A Phase 2 Randomized Trial of a Rifapentine plus Moxifloxacin-Based Regimen for Treatment of Pulmonary Tuberculosis
A Phase 2 Randomized Trial of a Rifapentine plus Moxifloxacin-Based Regimen for Treatment of Pulmonary Tuberculosis
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DOI：
10.1371/journal.pone.0154778
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发表时间：
2016-05-09
期刊：
影响因子：
3.7
通讯作者：
Dorman, Susan E.
中科院分区：
文献类型：
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作者：
Conde, Marcus B.;Mello, Fernanda C. Q.;Dorman, Susan E.
研究背景利福喷丁和利福沙星每日联合其他抗结核药物对小鼠结核病化疗模型有较高的疗效。这项2期临床试验的目的是确定在肺结核治疗的前8周内每天给予利福喷丁、利福沙星、异烟肼和吡嗪酰胺的方案的杀菌活性、安全性和耐受性。（约7.5 mg/kg）加替诺沙星（研究组），或利福平（约10 mg/kg）加乙胺丁醇（对照组），沿着异烟肼和吡嗪酰胺，持续8周。主要终点是完成8周治疗时的痰培养状态。结果121例参与者（累积目标的56%）入组。在8周治疗结束时，使用Lowenstein-Jensen（LJ）培养基的阴性培养在研究组的47/60（78%）参与者中发生，对照组为84%，p = 0.47;使用液体培养基的阴性培养物发生在研究组的37/47（79%）例中，（66%，p = 0.23）。使用液体培养基的研究组与对照组相比，达到稳定培养转化的时间更短（p = 0.03），但使用LJ培养基时无差异。中位利福喷丁浓度-时间曲线下面积（AUC 0 -24）为313 mcg*h/mL，与最近的利福喷丁每日450-600 mg给药研究相似。莫西沙星的中位AUC 0 -24为28.0 mcg*h/mL，远低于利福喷丁仅与莫西沙星间歇给药的试验。研究组中因微生物学不合格以外的原因而中止分配治疗的受试者比例高于对照组（11/62 [18%] vs. 3/59 [5%]，p = 0.04），尽管3级或以上不良事件的比例相似（研究组5/62 [8%]对对照组6/59 [10%，p = 0.76]）结论对于每日结核病强化治疗阶段联合异烟肼和吡嗪酰胺，含有利福沙星加低剂量利福喷丁的方案至少与含有乙胺丁醇加标准剂量的对照方案一样具有杀菌性利福平
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 Lowenstein-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.