The Lancet Gastroenterology & Hepatology ( IF 35.7 ) Pub Date : 2021-08-11 , DOI: 10.1016/s2468-1253(21)00252-1 Stephen Hanauer 1 , Bernd Liedert 2 , Sigrid Balser 3 , Ekkehard Brockstedt 4 , Viktoria Moschetti 4 , Stefan Schreiber 5
Background
BI 695501 is a biosimilar that has demonstrated similar efficacy, safety, and immunogenicity to adalimumab reference product in patients with rheumatoid arthritis and chronic plaque psoriasis. The VOLTAIRE-CD study aimed to compare the efficacy and safety of BI 695501 with adalimumab reference product in patients with Crohn's disease.
Methods
This phase 3, randomised, double-blind study was done at 92 centres in 12 countries across Europe and the USA in patients aged 18–80 years with moderately to severely active Crohn's disease (Crohn's Disease Activity Index [CDAI] score 220–450). Patients were randomly assigned 1:1 using an interactive response technology system to the BI 695501 group or adalimumab reference product group, stratified by previous exposure to infliximab (yes vs no) and simple endoscopic score for Crohn's disease at screening (<16 vs ≥16). All investigators involved in trial assessments or procedures and all patients were masked to treatment allocation until week 24. Patients received BI 695501 (40 mg/0·8 mL formulation) or adalimumab reference product (either 40 mg/0·4 mL citrate-free or 40 mg/0·8 mL) 160 mg on day 1 and 80 mg on day 15, followed by 40 mg every 2 weeks, via subcutaneous injection. The primary endpoint was the proportion of patients with clinical response (CDAI decrease ≥70 points) at week 4, with an exploratory non-inferiority margin of 0·76 for the lower limit of the two-sided 90% CI of the risk ratio (RR). The primary analysis was done in a modified full analysis set of all patients who received at least one dose of study medication and had a baseline and at least one post-baseline CDAI assessment. Safety was assessed in all patients who received at least one dose of study medication. After week 4, responders were treated until week 46; those randomly assigned to adalimumab reference product switched to BI 695501 at week 24. This study is registered at ClinicalTrials.gov (NCT02871635) and EudraCT (2016-000612-14).
Findings
Between Jan 4, 2017, and April 5, 2018, 147 patients were enrolled and randomly assigned to BI 695501 (n=72) or adalimumab reference product (n=75). At week 4, 61 (90%) of 68 patients in the BI 695501 group and 68 (94%) of 72 in the adalimumab reference product group had a clinical response (adjusted RR 0·945 [90% CI 0·870–1·028]). In the safety analysis set, 45 (63%) of 72 patients in the BI 695501 group and 42 (56%) of 75 in the adalimumab reference product group had an adverse event during weeks 0–24; 31 (43%) and 34 (45%) had adverse events during weeks 24–56. The most common drug-related treatment-emergent adverse events during weeks 0–24 were weight increase (three [4%] patients in the BI 695501 group) and injection-site erythema and upper respiratory tract infection (three [4%] patients for each event) in the adalimumab reference product group. The only drug-related TEAEs reported in two or more patients during weeks 24–56 were weight increase and increased γ-glutamyltransferase, which occured in two (3%) patients each in the BI 695501 group. No drug-related TEAEs were reported in two or more patients during weeks 24–56 in the adalimumab reference product followed by BI 699501 group. Serious adverse events occurred in six (8%) patients in the BI 695501 group and eight (11%) in the adalimumab reference group between weeks 0–24, and two (3%) and nine (12%) patients between weeks 24–56. Adverse events of special interest occurred in two (3%) patients in each treatment group during weeks 0–24 (acute sinusitis and pulmonary tuberculosis in the BI 695501 group and anal abscess and postoperative wound infection in the adalimumab reference product group) and two (3%) patients in each group during weeks 24–56 (psoas abscess and hypersensitivity in the BI 695501 group and pulmonary tuberculosis and erythematous rash in the adalimumab reference product followed by BI 699501 group).
Interpretation
Safety and efficacy were similar in patients with Crohn's disease treated with BI 695501 or adalimumab reference product. Treatment benefits were maintained in patients receiving adalimumab reference product who switched to BI 695501. These results further support the existing licensure of BI 695501 as an alternative to adalimumab reference product for patients with Crohn's disease, as well as the other indications for which BI 695501 is approved.
Funding
Boehringer Ingelheim.
中文翻译:
BI 695501 与阿达木单抗参考产品在晚期克罗恩病 (VOLTAIRE-CD) 患者中的安全性和有效性:一项多中心、随机、双盲、3 期试验
背景
BI 695501 是一种生物仿制药,在类风湿性关节炎和慢性斑块状银屑病患者中已证明与阿达木单抗参考产品相似的疗效、安全性和免疫原性。VOLTAIRE-CD 研究旨在比较 BI 695501 与阿达木单抗参考产品在克罗恩病患者中的疗效和安全性。
方法
这项 3 期随机双盲研究在欧洲和美国 12 个国家的 92 个中心进行,对象为 18-80 岁中度至重度活动性克罗恩病(克罗恩病活动指数 [CDAI] 评分 220-450) . 使用交互响应技术系统将患者按 1:1 随机分配至 BI 695501 组或阿达木单抗参考产品组,根据之前英夫利昔单抗暴露史(是vs否)和筛选时克罗恩病的简单内窥镜评分(<16 vs≥16)。参与试验评估或程序的所有研究人员和所有患者在第 24 周之前对治疗分配不知情。患者接受 BI 695501(40 mg/0·8 mL 制剂)或阿达木单抗参考产品(40 mg/0·4 mL 无柠檬酸或 40 毫克/0·8 毫升)第 1 天 160 毫克,第 15 天 80 毫克,然后每 2 周 40 毫克,通过皮下注射。主要终点是第 4 周出现临床反应(CDAI 降低≥70 分)的患者比例,其中风险比的两侧 90% CI 下限的探索性非劣效性边际为 0·76( RR)。主要分析是在所有接受至少一剂研究药物并进行基线和至少一次基线后 CDAI 评估的所有患者的改良全分析集中进行的。在接受至少一剂研究药物的所有患者中评估安全性。第 4 周后,对应答者进行治疗直至第 46 周;那些随机分配到阿达木单抗参考产品的人在第 24 周切换到 BI 695501。该研究在 ClinicalTrials.gov (NCT02871635) 和 EudraCT (2016-000612-14) 上注册。
发现
2017 年 1 月 4 日至 2018 年 4 月 5 日期间,147 名患者被纳入并随机分配至 BI 695501(n=72)或阿达木单抗参考产品(n=75)。在第 4 周时,BI 695501 组 68 名患者中的 61 名 (90%) 和阿达木单抗参考产品组中 72 名患者中的 68 名 (94%) 具有临床反应(调整后的 RR 0·945 [90% CI 0·870-1 ·028])。在安全性分析集中,BI 695501 组 72 名患者中有 45 名 (63%) 和阿达木单抗参比产品组 75 名患者中有 42 名 (56%) 在第 0-24 周发生不良事件;31 (43%) 和 34 (45%) 在第 24-56 周出现不良事件。在第 0-24 周期间,最常见的药物相关治疗紧急不良事件是体重增加(BI 695501 组中的三名 [4%] 患者)和注射部位红斑和上呼吸道感染(三名 [4%] 患者用于每个事件)在阿达木单抗参考产品组中。在第 24-56 周期间,在两名或更多患者中报告的唯一与药物相关的 TEAE 是体重增加和 γ-谷氨酰转移酶增加,这发生在 BI 695501 组的两名 (3%) 患者中。在第 24-56 周的阿达木单抗参考产品和 BI 699501 组中,两名或更多患者未报告与药物相关的 TEAE。BI 695501 组的 6 名 (8%) 患者和阿达木单抗参考组的 8 名 (11%) 患者在 0-24 周之间发生了严重不良事件,24-24 周之间发生了 2 名 (3%) 和 9 名 (12%) 患者56.
解释
使用 BI 695501 或阿达木单抗参考产品治疗的克罗恩病患者的安全性和有效性相似。接受阿达木单抗参考产品的患者改用 BI 695501 后仍保持治疗获益。这些结果进一步支持了 BI 695501 的现有许可,作为克罗恩病患者的阿达木单抗参考产品的替代品,以及 BI 695501 适用的其他适应症得到正式认可的。
资金
勃林格殷格翰。