Aspirin for cancer prevention in individuals with Lynch syndrome: first results from the CaPP3 multicentre, randomised, double-blind, non-inferiority trial.

CaPP3 aimed to assess the efficacy of two lower doses of aspirin.

CaPP3旨在评估两种较低剂量阿司匹林的疗效。

Methods

CaPP3 was a multicentre, parallel-group, randomised, double-blind, dose non-inferiority trial that compared 100 mg or 300 mg daily aspirin with 600 mg daily aspirin in Lynch syndrome carriers aged older than 18 years; patients were recruited from clinical genetics centres in the UK, Australia, Finland, Israel, and Spain.

CaPP3 是一项多中心、平行组、随机、双盲、剂量非劣效试验，比较了18岁以上携带林奇综合征的个体每天使用100毫克或300毫克阿司匹林与每天使用600毫克阿司匹林的效果；患者从英国、澳大利亚、芬兰、以色列和西班牙的临床遗传学中心招募而来。

The trial was double-blinded for 2 years, and open label on the same dose for three subsequent years with consent for cancer follow-up (except in the UK, where 75 mg aspirin replaced the 100 mg dose in the open phase).

该试验在前两年进行了双盲处理，随后的三年在相同剂量下进行开放标签试验，并获得了癌症随访的同意（除了在英国，开放阶段用75毫克阿司匹林替换了100毫克剂量）。

Participants from the five countries were randomly assigned by the Newcastle Clinical Trials Unit in a 3:3:4 ratio to receive daily doses of 100 mg, 300 mg, and 600 mg.

来自五个国家的参与者由纽卡斯尔临床试验单位按照3:3:4的比例随机分配，每天分别接受100毫克、300毫克和600毫克的剂量。

Participants received blinded doses of aspirin, identically packaged so as not to indicate dose, every 6 months.

参与者每六个月接受一次相同包装的阿司匹林剂量，以确保不显示剂量，从而保持盲法。

Information on compliance was collected on a self-report basis.

合规性信息是基于自我报告收集的。

The dose was revealed at 2 years of recruitment; subsequently, aspirin was obtained via hospital prescriptions during this open-label phase.

招募2年后公开了剂量；随后，在这个开放标签阶段，阿司匹林是通过医院处方获得的。

The primary outcome was the number of new primary mismatch repair-deficient cancers (referred to as Lynch syndrome cancers) developing in participants and diagnosed in the period from the start of the intervention for each participant.

主要结果是研究期间参与者新发的主要错配修复缺陷癌症（称为林奇综合征癌症）的数量，从每位参与者的干预开始时计算。

The safety outcome was the number of adverse events of interest in the first 2 years of blinded treatment.

安全性结果是盲测治疗的前两年中，关注的不良事件的数量。

Aspirin-specific adverse events were recorded at regular participant interviews as a measure of harm during the blinded phase.

在盲测阶段，通过定期参与者访谈记录了与阿司匹林相关的不良事件，作为伤害的衡量标准。

A non-inferiority margin of 1·5 was chosen for each lower dose against 600 mg daily for the primary endpoint.

对于主要终点，针对每日600毫克剂量，为每种较低剂量选择了1.5的非劣效性边界。

The effects of the two lower doses (compared to 600 mg daily) were examined with Cox proportional hazards examining time to first Lynch syndrome cancer, with the effect being assessed by hazard ratios (HRs), while negative binomial regression examined the relative cancer burden assessed by incidencerate ratios (IRRs).

研究了两种较低剂量（与每日600毫克相比）的效果，使用Cox比例风险模型评估首次发生林奇综合征癌症的时间，通过风险比（HRs）评估效果，而负二项回归则评估通过发病率比（IRRs）评估相对癌症负担。

Non-inferiority was proposed with either lower dose if the upper 95% CI of both the HR and IRR in comparison with 600 mg were below the non-inferiority boundary of 1·5.

如果与600毫克相比，两种较低剂量的HR和IRR的上限95%置信区间均低于1.5的非劣效性界限，则提出了非劣效性。

Participants were deemed per protocol if they had adhered to the protocol and continued taking aspirin into the unblinded phase (ie, they agreed to remain in the study at the 2-year review); non-inferiority required consistency of effects within both intention-to-treatand per-protocol populations and for both HR and IRR analyses.

如果参与者遵守了研究方案并在盲态阶段继续服用阿司匹林（即他们在2年回顾时同意留在研究中），则被视为符合方案；非劣效性要求在意向治疗人群和符合方案人群中效果的一致性，并且适用于风险比（HR）和发生率比（IRR）分析。

CaPP3 is registered on the ISRCTN registry (ISRCTN16261285) and ClinicalTrials.gov (NCT02497820), and was closed to recruitment in March 2019; this analysis was timed for when all participants reached 5 years past recruitment.

CaPP3已在ISRCTN注册（ISRCTN16261285）和ClinicalTrials.gov（NCT02497820）上注册，并于2019年3月关闭招募；此次分析是在所有参与者招募后5年进行的。

Further follow-up is planned until all participants reach 10 years past recruitment.

计划进一步随访，直到所有参与者达到招募后的10年。

Results

Between October, 2014, and March, 2019, 1879 patients with Lynch syndrome were recruited and randomly assigned: 564 (30·0%) to 100 mg aspirin daily, 565 (30·1%) to 300 mg daily, and 750 (39·9%) to 600 mg daily.

在2014年10月至2019年3月期间，共有1879名林奇综合征患者被招募并随机分配：564名（30.0%）每天服用100毫克阿司匹林，565名（30.1%）每天服用300毫克，以及750名（39.9%）每天服用600毫克。

Following the exclusion of 13 participants, the intention-to-treatpopulation consisted of 1866 participants; 559 (30·0%) received 100 mg, 562 (30·1%) received 300 mg, and 745 (39·9%) received 600 mg. 730 (39·1%) of 1866 participants stopped taking aspirin within the 2-year blinded phase, while 937 (50·2%) completed 5 years of aspirin, taking aspirin during the subsequent 3-year unblinded open phase.

排除了13名参与者后，意向治疗人群包括1866名参与者；559名（30.0%）接受了100毫克，562名（30.1%）接受了300毫克，745名（39.9%）接受了600毫克。在2年的双盲阶段，1866名参与者中有730名（39.1%）停止服用阿司匹林，而937名（50.2%）完成了5年的阿司匹林治疗，在随后的3年非盲开放阶段继续服用阿司匹林。

The per-protocol population consisted of 1136 participants: 336 (29·6%) on 100 mg, 357 (31·4%) on 300 mg, and 443 (39·0%) on 600 mg.

按方案人群包括1136名参与者：336名（29.6%）服用100毫克，357名（31.4%）服用300毫克，443名（39.0%）服用600毫克。

Up to a median of 66·4 months (IQR 32·1-84·0) of follow-up, 176 participants had been diagnosed with 216 Lynch syndrome cancers (57 cancers in patients on 100 mg, 75 in those on 300 mg, and 84 in those on 600 mg), including 83 of 1846 participants with colorectal cancer (21 participants on 100 mg, 30 on 300 mg, and 32 on 600 mg).

在中位随访时间为66.4个月（四分位数间距32.1-84.0）时，共有176名参与者被诊断出216例林奇综合征相关癌症（100毫克组57例，300毫克组75例，600毫克组84例），其中包括1846名参与者中的83例结直肠癌患者（100毫克组21例，300毫克组30例，600毫克组32例）。

For Lynch syndrome cancers, the 100 mg dose was non-inferior to 600 mg in the intention-to-treatanalysis (HR for time to first Lynch syndrome cancer 0·97 [95% CI 0·67-1·42], IRR for cancer burden 0·94 [95% CI 0·65-1·38]).

在林奇综合征相关癌症的意向治疗分析中，100毫克剂量与600毫克剂量相比显示出非劣效性（首次林奇综合征癌症发生时间的风险比为0.97 [95%置信区间0.67-1.42]，癌症负担的相对风险比为0.94 [95%置信区间0.65-1.38]）。

For the per-protocol analysis, the cancer burden was non-inferior with the 100 mg dose (IRR 0·90 [95% CI 0·55-1·46]) but time to first Lynch syndrome cancer was not (HR 1·00 [95% CI 0·61-1·63]).

在按方案分析中，100毫克剂量的癌症负担是非劣效的（IRR 0.90 [95% CI 0.55-1.46]），但首次Lynch综合征癌症的时间并非如此（HR 1.00 [95% CI 0.61-1.63]）。

Non-inferiority was not established for the 300 mg dose for either time to first Lynch syndrome cancer or cancer burden, in both intention-to-treatand per-protocol analyses (intention-to-treatpopulation: HR 1·28 [95% CI 0·91-1·80], IRR 1·12 [95% CI 0·79-1·61]; per-protocol population: HR 1·42 [0·91-2·19], IRR 1·28 [0·82-1·98]).

在意向治疗和按方案分析中，300毫克剂量对于首次Lynch综合征癌症的时间或癌症负担均未确立非劣效性（意向治疗人群：HR 1.28 [95% CI 0.91-1.80]，IRR 1.12 [95% CI 0.79-1.61]；按方案人群：HR 1.42 [0.91-2.19]，IRR 1.28 [0.82-1.98]）。

The proportion of participants with any reported adverse events of interest increased modestly but significantly with dose: 140 (25·0%) of 561 participants on 100 mg, 151 (26·8%) of 564 on 300 mg, and 234 (31·2%) of 750 on 600 mg (p=0·03 for heterogeneity).

感兴趣不良事件的参与者比例随着剂量的增加而适度但显著增加：在100 mg剂量下，561名参与者中有140名（25.0%），在300 mg剂量下，564名中有151名（26.8%），在600 mg剂量下，750名中有234名（31.2%）（异质性p=0.03）。

Over the 5 years, serious adverse events due to bleeding occurred in no patients on 100 mg, three (0·5%) on 300 mg, and 11 (1·5%) participants on 600 mg (p=0·004 for heterogeneity).

在5年期间，因出血导致的严重不良事件在100 mg剂量下没有患者发生，300 mg剂量下有三名（0.5%），而在600 mg剂量下有11名（1.5%）参与者发生（异质性p=0.004）。

interpretation

Although non-inferiority could not formally be concluded for either 100 mg or 300 mg of aspirin daily by comparison with 600 mg aspirin daily, there was evidence that the 100 mg dose had similar characteristics to 600 mg in terms of cancer risk but with fewer side-effects and less risk of bleeding.

尽管无法正式得出每日100毫克或300毫克阿司匹林与每日600毫克阿司匹林相比具有非劣效性的结论，但有证据表明，100毫克剂量在癌症风险方面与600毫克相似，但副作用更少，出血风险更低。

funding

Cancer Research UK; Bayer Pharma; Newcastle Hospitals NHS Foundation Trust.

癌症研究英国；拜耳制药；纽卡斯尔医院NHS基金会信托。