AQ-13, an investigational antimalarial, versus artemether plus lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria: a randomised, phase 2, non-inferiority clinical trial.
AQ-13, an investigational antimalarial, versus artemether plus lumefantrine for the treatment of uncomplicated Plasmodium falciparum malaria: a randomised, phase 2, non-inferiority clinical trial.
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DOI：
10.1016/s1473-3099(17)30365-1
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发表时间：
2017-12
期刊：
影响因子：
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通讯作者：
Krogstad DJ
中科院分区：
文献类型：
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作者：
Koita OA;Sangaré L;Miller HD;Sissako A;Coulibaly M;Thompson TA;Fongoro S;Diarra Y;Ba M;Maiga A;Diallo B;Mushatt DM;Mather FJ;Shaffer JG;Anwar AH;Krogstad DJ
氯喹被用于疟疾治疗，直到发现抗药性恶性疟原虫。因为具有修饰侧链的4-氨基喹啉类，如AQ-13，对抗性寄生虫有活性，我们比较了AQ-13与蒿甲醚加本芴醇治疗单纯恶性疟原虫疟疾的效果。我们做了一个随机的非劣效性试验。我们在Missira（马里东北部）和巴马科（马里首都）筛选了患有无并发症疟疾的男性（≥18岁），以确定合格性（≥2000个无性恶性疟原虫/μL血液）。合格的参与者被随机分配到蒿甲醚加本芴醇组或AQ-13组，通过随机数发生器排列四个区块。除了接受治疗的受试者和实施随机化并提供治疗的研究药剂师外，医生和其他照顾受试者的人均被设盲。参与者接受80 mg口服蒿甲醚和480 mg口服本芴醇，每天两次，持续3天，或在第1天和第2天接受638·50 mg AQ-13碱（两粒口服胶囊），并在第3天接受319·25 mg碱（一粒口服胶囊）。在第1周期间，监测受试者的寄生虫清除率（50 μL血样，每天两次，间隔12小时，直至获得连续两个阴性样本），并作为住院患者对不良事件进行访谈（每天一次）。在为期5周的门诊随访期间，每周两次检查参与者的不良事件和复发性感染。所有参与者都被纳入意向治疗分析和符合方案分析，除了那些在符合方案分析中脱落的人。复合主要结局是第7天无性寄生虫和发热的清除，以及第8天至第42天无具有相同分子标记物的寄生虫复发感染（定义为治愈）。如果蒿甲醚+本芴醇组治愈的患者比例高于AQ-13组，并且95% CI的上限小于非劣效性界值15%，则认为确立了非劣效性。本试验在ClinicalTrials.gov上注册，编号为NCT 01614964。在2013年8月6日至11月18日期间，以及2015年9月18日至11月20日期间，招募了66名患有无并发症疟疾的马里男性。33名参与者被随机分配到每组。两组均未发生严重不良事件（2-4级），且无性寄生虫均在第7天清除。报告了453起不太严重的不良事件（≤ 1级）：联合用药组214起，AQ-13组239起。两名参与者在寄生虫清除后退出AQ-13组，三名参与者失访。在蒿甲醚加苯芴醇组中，两名参与者晚期治疗失败（与原始分离株相同的标记物）。根据符合方案分析，AQ-13组和蒿甲醚加本芴醇组的治愈比例相似（28/28 [100%] vs 31/33 [93.9%]; p= 0.50），AQ-13并不劣于蒿甲醚加本芴醇组（差异-6.1%，95%CI-14.7至2.4）。在意向治疗分析中，两组的治愈比例也相似（AQ-13组为28/33，84.8%;蒿甲醚和本芴醇组为31/33，93.9%; p= 0.43），但95%CI的上限超过了15%的非劣效性界值（差异9.1%，95%CI − 5.6至23.8）。符合方案分析表明AQ-13非劣效于蒿甲醚+本芴醇。相比之下，意向治疗分析包括AQ-13组的两名退出者和三名失访者，不符合AQ-13的非劣效性标准，尽管没有AQ-13治疗失败。需要更多参与者（和非免疫参与者）的研究来决定是否应该推荐广泛使用修饰的4-氨基喹诺酮类药物。美国食品和药物管理局孤儿产品开发部、美国国立卫生研究院、美国疾病控制和预防中心、Burroughs-Wellcome基金会、美国国务院和世卫组织。
Chloroquine was used for malaria treatment until resistant Plasmodium falciparum was identified. Because 4-aminoquinolines with modified side chains, such as AQ-13, are active against resistant parasites, we compared AQ-13 against artemether plus lumefantrine for treatment of uncomplicated P falciparum malaria. We did a randomised, non-inferiority trial. We screened men (≥18 years) with uncomplicated malaria in Missira (northeast Mali) and Bamako (capital of Mali) for eligibility (≥2000 asexual P falciparum parasites per μL of blood). Eligible participants were randomly assigned to either the artemether plus lumefantrine group or AQ-13 group by permuting blocks of four with a random number generator. Physicians and others caring for the participants were masked, except for participants who received treatment and the research pharmacist who implemented the randomisation and provided treatment. Participants received either 80 mg of oral artemether and 480 mg of oral lumefantrine twice daily for 3 days or 638·50 mg of AQ-13 base (two oral capsules) on days 1 and 2, and 319·25 mg base (one oral capsule) on day 3. Participants were monitored for parasite clearance (50 μL blood samples twice daily at 12 h intervals until two consecutive negative samples were obtained) and interviewed for adverse events (once every day) as inpatients during week 1. During the 5-week outpatient follow-up, participants were examined for adverse events and recurrent infection twice per week. All participants were included in the intention-to-treat analysis and per-protocol analysis, except for those who dropped out in the per-protocol analysis. The composite primary outcome was clearance of asexual parasites and fever by day 7, and absence of recrudescent infection by parasites with the same molecular markers from days 8 to 42 (defined as cure). Non-inferiority was considered established if the proportion of patients who were cured was higher for artemether plus lumefantrine than for AQ-13 and the upper limit of the 95% CI was less than the non-inferiority margin of 15%. This trial is registered at ClinicalTrials.gov, number NCT01614964. Between Aug 6 and Nov 18, 2013, and between Sept 18 and Nov 20, 2015, 66 Malian men with uncomplicated malaria were enrolled. 33 participants were randomly assigned to each group. There were no serious adverse events (grade 2–4) and asexual parasites were cleared by day 7 in both groups. 453 less-severe adverse events (≤grade 1) were reported: 214 in the combination group and 239 in the AQ-13 group. Two participants withdrew from the AQ-13 group after parasite clearance and three were lost to follow-up. In the artemether plus lumefantrine group, two participants had late treatment failures (same markers as original isolates). On the basis of the per-protocol analysis, the AQ-13 and artemether plus lumefantrine groups had similar proportions cured (28 [100%] of 28 vs 31 [93·9%] of 33; p=0·50) and AQ-13 was not inferior to artemether plus lumefantrine (difference −6·1%, 95% CI −14·7 to 2·4). Proportions cured were also similar between the groups in the intention-to-treat analysis (28 of 33, 84·8% for AQ-13 vs 31 of 33, 93·9% for artemether and lumefantrine; p=0·43) but the upper bound of the 95% CI exceeded the 15% non-inferiority margin (difference 9·1%, 95% CI −5·6 to 23·8). The per-protocol analysis suggested non-inferiority of AQ-13 to artemether plus lumefantrine. By contrast, the intention-to-treat analysis, which included two participants who withdrew and three who were lost to follow-up from the AQ-13 group, did not meet the criterion for non-inferiority of AQ-13, although there were no AQ-13 treatment failures. Studies with more participants (and non-immune participants) are needed to decide whether widespread use of modified 4-aminoquinolones should be recommended. US Food and Drug Administration Orphan Product Development, National Institutes of Health, US Centers for Disease Control and Prevention, Burroughs-Wellcome Fund, US State Department, and WHO.