Is siponimod an effective treatment for multiple sclerosis (MS) and does it cause unwanted effects?

关键信息

·我们不知道Siponimod是否是多发性硬化症患者(MS)的有效治疗方法。每天每天2 mg剂量,Siponimod可能会在治疗六个月后降低症状复发(复发,计算为年速率),并可能减少三个月治疗后残疾恶化的参与者数量。

· We don’t know if siponimod causes unwanted effects because studies did not last long enough to fully assess them.

·未来的研究应持续更长的时间,以便更好地监测锡尼莫德的不必要和有益作用,并应使用更健壮的方法。他们应该将siponimod与其他药物进行比较。

什么是多发性硬化症?

多发性硬化症(MS) is a condition caused when the body’s immune system – which defends the body against disease and infection – mistakenly attacks parts of the central nervous system (the brain and spinal cord). Symptoms include problems with balance and walking, and blurred vision. MS is a lifelong condition that can cause serious disability. Some people’s symptoms may develop gradually. However, most people experience ‘attacks’ when new symptoms develop or existing symptoms worsen (called ‘relapse’), followed by periods with no changes to their symptoms (called ‘remittance’). This type of MS is called ‘relapsing remitting’ MS. Eventually, the course of their MS may change. These periods when there are no symptoms, or no worsening of symptoms, may stop and then symptoms may worsen continually. This is called ‘secondary progressive MS’.

Siponimod如何工作?

Siponimod是一种附着在攻击中枢神经系统的白细胞(淋巴细胞)上的药物。这会导致淋巴细胞留在淋巴腺中,而不是在血液中循环到大脑。较少的淋巴细胞到达大脑,因此免疫系统的攻击降低。Siponimod是每天服用一次的平板电脑。

我们想找出什么?

We wanted to know if siponimod is an effective treatment for MS and whether it causes any unwanted effects.

我们对人数感兴趣:

·谁经历了复发;

·残疾恶化;

· who left the studies because of unwanted effects of siponimod;

·谁患有新的或更大的脑病变(对大脑的损害);和

·谁遇到了严重的不必要的影响,以及他们经历了哪些不必要的效果。

我们做了什么?
我们搜索了与安慰剂(一种外观和味道相同但没有活性成分相同的假药)或其他药物治疗MS的研究。研究可以单独研究siponimod或与其他剂量相结合的任何剂量。参与者必须年龄在18岁以上,并确认了MS。

我们根据研究方法和大小等因素进行了比较并总结了研究结果,并对证据的信心进行了评估。

What did we find?

我们发现了1948年参与者的两项研究。两项研究都将siponimod与安慰剂进行了比较。一项研究包括1651人患有继发性MS的人,他们获得了2毫克的siponimod长达3年。另一项研究包括297名参与者,有复发的MS,他们以10 mg,2 mg或0.5 mg的剂量给予siponimod 6个月,或1.25 mg或0.25 mg,持续3个月。我们报告每天2 mg的结果,因为两项研究都研究了这种剂量。

At 2 mg a day, compared to placebo:

·siponimod可能导致少量减少(每1000人每1000人减少166人),在开始治疗后六个月的新复发人数减少了,并且在以年率计算时也可能减少复发;

·siponimod可能会减少在开始治疗后六个月内残疾恶化的人数(每1000人的56人);

·由于不良影响,在开始治疗后的六个月内离开研究的人数可能没有区别(每1000人的14人)。

· siponimod may reduce the number of brain lesions of different types after six months and after two years of follow-up.

·siponimod在开始治疗后的六个月内至少有一个严重不良影响的人数没有什么区别。与siponimod相关的最常见的不良影响是头痛,背痛,头晕,疲倦,流感,尿路感染,白细胞减少(淋巴细胞减少),感到恶心,可能的肝脏损害以及口腔和鼻子的感染。没有有关心脏有关的不良影响的信息。

证据的局限性是什么?

Our confidence in the evidence is limited because we found only 2 studies. They did not provide information about everything we were interested and they included people with different types of MS. Also, they did not last long enough to judge the impact of unwanted effects. Both studies were funded by the company that makes siponimod.

作者的结论:

根据本综述中包含的RCT的发现,我们尚不确定Siponimod干预措施是否对MS患者有益。有低确定性的证据可以支持表明每天口服2 mg的siponimod,因为与安慰剂相比,单药治疗可能会降低年度复发率和6个月后残疾人的参与者数量恶化。但是,证据支持减少复发人数的证据的确定性非常低。

由于不良事件而导致的提款风险需要随着时间的推移仔细监视参与者。所有研究的持续时间均不到24个月,因此24个月内siponimod的功效和安全性仍然不确定,将来需要进一步探索。没有可用的高确定性数据来评估MRI结果的好处。我们评估了由于严重的研究局限性,不精确和间接性,我们评估了所有结果证据的确定性低至很低,因此被降低。我们不确定Siponimod是否对MS患者有益。

More new studies with robust methodology and longer follow-up are needed to evaluate the benefit of siponimod for the management of MS and to observe long-term adverse effects. Also, in addition to comparing with placebo, more new studies are needed to evaluate siponimod versus other therapeutic options.

阅读完整的抽象...
背景:

多发性硬化症(MS) is a chronic immune-mediated disease of the central nervous system, with an unpredictable course. Current MS therapies such as disease-modifying therapies focus on treating exacerbations, preventing new exacerbations and avoiding the progression of disability. Siponimod (BAF312) is an oral treatment, a selective sphingosine-1-phosphate (S1P) receptor modulator, for the treatment of adults with relapsing forms of MS including active, secondary progressive MS with relapses.

目标:

为了评估siponimod作为单一疗法或联合疗法与安慰剂的益处和不利影响,或者对被诊断为MS的人的任何主动比较器。

搜索策略:

我们搜索了CNS试验登记册的Cochrane多发性硬化症和罕见疾病,其中包含来自中央,MEDLINE和EMBASE的研究,以及试验注册表数据库ClinicalTrials.gov和WHO国际临床试验注册表(ICTRP)。我们也于2021年进行。进行了研究的相关期刊,并筛选了已发表的评论的参考列表,并从欧洲和美国的MS Societies中删除了已发表的评论和搜索文章(2004年至2021年9月)。

选择标准:

We included randomised parallel controlled clinical trials (RCTs) that evaluated siponimod, as monotherapy or combination therapy, versus placebo or any active comparator in people with MS. There were no restrictions on dose or administration frequency.

数据收集和分析:

我们使用了Cochrane预期的标准方法论程序。我们讨论了分歧,并通过评论作者之间的共识解决。我们的主要结果是荒原残疾,复发和不良事件以及次要结果,是年化复发率,增强症状病变,新病变或肿大的预先存在病变以及大脑体积的平均变化。我们使用等级方法独立评估了证据的确定性。我们联系了纳入研究的主要研究人员,以获取其他数据或数据确认。

主要结果:

两项研究(1948年参与者)符合我们的选择标准,608个对照和1334个用siponimod处理。纳入的研究将siponimod与安慰剂进行了比较。总体而言,由于选择性报告和流失偏见,所有研究都有偏见的高风险。

比较以2 mg剂量给予安慰剂的siponimod,我们发现siponimod可以减少六个月时残疾进展的参与者数量(每1000人少56人;风险比率(RR)0.78,95%置信区间(CI)0.65到0.94; 1研究,1641名参与者;低确定性证据)和年化复发率(RR 0.43,95%CI 0.34至0.56; 2个研究,1739名参与者;低确定性证据)。但这可能会导致新复发的参与者人数减少(每1000人少166人; RR 0.38,95%CI 0.15至1.00; 1个研究,94名参与者;非常低的确定性证据)。我们没有观察到与安慰剂相比,由于siponimod的不良事件导致差异的证据(14人/ 1000;相对危险度1.52,95%可信区间0.85到2.71; 2 studies, 1739 participants, low-certainty evidence). In addition, due to the high risk of inaccurate magnetic resonance imaging (MRI) data in the two included studies, we could not combine data for active lesions on MRI scans. Both studies had high attrition bias resulting from the unbalanced reasons for dropouts among groups and high risk of bias due to conflicts of interest. Siponimod may reduce the number of gadolinium-enhancing T1-weighted lesions at two years of follow-up (RR 0.14, 95% CI 0.10 to 0.19; P < 0.0001; 1 study, 1641 participants; very low-certainty evidence). There may be no evidence of a difference between groups in the number of participants with at least one serious adverse event excluding relapses (113 more people per 1000; RR 1.80, 95% CI 0.37 to 8.77; 2 studies, 1739 participants; low-certainty evidence) at six months. No data were available regarding cardiac adverse events.

In terms of safety profile, the most common adverse events associated with siponimod were headache, back pain, bradycardia, dizziness, fatigue, influenza, urinary tract infection, lymphopenia, nausea, alanine amino transferase increase and upper respiratory tract infection. These adverse events have dose-related effects and rarely led to discontinuation of treatment.