CGRP monoclonal antibody for preventive treatment of chronic migraine: An update of meta‐analysis

Abstract Background CGRP monoclonal antibody (mAb) is a promising preventive treatment for episodic migraine and has been approved by US FDA recently. But the treatments for chronic migraine are rare. Therefore, we performed meta‐analysis to assess the efficacy and safety of CGRP mAbs in preventing chronic migraine. Methods Database including Cochrane Library and PubMed were systematically searched for randomized controlled trials (RCTs) which are about CGRP mAb in preventing treatment of chronic migraine. Evaluating the bias and quality of RCTs was carried out according to the Cochrane collaboration's tool for assessing risk of bias. The data analysis was carried out by reviewer manager 5.2. Results Totally, 6 articles enrolled in the present meta‐analysis, including 4 independent clinical trials and 3,166 patients. After pooled analysis, it indicated that CGRP mAb improved 50% responder rate (OR = 2.42, 95% CI = [2.04, 2.87], I 2 = 0%, p < 0.00001) and 75% responder rate (OR = 1.95, 95% CI = [1.30, 2.91], I 2 = 0%, p = 0.001), as compared with placebo. And there was no difference in incidence of adverse events between CGRP mAb group and placebo group except incidence of injection site discomfort. Conclusions CGRP mAb is an effective and safety preventive treatment for chronic migraine.


| INTRODUC TI ON
Chronic migraine is a disabling primary headache disorder, defined as headache occurring no less than 15 days per month for more than three months and has the features of migraine headache for no less than eight days per month according to the International Classification of Headache Disorders, 3rd edition (ICHD-3) (Headache Classification Committee of the International Headache Society, 2013). Approximately 2% of the population occurs chronic migraine, which leads to lower health-related quality of life and functional impairment as compared with episodic migraine (Bigal et al., 2015;Silberstein et al., 2017;Tepper et al., 2017). Patients with chronic migraine are more likely suffering from be divorced, be unemployed psychological comorbidity, and high risk with acute medication overuse for headache treatment (Bigal et al., 2015;Silberstein et al., 2017;Tepper et al., 2017).
The expert opinion suggests that patients with chronic migraine should receive abortive and preventive treatments (Giacomozzi et al., 2013;Irimia, Carmona-Abellan, & Martinez-Vila, 2012;Lionetto et al., 2012;Pringsheim et al., 2012;Puledda, Messina, & Goadsby, 2017). But there are few treatments for preventing chronic migraine. And the onabotulinum toxin A and topiramate are the class I drugs with level A evidence (Giacomozzi et al., 2013). Sodium valproate, gabapentin, pregabalin, amitriptyline, tizanidine, and methysergide are the alternative preventive treatments for chronic migraine with lower evidence levels (Giacomozzi et al., 2013). Although about 40% migraineurs would benefit from preventive treatments, only a minority receive it because of treatment failure, resulting from lack of efficacy and adverse events (Reuter, 2018).
Calcitonin gene-related peptide (CGRP) is a promising target to treat migraine, which has a crucial role in migraine pathophysiology.

| Data selection
Database including Cochrane Library and PubMed were queried using the following terms: migraine, calcitonin gene-related peptide, and CGRP. The cutoff date was 4 July 2018, and we would pay attention to the advance of this area and revise our data before the manuscript has been published.
The literatures of randomized controlled trials (RCTs) in English and matching the following criteria were enrolled: (a) Patients diagnosed for chronic migraine according to the ICHD-3 and (b) intervention is CGRP mAb.

| Data extraction and analysis
The literatures screening and quality and bias of RCTs assessing are described in our previous articles . The primary efficacy outcomes included 50%, 75%, or 100% responder rate, defined as a at least 50%, 75%, or 100% reduction in monthly headache/migraine-days from baseline to weeks 9-12.
The secondary efficacy outcomes included change of migraine-days from baseline to weeks 9-12, change of days using acute drugs from baseline to weeks 9-12, and change of headache-hours from baseline to weeks 9-12. The safety outcomes were incidence of adverse events after drug administrated.

| Data analysis
Data analysis was described in our previous articles . In briefly, Review manager 5.3 (Cochrane Collaboration) is utilized for data analysis and the threshold P value less than 0.05 was set as the significant level.

| RE SULTS
According to the retrieval strategy, we found 481 literatures; 6 articles were left after removal of the repetition and unmatched articles. The screening process was presented in Figure 1. The 6 articles included 2 phase 2b complete RCTs (Bigal et al., 2015;Tepper et al., 2017), 2 phase 3 complete RCTs (Detke et al., 2018;, and 1 phase 3 ongoing RCT (Smith et al., 2017). So we analyzed the 4 complete trials with 3,166 chronic migraineurs. Out of 3,166 patients, 1,862 patients received the CGRP mAb, and the rest 1,304 patients received placebo. Erenumab was used in 1 trial with 70 mg or 140 mg subcutaneous every 4 weeks for 12 weeks (Tepper et al., 2017). Fremanezumab was used in 2 trials with different usage for 12 weeks (Bigal et al., 2015;Silberstein et al., 2017).
And the galcanezumab was used in 1 trial with 120 mg or 240 mg subcutaneous every 4 weeks for 12 weeks (Detke et al., 2018). The detail information is shown in Table 1. Among above mentioned, erenumab is a human monoclonal antibody against CGRP receptor, fremanezumab, and galcanezumab are monoclonal antibody against CGRP ligand.
In the 5 independent trials, all of the terms of risk bias are low risk except the PROMISE 2 trial according to tool for assessing risk of bias in the Cochrane handbook. Therefore, the enrolled trials were of high quality. The detail information was shown in Table 2.
Regard with the primary efficacy outcomes, there were 4 trials had reported the 50% responder rate. And 37.4% (689/1844) achieved the 50% responder rate in CGRP mAb group, which was  Figure 2.
Regarding the secondary efficacy outcomes, three trials had reported the change of migraine-days from baseline to weeks 9-12.
We found that the erenumab, fremanezumab, and galcanezumab have significant difference in this clinical index, as compared with placebo. After pool estimated, the CGRP mAb was larger than placebo in change of migraine-days from baseline to weeks 9-12 Regarding the safety of CGRP mAb, we found that the incidence of injection discomfort was 676/1862 in CGRP mAb group, which is greater than 290/1,304 in placebo group (OR = 2.11, 95% CI = [1.37, 3.26], I 2 = 59%, p = 0.0007). Meanwhile, we found that the incidence of liver injury was higher in CGRP mAb group without significant difference, as compared with placebo (OR = 2.09, 95% CI = [0.65, 6.75], I 2 = 0%, p = 0.21). And we assessed discontinuation due to the adverse events, nausea, and the infection/inflammation-related adverse events and found that there are no difference in the incidence of discontinuation, nausea, upper respiratory tract infection, sinusitis, and urinary tract infection between CGRP mAbs and placebo. The results were summarized in Table 3.

| D ISCUSS I ON
The present meta-analysis assesses efficacy and safety of CGRP mAb in preventing chronic migraine by meta analyze 4 RCTs with high quality. The meta-analysis demonstrates that CGRP mAb led to improvement in 50% responder rate, 75% responder rate, migraine-days, days using acute drugs and headache-hours after CGRP mAb administrated and well tolerated, as compared with placebo. These results are in line with previous published RCTs results.
The CGRP mAbs included in present study were administrated subcutaneous. And the injection site discomfort was the most common adverse event. And this discomfort included pain, pruritus, erythema, induration, edema, and bruising (Bigal et al., 2015;Detke et al., 2018;Silberstein et al., 2017;Tepper et al., 2017). In REGAIN study, one patient in CGRP mAb group discontinued because of the injection site pain (Detke et al., 2018). In the present meta-analysis, we found that patients in CGRP mAb group experienced more injection site discomfort than placebo group, but the incidence of discontinuation due to adverse event were similar between these two groups. These results demonstrate that CGRP mAb is a well-tolerated drug.
Liver function impairment was the most serious problems of CGRP receptor antagonisms in preventing migraine . But in the CGRP mAbs for episodic migraine clinical trials, there was no drug-associated hepatotoxicity had been reported . In the present analysis, we found that 14/1,484 patients in CGRP mAb group and 5/1,022 patients in placebo group suffer from liver injury, but there is no significant difference. Bigal et al. (2015) reported that four patients had transient liver enzyme increasement with nontreatment related. But Silberstein et al. (2017) found that 10 patients suffered from possible trial-agent-induced liver injury in CGRP mAbs group and three patients in placebo group. And eight patients in CGRP mAb group and three patients in placebo group had liver enzyme level <3-5 times the upper limits of normal range and had used acetaminophen or nonsteroidal anti-inflammatory drugs frequently or antidepressants daily . Two patients in CGRP mAb group suffered from alanine transaminase or aspartate aminotransferase level more than five times the normal range's upper limit, one patient's aspartate aminotransferase level was normalized without intervention, and the other was normalized after the ethanol-containing drug was discontinued

TA B L E 3 The summary of adverse events
The limitation of the present meta-analysis was the lack of the best dose or regimen of CGRP mAbs for preventive treatment of chronic migraine because of the small sample size. Further trials with larger sample and real-world data should be estimated in the future.
In conclusion, CGRP mAb is an effective and safety preventive treatment for chronic migraine.

ACK N OWLED G M ENT
None.

CO N FLI C T O F I NTE R E S T
The author declares that he has no conflict of interests.

AUTH O R S' CO NTR I B UTI O N S
All author read and approved the final manuscript.