A Phase I/II Randomized, Open-label Trial to Evaluate the Pharmacokinetics, Safety, and Treatment Outcomes of Multidrug Treatment Including High Dose Rifampicin with or without Levofloxacin versus Standard Treatment for Pediatric Tuberculous Meningitis
试验速览
- 阶段
- 1/2 期
- 状态
- 已完成
- 入组人数
- 120
- 试验地点
- 3
- 主要终点
- 3.Grade 3 or higher AEs during treatment phase
研究概览
简要总结
Of 2487 children prescreened, 79 were screened and 37 enrolled. Median age was 72 months; 49%, 43%, and 8% had stage I, II, and III disease, respectively. Grade 3 or higher adverse events occurred in 58%, 55%, and 36% of children in arms 1, 2, and 3, with 1 death (arm 1) and 6 early treatment discontinuations (4 in arm 1, 1 each in arms 2 and 3). By week 8, all children recovered to MRS score of 0 or 1. Average MSEL scores were significantly better in arm 1 than arm 3 in fine motor, receptive language, and
expressive language domains (P < .01).
in this first-ever trial of antimicrobials specifically for pediatric TBM, functional outcomes were favorable, across arms. Neurocognitive outcomes were statistically better in children who received high-dose rifampicin compared to those who did not, but this finding requires replication in larger trials. There was no discernable benefit of levofloxacin, though small sample size precluded a thorough assessment of the potential risks and benefits of levofloxacin substitution for ethambutol.
研究设计
- 研究类型
- Interventional
- 分配方式
- Computer generated randomization
- 盲法
- Open Label
入排标准
- 年龄范围
- 6.00 Month(s) 至 12.00 Year(s)（—）
- 性别
- All
入选标准
- •Weight > 6kg
- •Age greater than or equal to 6 months to less than or equal to 12 years and, in the opinion of the investigator, can tolerate the treatment and study participation.
- •Probable or definite TBM according to diagnostic criteria (Appendix II) or a positive Gene Xpert CSF test.
- •4.Since participants will all be under legal age of independent consent, a parent or legal guardian must be willing and able to provide informed consent.
- •If the subject is of appropriate age, she/he will also be asked to give assent if developmentally appropriate and clinically possible.
- •Participant can comply with the protocol requirements in the opinion of the site investigator.
排除标准
- •TB treatment for more than 7 days within 30 days prior to enrollment
- •Exposure via close contact with someone with MDR-TB (or rifampicin mono-resistant TB) or personal history of MDR-TB (or rifampicin mono-resistant TB)
- •Known intolerance or allergy to any of the study drugs
- •Death imminent and expected within 24 hours, as assessed by the site investigator
- •Moderate to severe renal or liver dysfunction (Grade 2 or higher abnormalities of creatinine, ALT, or direct bilirubin)
- •HIV infection with any of the following: Planned initiation of antiretroviral treatment (ART) during the experimental treatment phase (first 8 weeks), as initiation of ART is contraindicated in that time period with TBM.
- •On ART with planned continued use of a protease inhibitor or nevirapine (children can be switched to an acceptable alternative regimen and then participate) 7.Having participated in other clinical studies with investigational agents or treatments within 8 weeks prior to enrollment.
- •8.A clinically significant active medical condition or the presence of any concomitant severe illness or rapidly deteriorating health condition (outside of TB), which, in the opinion of the site investigator, would prevent appropriate participation in the trial, or that would make implementation of the protocol or interpretation of the study results difficult, or otherwise make the subject a poor candidate for a clinical trial.
结局指标
主要结局
3.Grade 3 or higher AEs during treatment phase
时间窗: 18 months
1.Population plasma and CSF PK of rifampicin and levofloxacin: A population modelling approach will be used to describe pharmacokinetics of rifampicin and levofloxacin in plasma and CSF. This PK model will represent an immediate basis for linkage to the longitudinal efficacy measurements.
时间窗: 18 months
2.Population PK/PD model assessing the relationship between PK of rifampicin and the primary efficacy endpoint, Modified Ranking Score (MRS) for children.
时间窗: 18 months
次要结局
- 1.Overall longitudinal cognitive score and subscale (gross motor, visual reception, fine motor receptive language, expressive language) MSEL scoring system longitudinally, at baseline, 2, 12, and 18 months.(2.Favorable TB treatment response at 48 weeks will be reported as a binary variable (favorable or unfavorable) at 48 weeks.)