Efficacy and Safety of AmBisome in Combination with Sodium Stibogluconate or Miltefosine and Miltefosine Monotherapy for African Visceral Leishmaniasis: Phase II Randomized Trial.
Efficacy and Safety of AmBisome in Combination with Sodium Stibogluconate or Miltefosine and Miltefosine Monotherapy for African Visceral Leishmaniasis: Phase II Randomized Trial.
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DOI：
10.1371/journal.pntd.0004880
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发表时间：
2016-09
影响因子：
3.8
通讯作者：
Musa A
中科院分区：
文献类型：
--
作者：
Wasunna M;Njenga S;Balasegaram M;Alexander N;Omollo R;Edwards T;Dorlo TP;Musa B;Ali MH;Elamin MY;Kirigi G;Juma R;Kip AE;Schoone GJ;Hailu A;Olobo J;Ellis S;Kimutai R;Wells S;Khalil EA;Strub Wourgaft N;Alves F;Musa A
在东非，建议将超过17天的SSG&PM作为内脏利什曼病的一线治疗方法，但这是痛苦的，需要住院治疗。包括AmBisome和米特福辛在内的联合治疗方案在印度是安全有效的，但是没有来自包括这些非洲药物在内的联合治疗试验的公开数据。在苏丹和肯尼亚进行了一项II期开放标签，非比较随机试验，以评估三种治疗方案的有效性和安全性：10mg /kg单剂量AmBisome加10天SSG （20mg /kg/天），10mg /kg单剂量AmBisome加10天米替福辛（2.5mg/kg/天）和米替福辛单独（2.5mg/kg/天，28天）。主要终点是第28天的初始寄生虫学治愈，次要终点包括第210天的最终治愈，以及药代动力学（米替福辛）和药效学评估。在每组49-51例患者的序贯分析中，所有组的初始治愈率为85% （95% CI: 73-92）。在D210时，AmBisome + SSG的最终治愈率为87% (95% CI: 77-97)， AmBisome +米特福辛的最终治愈率为77% (95% CI: 64-90)，米特福辛单独治愈率为72% (95% CI: 60-85)，在体重较轻的年轻患者中，治愈率较低。米替福辛的药代动力学数据显示，儿童与成人相比暴露不足。没有发现主要的安全性问题，但每个方案的最终治愈率点估计低于90%，因此目前形式的III期试验不会对其进行评估。米替福辛在儿童中的异速给药需要评估。该研究已在ClinicalTrials.gov注册，注册号NCT01067443内脏利什曼病，或黑热病，是一种未经治疗可致死的寄生虫病。东部非洲推荐的治疗方法是用帕罗霉素（PM）治疗顽抗葡萄糖酸钠（SSG），为期17天，但需要进行痛苦的注射，导致不良事件，并且患者在治疗期间需要住院。最好是一种负担得起的、安全有效的口服治疗方法。在寻找全新药物的研究正在进行的同时，现有的治疗方法正在被优化，作为一种短期解决方案。基于AmBisome和米特福辛的联合治疗方案已被证明在治疗印度患者方面是安全有效的，但是没有关于非洲在联合治疗方案中使用这些药物的公开数据，那里的治疗效果可能与印度不同。评估了三种治疗东非VL的方案，AmBisome与SSG或米替福辛联合使用，或单独使用米替福辛。同样，在印度有效的药物在非洲患者中效果较差，而且没有一种试验方案显示出足够高的最终治愈率，无法在第三期试验中进行评估。结果还表明，米替福辛在儿童中的剂量不足，因此需要研究异速剂量，考虑到儿童与成人在药物代谢方面的差异。
SSG&PM over 17 days is recommended as first line treatment for visceral leishmaniasis in eastern Africa, but is painful and requires hospitalization. Combination regimens including AmBisome and miltefosine are safe and effective in India, but there are no published data from trials of combination therapies including these drugs from Africa. A phase II open-label, non-comparative randomized trial was conducted in Sudan and Kenya to evaluate the efficacy and safety of three treatment regimens: 10 mg/kg single dose AmBisome plus 10 days of SSG (20 mg/kg/day), 10 mg/kg single dose AmBisome plus 10 days of miltefosine (2.5mg/kg/day) and miltefosine alone (2.5 mg/kg/day for 28 days). The primary endpoint was initial parasitological cure at Day 28, and secondary endpoints included definitive cure at Day 210, and pharmacokinetic (miltefosine) and pharmacodynamic assessments. In sequential analyses with 49–51 patients per arm, initial cure was 85% (95% CI: 73–92) in all arms. At D210, definitive cure was 87% (95% CI: 77–97) for AmBisome + SSG, 77% (95% CI 64–90) for AmBisome + miltefosine and 72% (95% CI 60–85) for miltefosine alone, with lower efficacy in younger patients, who weigh less. Miltefosine pharmacokinetic data indicated under-exposure in children compared to adults. No major safety concerns were identified, but point estimates of definitive cure were less than 90% for each regimen so none will be evaluated in Phase III trials in their current form. Allometric dosing of miltefosine in children needs to be evaluated. The study was registered with ClinicalTrials.gov, number NCT01067443 Visceral leishmaniasis, or kala-azar, is a parasitic disease which is fatal without treatment. A 17-day treatment of sodium stibogluconate (SSG) with paromomycin (PM) is the recommended treatment in eastern Africa, but requires painful injections, causes adverse events, and patients need to stay in the hospital during treatment. An affordable, safe and effective oral treatment would be preferable. Whilst research to identify entirely new drugs is underway, existing treatments are being optimized as a short-term solution. Combination regimens based on AmBisome and miltefosine have been shown to be safe and effective in treating Indian patients, but there are no published data from use of these drugs in combination regimens from Africa, where efficacy of treatments can be different from India. Three regimens were evaluated for treating VL in eastern Africa, using AmBisome in combination with SSG or miltefosine, or miltefosine alone. Once again, drugs which are effective in India were found to be less so in African patients, and none of the regimes tested showed sufficiently high definitive cure rates to evaluate in Phase III trials. The results also suggest miltefosine was under-dosed in children and so allometric dosing, which takes into account the differences in drug metabolism seen in children compared to adults, needs to be studied.
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影响因子：
3.8
作者：
Khalil, Eltahir A. G.;Weldegebreal, Teklu;Hailu, Asrat
通讯作者：
Hailu, Asrat
影响因子：
3
作者：
Ranque, Stephane;Badiaga, Sekene;Brouqui, Philippe
通讯作者：
Brouqui, Philippe
影响因子：
168.9
作者：
Sundar, Shyam;Sinha, Prabhat Kumar;Modabber, Farrokh
通讯作者：
Modabber, Farrokh
影响因子：
11.8
作者：
Bhattacharya, SK;Jha, TK;Berman, JD
通讯作者：
Berman, JD
影响因子：
158.5
作者：
Sundar, S;Jha, TK;Berman, J
通讯作者：
Berman, J