Safety and tolerability of long-acting cabotegravir injections in HIV-uninfected men (ECLAIR): a multicentre, double-blind, randomised, placebo-controlled, phase 2a trial
Safety and tolerability of long-acting cabotegravir injections in HIV-uninfected men (ECLAIR): a multicentre, double-blind, randomised, placebo-controlled, phase 2a trial
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DOI：
10.1016/s2352-3018(17)30068-1
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发表时间：
2017-08-01
期刊：
影响因子：
16.1
通讯作者：
Spreen, William R.
中科院分区：
文献类型：
--
作者：
Markowitz, Martin;Frank, Ian;Spreen, William R.
背景Cabotegravir（GSK 1265744）是一种HIV-1整合酶链转移抑制剂，注射给药时具有强效抗病毒活性和长半衰期，可预防雄性猕猴重复直肠内激发后的猴-HIV感染。我们的目的是评估的安全性，耐受性和药物代谢动力学的长效cabotegravir注射剂在健康男性不处于HIV-1 infection.Methods的高风险，我们做了这个多中心，双盲，随机，安慰剂对照，2A期试验在美国的10个网站。通过计算机生成的中心随机化时间表，将筛选时被认为不具有感染HIV-1高风险的健康男性（年龄18-65岁）随机分配（5：1）接受cabotegravir或安慰剂。参与者在4周的口服导入期期间每天一次接受口服卡替拉韦30 mg片剂或匹配的安慰剂，随后是1周的洗脱期，并且在安全性评估后，以12周的间隔三次肌内注射长效卡替拉韦800 mg或生理盐水安慰剂。从入组至第41周（末次注射时间），研究中心工作人员和受试者对治疗分配设盲。主要终点是从首次注射（第5周）至末次注射后12周的安全性和耐受性。我们在安全性人群中进行了分析，安全性人群定义为所有参加研究并接受至少一剂研究药物的个体。研究结果在2014年3月27日至2016年2月23日期间，我们随机分配了127名参与者接受cabotegravir（n=106）或安慰剂（n=21）; 126（99%）名参与者组成了安全人群。ClinicalTrials.gov大多数参与者是男男性行为者（MSM; n=106 [83%]）和白色人（n=71 [56%]）。cabotegravir组的87名（82%）参与者和安慰剂组的20名（95%）参与者完成了注射阶段。不良事件（n=7 [7%]）和注射不耐受（n=4 [4%]）是cabotegravir组退出的主要原因。长效cabotegravir组（n=75 [80%]）中2级或更高级别不良事件的频率高于安慰剂组（n=10 [48%]; p=0.0049），主要是由于注射部位疼痛（n=55 [59%]）。合并用药、实验室检查异常、心电图和生命体征评估方面没有观察到显着差异。注射1次、2次和3次的几何平均血浆谷浓度分别为0.302 μ g/mL（95% CI 0.237-0.385）、0.331 μ g/mL（0.253-0.435）和0.387 μ g/mL（0.296-0.505），表明低于预测暴露量。第三次注射后估计的几何平均表观终末半衰期为40天。两个（2%）男男性接触者获得HIV-1感染，一个在注射阶段的安慰剂组和一个在cabotegravir组24周后的最后一次注射时，cabotegravir暴露远低于蛋白结合调整的90%抑制concentration.Interpretation尽管短暂的，轻度至中度的注射部位反应的发生率高，长效cabotegravir耐受性良好，具有可接受的安全性。药代动力学数据表明，800 mg每12周一次给药是次优方案;正在研究替代给药策略。我们的研究结果支持进一步研究长效注射剂cabotegravir作为口服暴露前预防方案的替代方案。
Background Cabotegravir (GSK1265744) is an HIV-1 integrase strand transfer inhibitor with potent antiviral activity and a long half-life when administered by injection that prevented simian-HIV infection upon repeat intrarectal challenge in male macaques. We aimed to assess the safety, tolerability, and pharmacokinetics of long-acting cabotegravir injections in healthy men not at high risk of HIV-1 infection.Methods We did this multicentre, double-blind, randomised, placebo-controlled, phase 2a trial at ten sites in the USA. Healthy men (aged 18-65 years) deemed not at high risk of acquiring HIV-1 at screening were randomly assigned (5: 1), via computer-generated central randomisation schedules, to receive cabotegravir or placebo. Participants received oral cabotegravir 30 mg tablets or matching placebo once daily during a 4 week oral lead-in phase, followed by a 1 week washout period and, after safety assessment, three intramuscular injections of long-acting cabotegravir 800 mg or saline placebo at 12 week intervals. Study site staff and participants were masked to treatment assignment from enrolment through week 41 (time of the last injection). The primary endpoint was safety and tolerability from the first injection (week 5) to 12 weeks after the last injection. We did analysis in the safety population, defined as all individuals enrolled in the study who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov identifier, NCT02076178.Findings Between March 27, 2014, and Feb 23, 2016, we randomly assigned 127 participants to receive cabotegravir (n=106) or placebo (n=21); 126 (99%) participants comprised the safety population. Most participants were men who have sex with men (MSM; n=106 [83%]) and white (n=71 [56%]). 87 (82%) participants in the cabotegravir group and 20 (95%) participants in the placebo group completed the injection phase. Adverse events (n=7 [7%]) and injection intolerability (n=4 [4%]) were the main reasons for withdrawal in the cabotegravir group. The frequency of grade 2 or higher adverse events was higher in participants in the long-acting cabotegravir group (n=75 [80%]) than in those in the placebo group (n=10 [48%]; p=0.0049), mostly due to injection-site pain (n=55 [59%]). No significant differences were noted in concomitant medications, laboratory abnormalities, electrocardiogram, and vital sign assessments. Geometric mean trough plasma concentrations were 0.302 mu g/mL (95% CI 0.237-0.385), 0.331 mu g/mL (0.253-0.435), and 0.387 mu g/mL (0.296-0.505) for injections one, two, and three, respectively, indicating lower than predicted exposure. The geometric mean apparent terminal phase half-life estimated after the third injection was 40 days. Two (2%) MSM acquired HIV-1 infection, one in the placebo group during the injection phase and one in the cabotegravir group 24 weeks after the final injection when cabotegravir exposure was well below the protein-binding-adjusted 90% inhibitory concentration.Interpretation Despite high incidence of transient, mild-to-moderate injection-site reactions, long-acting cabotegravir was well tolerated with an acceptable safety profile. Pharmacokinetic data suggest that 800 mg administered every 12 weeks is a suboptimal regimen; alternative dosing strategies are being investigated. Our findings support further investigation of long-acting injectable cabotegravir as an alternative to orally administered pre-exposure prophylaxis regimens.