单剂量贝达喹啉联合利福平用于麻风病暴露后预防的安全性:在科摩罗群岛进行的第 2 阶段随机非劣效性试验。

IF 15.8 1区 医学 Q1 Medicine
PLoS Medicine Pub Date : 2024-10-21 eCollection Date: 2024-10-01 DOI:10.1371/journal.pmed.1004453
Bouke Catherine de Jong, Said Nourdine, Auke Thomas Bergeman, Zahara Salim, Silahi Halifa Grillone, Sofie Marijke Braet, Mohamed Wirdane Abdou, Rian Snijders, Maya Ronse, Carolien Hoof, Achilleas Tsoumanis, Nimer Ortuño-Gutiérrez, Christian van der Werf, Alberto Piubello, Aboubacar Mzembaba, Younoussa Assoumani, Epco Hasker
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引用次数: 0

摘要

背景:为了将麻风病人接触者的麻风病风险降低约50%,世界卫生组织(WHO)建议使用单剂量利福平(SDR)进行麻风病暴露后预防(PEP)。在科摩罗和马达加斯加进行的一项分组随机试验结果表明,使用双剂量利福平进行麻风病暴露后预防同样可以减少麻风病的发病率,因此有必要加强麻风病暴露后预防。这项2期试验的目的是评估贝达喹啉强化PEP方案(干预组,贝达喹啉800毫克加利福平600毫克,BE-PEP)相对于世界卫生组织推荐的单用利福平600毫克PEP方案(对照组,SDR-PEP)的安全性:从2022年7月到2023年1月,对同意的参与者进行了资格筛选,包括服用PEP后心率校正QT间期(QTc)为50毫秒或超过450毫秒。根据方案,对所有儿童进行了综合分析,与 SDR-PEP 相比,BE-PEP 的平均 QTc 升高没有显著差异,但在未经调整的分析中,BE-PEP 在儿童中的非劣效性未得到证实,因为 95% CI 的上限为 10.4 毫秒,超过了预先设定的 10 毫秒。调整基线 QTc 后,回归系数和 95% CI (3.3; -1.4, 8.0) 达到了 10 毫秒的非劣效边距。干预组和对照组之间的谷丙转氨酶(ALT)或谷草转氨酶(AST)水平无明显差异,但研究的一个局限性是在成人招募过程中由于技术错误导致谷丙转氨酶(ALT)/谷草转氨酶(AST)假性升高。两个研究组均报告了一起严重不良事件,均被认为与研究药物无关。成人头晕、恶心、头痛和腹泻以及儿童头痛在BE-PEP组中的发生率较高,但无显著性差异:在这项研究中,我们观察到单剂量贝达喹啉 800 毫克与利福平联用的安全性与单用利福平相当,但只有在调整基线 QTc 测量值后,儿童的 QTc 变化才显示出非劣效性。目前正在科摩罗进行一项第 3 期分组随机疗效试验:试验注册:ClinicalTrials.gov NCT05406479。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Safety of single-dose bedaquiline combined with rifampicin for leprosy post-exposure prophylaxis: A Phase 2 randomized non-inferiority trial in the Comoros Islands.

Background: To reduce leprosy risk in contacts of patients with leprosy by around 50%, the World Health Organization (WHO) recommends leprosy post-exposure prophylaxis (PEP) using single-dose rifampicin (SDR). Results from a cluster randomized trial in the Comoros and Madagascar suggest that PEP with a double dose of rifampicin led to a similar reduction in incident leprosy, prompting the need for stronger PEP. The objective of this Phase 2 trial was to assess safety of a bedaquiline-enhanced PEP regimen (intervention arm, bedaquiline 800 mg with rifampicin 600 mg, BE-PEP), relative to the WHO recommended PEP with rifampicin 600 mg alone (control arm, SDR-PEP).

Methods and findings: From July 2022 to January 2023, consenting participants were screened for eligibility, including a heart rate-corrected QT interval (QTc) <450 ms and liver enzyme tests (ALT/AST) below 3× the upper limit of normal (ULN), before they were individually randomized 1:1 in an open-label design. Recruitment was sequential, by age group. Pediatric dosages were weight adjusted. Follow-up was done at day 1 post-dose (including ECG) and day 14 (including ALT/AST), with repeat of ALT/AST on the last follow-up at day 30 in case of elevation on day 14. The primary outcome was non-inferiority of BE-PEP based on a <10 ms difference in QTc 24 h after treatment administration, both unadjusted and adjusted for baseline QTc. Of 408 screened participants, 313 were enrolled, starting with 187 adults, then 38 children aged 13 to 17 years, and finally 88 children aged 5 to 12 years, of whom 310 (99%) completed all visits. Across all ages, the mean QTc change on BE-PEP was from 393 ms to 396 ms, not significantly different from the change from 392 ms to 394 ms on SDR-PEP (difference between arms 1.8 ms, 95% CI -1.8, 5.3, p = 0.41). No individual's QTc increased by >50 ms or exceeded 450 ms after PEP administration. Per protocol, all children were analyzed together, with no significant difference in mean QTc increase for BE-PEP compared to SDR-PEP, although non-inferiority of BE-PEP in children was not demonstrated in unadjusted analysis, as the upper limit of the 95% CI of 10.4 ms exceeded the predefined margin of 10 ms. Adjusting for baseline QTc, the regression coefficient and 95% CI (3.3; -1.4, 8.0) met the 10 ms non-inferiority margin. No significant differences in ALT or AST levels were noted between the intervention and control arms, although a limitation of the study was false elevation of ALT/AST during adult recruitment due to a technical error. In both study arms, one serious adverse event was reported, both considered unlikely related to the study drugs. Dizziness, nausea, headache, and diarrhea among adults, and headaches in children, were nonsignificantly more frequently observed in the BE-PEP group.

Conclusions: In this study, we observed that safety of single-dose bedaquiline 800 mg in combination with rifampicin is comparable to rifampicin alone, although non-inferiority of QTc changes was demonstrated in children only after adjusting for the baseline QTc measurements. A Phase 3 cluster randomized efficacy trial is currently ongoing in the Comoros.

Trial registration: ClinicalTrials.gov NCT05406479.

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来源期刊
PLoS Medicine
PLoS Medicine MEDICINE, GENERAL & INTERNAL-
CiteScore
17.60
自引率
0.60%
发文量
227
审稿时长
4-8 weeks
期刊介绍: PLOS Medicine is a prominent platform for discussing and researching global health challenges. The journal covers a wide range of topics, including biomedical, environmental, social, and political factors affecting health. It prioritizes articles that contribute to clinical practice, health policy, or a better understanding of pathophysiology, ultimately aiming to improve health outcomes across different settings. The journal is unwavering in its commitment to uphold the highest ethical standards in medical publishing. This includes actively managing and disclosing any conflicts of interest related to reporting, reviewing, and publishing. PLOS Medicine promotes transparency in the entire review and publication process. The journal also encourages data sharing and encourages the reuse of published work. Additionally, authors retain copyright for their work, and the publication is made accessible through Open Access with no restrictions on availability and dissemination. PLOS Medicine takes measures to avoid conflicts of interest associated with advertising drugs and medical devices or engaging in the exclusive sale of reprints.
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