combination with bedaquiline, delamanid and moxifloxacin.MethodsSeventy-five participants with drug-sensitive, pulmonary tuberculosis will receive bedaquiline, delamanid and moxifloxacin, and will be randomized to delpazolid dosages of 0 mg, 400 mg, 800 mg, 1200 mg once daily, or 800 mg twice daily, for 16 weeks. The primary efficacy endpoint will be the rate of decline of bacterial load on treatment, measured by MGIT liquid culture time to detection from weekly sputum cultures. The primary safety endpoint will be the proportion of oxazolidinone class toxicities; neuropathy, myelosuppression, or tyramine pressor response. Participants who convert to negative liquid media culture by week 8 will stop treatment after the end of their 16-week course and will be observed for relapse until week 52. Participants who do not convert to negative culture will receive continuation phase treatment with rifampicin and isoniazid to complete a six-month treatment course.DiscussionDECODE is an innovative dose-finding trial, designed to support exposure-response modelling for safe and effective dose selection. The trial design allows assessment of occurrence of late toxicities as observed with linezolid, which is necessary in clinical evaluation of novel oxazolidinones. The primary efficacy endpoint is the change in bacterial load, an endpoint conventionally used in shorter dose-finding trials. Long-term follow-up after shortened treatment is possible through a safety rule excluding slow-and non-responders from potentially poorly performing dosages.Trial registrationDECODE was registered in ClinicalTrials.gov before recruitment start on 22 October 2021 (NCT04550832).

Project description:BackgroundTuberculosis regimens that are shorter and simpler than the current 6-month daily regimen are needed.MethodsWe randomly assigned patients with newly diagnosed, smear-positive, drug-sensitive tuberculosis to one of three regimens: a control regimen that included 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 one weekly dose of both moxifloxacin and 1200 mg of rifapentine for 4 months. Sputum specimens were examined on microscopy and after culture at regular intervals. The primary end point was a composite treatment failure and relapse, with noninferiority based on a margin of 6 percentage points and 90% confidence intervals.ResultsWe enrolled a total of 827 patients from South Africa, Zimbabwe, Botswana, and Zambia; 28% of patients were coinfected with the human immunodefiency virus. In the per-protocol analysis, the proportion of patients with an unfavorable response was 4.9% in the control group, 3.2% in the 6-month group (adjusted difference from control, -1.8 percentage points; 90% confidence interval [CI], -6.1 to 2.4), and 18.2% in the 4-month group (adjusted difference from control, 13.6 percentage points; 90% CI, 8.1 to 19.1). In the modified intention-to-treat analysis these proportions were 14.4% in the control group, 13.7% in the 6-month group (adjusted difference from control, 0.4 percentage points; 90% CI, -4.7 to 5.6), and 26.9% in the 4-month group (adjusted difference from control, 13.1 percentage points; 90% CI, 6.8 to 19.4).ConclusionsThe 6-month regimen that included weekly administration of high-dose rifapentine and moxifloxacin was as effective as the control regimen. The 4-month regimen was not noninferior to the control regimen. (Funded by the European and Developing Countries Clinical Trials Partnership and the Wellcome Trust; RIFAQUIN Current Controlled Trials number, ISRCTN44153044.).

Dataset Information

A Moxifloxacin-based Regimen for the Treatment of Recurrent, Drug-sensitive Pulmonary Tuberculosis: An Open-label, Randomized, Controlled Trial.

Background

Methods

Results

Conclusions

Clinical trials registration

Publications

A Moxifloxacin-based Regimen for the Treatment of Recurrent, Drug-sensitive Pulmonary Tuberculosis: An Open-label, Randomized, Controlled Trial.

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