Efficacy and safety of subcutaneous guselkumab induction therapy in participants with moderately to severely active ulcerative colitis (ASTRO): a double-blind, treat-through, randomised, placebo-controlled, phase 3 trial.

We aimed to evaluate the efficacy and safety of subcutaneous guselkumab induction in adults with moderately to severely active ulcerative colitis.

我们旨在评估皮下注射guselkumab诱导治疗中度至重度活动性溃疡性结肠炎成人的疗效和安全性。

Methods

The ASTRO double-blind, treat-through, randomised, placebo-controlled, phase 3 trial enrolled adults (≥18 years) at 153 sites (community centres or hospitals) in 25 countries with moderately to severely active ulcerative colitis (modified Mayo score 5-9 with a Mayo endoscopic subscore [MES] ≥2 and a Mayo rectal bleeding subscore [RBS] ≥1) and current or history of inadequate response or intolerance to corticosteroids, azathioprine, 6-mercaptopurine, biologics, JAK inhibitors, or sphingosine 1-phosphate receptor (S1P) inhibitors or a history of corticosteroid dependence.

ASTRO双盲、治疗贯穿、随机、安慰剂对照的III期试验招募了年龄≥18岁的成人患者，他们在25个国家的153个地点（社区中心或医院）患有中度至重度活动性溃疡性结肠炎（改良Mayo评分5-9，内镜下Mayo评分[MES]≥2，直肠出血评分[RBS]≥1），且目前或既往对皮质类固醇、硫唑嘌呤、6-巯基嘌呤、生物制剂、JAK抑制剂或鞘氨醇1-磷酸受体（S1P）抑制剂反应不足或不耐受，或有皮质类固醇依赖史。

By permuted blocks and stratified by inadequate response or intolerance to biologics, JAK inhibitors, or S1P inhibitors (yes/no) and baseline MES (2 or 3), eligible participants were randomly assigned (1:1:1) to receive either subcutaneous guselkumab 400 mg at weeks 0, 4, and 8 followed by 100 mg every 8 weeks (400/100 mg group), subcutaneous guselkumab 400 mg at weeks 0, 4, and 8 followed by 200 mg every 4 weeks (400/200 mg group), or matched subcutaneous placebo.

通过置换分组，并根据对生物制剂、JAK抑制剂或S1P抑制剂反应不足或不耐受（是/否）以及基线MES（2或3）进行分层，符合条件的参与者被随机分配（1:1:1）接受皮下注射guselkumab 400 mg，在第0、4、8周给药，随后每8周注射100 mg（400/100 mg组），皮下注射guselkumab 400 mg，在第0、4、8周给药，随后每4周注射200 mg（400/200 mg组），或匹配的皮下注射安慰剂。

Investigators, study-site personnel, and participants were masked to treatment assignment.

研究人员、研究现场人员和参与者对治疗分配情况进行了盲法处理。

Participants who met rescue criteria at week 16 received subcutaneous guselkumab 400 mg at weeks 16, 20, and 24 followed by 100 mg every 8 weeks (placebo group) or continued their assigned guselkumab treatment (sham rescue).

在第16周符合救援标准的参与者接受了皮下注射guselkumab 400 mg，在第16、20和24周，随后每8周注射100 mg（安慰剂组），或继续接受指定的guselkumab治疗（模拟救援）。

The primary outcome of clinical remission at week 12 (defined as Mayo stool frequency subscore of 0 or 1 and not increased from baseline, Mayo RBS of 0, and MES of 0, or 1 with no friability) was assessed among all participants who were randomly assigned and received at least one dose of study drug according to the treatment group to which they were assigned.

在所有被随机分配并至少接受一次研究药物治疗的参与者中，评估了第12周的临床缓解情况（定义为Mayo排便频率子分数为0或1且不高于基线，Mayo RBS为0，MES为0或1且无脆性），根据他们被分配的治疗组进行评估。

Safety was assessed until week 24 among all participants who were randomly assigned and received at least one dose of study drug according to the treatment they received.

所有被随机分配并至少接受一次研究药物治疗的参与者的安全性评估一直持续到第24周，根据他们接受的治疗进行评估。

This trial is registered with ClinicalTrials.gov, NCT05528510, and is ongoing.

该试验已在ClinicalTrials.gov注册，注册号为NCT05528510，目前正在进行中。

Results

Between Sept 13, 2022, and April 2, 2024, 651 participants were screened for eligibility and 418 participants were randomly assigned to the guselkumab 400/100 mg group (n=139), the guselkumab 400/200 mg group (n=140), and the placebo group (n=139).

在2022年9月13日至2024年4月2日期间，共有651名参与者接受了资格筛查，最终有418名参与者被随机分配到guselkumab 400/100 mg组（n=139）、guselkumab 400/200 mg组（n=140）和安慰剂组（n=139）。

Mean age was 41·7 years (SD 14·2), 256 (61%) of 418 participants were male, and 162 (39%) were female.

平均年龄为41.7岁（标准差14.2），418名参与者中有256名（61%）为男性，162名（39%）为女性。

Mean ulcerative colitis duration was 7·6 years (SD 6·7) and mean modified Mayo score was 6·7 (1·2).

平均溃疡性结肠炎病程为7.6年（标准差6.7），平均改良Mayo评分为6.7（1.2）。

A significantly greater proportion of participants receiving guselkumab 400 mg induction versus placebo had clinical remission at week 12 (77 [28%] of 279 vs nine [6%] of 139; adjusted treatment difference 21 percentage points, 95% CI 14-28; p<0·0001).

在第12周时，接受guselkumab 400 mg诱导治疗的参与者中，有显著更高比例的患者达到临床缓解（279名中有77名[28%]，而139名安慰剂组中有9名[6%]；调整后的治疗差异为21个百分点，95%置信区间为14-28；p<0·0001）。

At week 24, 49 (35%) participants in the guselkumab 400/100 mg group, 51 (36%) in the guselkumab 400/200 mg group, and 13 (9%) in the placebo group were in clinical remission (the difference between both guselkumab groups and placebo was statistically significant).

在第24周时，guselkumab 400/100 mg组有49名（35%）参与者，guselkumab 400/200 mg组有51名（36%）参与者，以及安慰剂组有13名（9%）参与者处于临床缓解状态（guselkumab两个组与安慰剂组之间的差异具有统计学意义）。

The frequencies of adverse events in the guselkumab groups (74 [53%] of 139 for 400/100 mg and 85 [61%] of 140 for 400/200 mg) were similar to that in the placebo group (91 [65%] of 139).

在使用古塞尔库单抗的组别中（139人中有74人[53%]使用400/100 mg剂量，140人中有85人[61%]使用400/200 mg剂量），不良事件的发生频率与安慰剂组（139人中有91人[65%]）相似。

There were no treatment-related deaths, and no new safety concerns were identified.

没有治疗相关的死亡事件发生，也没有识别出新的安全问题。

The most frequently reported adverse events were worsening of ulcerative colitis (14 [10%] in the 400/100 mg group, nine [6%] in the 400/200 mg group, and 29 [21%] in the placebo group), arthralgia (11 [8%], seven [5%], and three [2%]), and upper respiratory tract infection (ten [7%], five [4%], and nine [6%]).

报告中最常见的不良事件是溃疡性结肠炎恶化（400/100 mg组14例[10%]，400/200 mg组9例[6%]，安慰剂组29例[21%]），关节痛（11例[8%]，7例[5%]，3例[2%]），以及上呼吸道感染（10例[7%]，5例[4%]，9例[6%]）。

Serious adverse events occurred in five (4%) participants in the 400/100 mg group, six (4%) in the 400/200 mg group, and 17 (12%) in the placebo group.

严重不良事件发生在400/100 mg组的五名（4%）参与者中，400/200 mg组的六名（4%）参与者中，以及安慰剂组的17名（12%）参与者中。

interpretation

Subcutaneous guselkumab induction and maintenance was safe and efficacious for 24 weeks in participants with moderately to severely active ulcerative colitis, establishing a fully subcutaneous guselkumab regimen as a treatment option in this patient population.

在中度至重度活动性溃疡性结肠炎患者中，皮下注射古塞尔库单抗诱导和维持治疗24周是安全且有效的，确立了完全皮下注射古塞尔库单抗方案作为这一患者群体的治疗选择。

funding

Johnson & Johnson.

强生公司。