Abstract：
BACKGROUND: To mimic as closely as possible a randomised controlled trial (RCT) and calibrate the real-world evidence (RWE) studies against a known treatment effect would be helpful to understand if RWE can support causal conclusions in selected circumstances. The aim was to emulate the TRANSFORMS trial comparing Fingolimod (FTY) versus intramuscular interferon β-1a (IFN) using observational data.
METHODS: We extracted from the MSBase registry all the patients with relapsing-remitting multiple sclerosis (RRMS) collected in the period 2011-2021 who received IFN or FTY (0.5 mg) and with the same inclusion and exclusion criteria of the TRANSFORMS RCT. The primary endpoint was the annualised relapse rate (ARR) over 12 months. Patients were 1:1 propensity-score (PS) matched. Relapse-rate ratio (RR) was calculated by mean of a negative binomial regression.
RESULTS: A total of 4376 patients with RRMS (1140 in IFN and 3236 in FTY) were selected. After PS, 856 patients in each group were matched. The ARR was 0.45 in IFN and 0.25 in FTY with a significant difference between the two groups (RR: 0.55, 95% CI: 0.45 to 0.68; p<0.001). The result of the emulation was very similar and fell within the 95% CI of that observed in the RCT (RR: 0.49, 95% CI: 0.37 to 0.64; p<0.001) with a standardised difference of 0.66 (p=0.51).
CONCLUSIONS: By applying the same inclusion and exclusion criteria used in the RCT and employing appropriate methodology, we successfully replicated the RCT results with only minor discrepancies. Also, even if the confounding bias cannot be fully eliminated, conducting a rigorous target trial emulation could still yield valuable insights for comparative effectiveness research.
METHODS: We extracted from the MSBase registry all the patients with relapsing-remitting multiple sclerosis (RRMS) collected in the period 2011-2021 who received IFN or FTY (0.5 mg) and with the same inclusion and exclusion criteria of the TRANSFORMS RCT. The primary endpoint was the annualised relapse rate (ARR) over 12 months. Patients were 1:1 propensity-score (PS) matched. Relapse-rate ratio (RR) was calculated by mean of a negative binomial regression.
RESULTS: A total of 4376 patients with RRMS (1140 in IFN and 3236 in FTY) were selected. After PS, 856 patients in each group were matched. The ARR was 0.45 in IFN and 0.25 in FTY with a significant difference between the two groups (RR: 0.55, 95% CI: 0.45 to 0.68; p<0.001). The result of the emulation was very similar and fell within the 95% CI of that observed in the RCT (RR: 0.49, 95% CI: 0.37 to 0.64; p<0.001) with a standardised difference of 0.66 (p=0.51).
CONCLUSIONS: By applying the same inclusion and exclusion criteria used in the RCT and employing appropriate methodology, we successfully replicated the RCT results with only minor discrepancies. Also, even if the confounding bias cannot be fully eliminated, conducting a rigorous target trial emulation could still yield valuable insights for comparative effectiveness research.
摘要：
背景：尽可能接近地模拟随机对照试验（RCT）并根据已知的治疗效果校准现实世界证据（RWE）研究将有助于了解RWE是否可以支持在选定情况下的因果结论。目的是使用观察数据来模拟比较芬戈莫德（FTY）与肌内干扰素β-1a（IFN）的TRANSFORMS试验。
方法：我们从MSBase注册表中提取了2011-2021年期间收集的所有复发缓解型多发性硬化症（RRMS）患者，这些患者接受了IFN或FTY（0.5mg），并且具有与TRANSFORMSRCT相同的纳入和排除标准。主要终点是12个月的年复发率（ARR）。患者为1：1倾向评分（PS）匹配。通过负二项回归的平均值计算复发率（RR）。
结果：选择了4376例RRMS患者（IFN为1140例，FTY为3236例）。PS之后,每组856例患者进行匹配。IFN的ARR为0.45，FTY的ARR为0.25，两组之间存在显着差异（RR：0.55，95％CI：0.45至0.68；p<0.001）。仿真结果非常相似，落在RCT中观察到的95%CI范围内（RR：0.49，95%CI：0.37至0.64；p<0.001），标准化差异为0.66（p=0.51）。
结论：通过应用RCT中使用的相同纳入和排除标准，并采用适当的方法，我们成功复制了RCT结果,但仅有微小差异.此外，即使混淆偏见不能完全消除，进行严格的目标试验仿真仍然可以为比较有效性研究提供有价值的见解.
方法：我们从MSBase注册表中提取了2011-2021年期间收集的所有复发缓解型多发性硬化症（RRMS）患者，这些患者接受了IFN或FTY（0.5mg），并且具有与TRANSFORMSRCT相同的纳入和排除标准。主要终点是12个月的年复发率（ARR）。患者为1：1倾向评分（PS）匹配。通过负二项回归的平均值计算复发率（RR）。
结果：选择了4376例RRMS患者（IFN为1140例，FTY为3236例）。PS之后,每组856例患者进行匹配。IFN的ARR为0.45，FTY的ARR为0.25，两组之间存在显着差异（RR：0.55，95％CI：0.45至0.68；p<0.001）。仿真结果非常相似，落在RCT中观察到的95%CI范围内（RR：0.49，95%CI：0.37至0.64；p<0.001），标准化差异为0.66（p=0.51）。
结论：通过应用RCT中使用的相同纳入和排除标准，并采用适当的方法，我们成功复制了RCT结果,但仅有微小差异.此外，即使混淆偏见不能完全消除，进行严格的目标试验仿真仍然可以为比较有效性研究提供有价值的见解.
