Safety and Efficacy of Fremanezumab for the Prevention of Migraine: a Meta-analysis from Random Clinical Trails

doi:10.21203/rs.2.22379/v1

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Safety and Efficacy of Fremanezumab for the Prevention of Migraine: a Meta-analysis from Random Clinical Trails

https://doi.org/10.21203/rs.2.22379/v1

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Background

Fremanezumab (TEV-48125) is a fully humanized immunoglobulin G isotype 2a selective monoclonal antibody that potently binds to calcitonin gene-related peptide (CGRP). It is one of novel therapeutic drugs for the prevention of migraine, which is one of the most common neurological diseases worldwide. Several clinical trails have been conducted to investigate the safety and efficacy of fremanezumab, but there is no systematic review of existing literature has been performed. Hence, we performed a meta-analysis to investigate the efficacy and safety of fremanezumab for prevention of migraine.

Method

Pubmed (MEDLINE), Embase, and Cochrane Library were searched from January 2001 to August 2019 for randomized controlled trials (RCTs). Five RCTs with 3379 patients were finally included in our study.

Result

We pooled 3379 patients from 5 RCTs, the primary endpoints were mean monthly migraine and headache days, baseline to week 12. We found that fremanezumab led to a significant reduction in migraine days (P < 0.0001) and headache days (P < 0.0001) during 12 weeks compared with placebo. In addition, after using fremanezumab, the risk of at least one adverse event (P=0.001) or related to the trail regimen (P=0.0005) significantly increase compared with placebo.

Conclusions

Fremanezumab has good efficacy for the prevention of migraine. The administration of fremanezumab can cause some mild adverse events but not serious adverse events.

Neurology

Clinical Pharmacology

Fremanezumab

migraine

chronic migraine

episodic migraine

preventive medication

meta-analysis

Migraine is one of the most common neurological disorders that is characterized by recrudescent attacks of pulsating headache pain of moderate or serious severity, affecting more than 16% of people worldwide.[1–3] Migraine can be divided into episodic and chronic migraine. Episodic migraine is the most common form of migraine with fewer than 15 days headache attacks per month.[4] However, chronic migraine occurs in approximately 2% of the population and is defined as headache that occurs at least 15 days per month for at least 3 months.[5] Also, about 8% of episodic migraine people have at least 10–14 headache days per month and are at risk of transition to chronic migraine (at least 15 headache days per month).[6, 7] Therefore, no matter what kind of migraine, timely and effective preventive measures are needed. The prevention of migraine is not to prevent the illness but to reduce the frequency of migraine attacks. Traditional migraine preventive medications frequently lead to early stop of treatment because of their little efficacy and poor tolerability in migraine people.

Monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor included eptinezumab, fremanezumab, galcanezumab and erenumab were specifically developed for the prevention of migraine. Among them, fremanezumab (TEV-48125) is a fully humanized immunoglobulin G isotype 2a selective monoclonal antibody that potently binds to CGRP.[8] Fremanezumab blocks CGRP mediated effects by binding to the peptide, and is almost given by subcutaneous injection.[9, 10] In previous clinical trials, fremanezumab was assessed the safety and efficacy over 12-week treatment period for the prevention of migraine. And fremanezumab has a flexible dosing regimen in these previous clinical trials. In chronic migraine, fremanezumab was administered by 675 mg in first month and 225 mg in 2nd and 3rd month or 900 mg in each month or 675 mg in first month and placebo in 2nd and 3rd month. In episodic migraine, fremanezumab was administered by 225 mg in each month or 675 mg in each month or 675 mg in first month and placebo in 2nd and 3rd month. Although several clinical trails had indicated the efficacy and safety of fremanezumab for prevention of migraine, there is no systematic review of existing literature has been performed. Our meta-analysis included five random clinical trails (RCTs), and combined different doses of fremanezumab to evaluate the efficacy and safety of fremanezumab for the prevention of both kinds of migraine.

Search strategy

Pubmed (MEDLINE), Embase and Cochrane Library were searched using the following terms: [(“fremanezumab, migraine”), (“TEV-48125 and migraine”) until December 2019 to find potentially eligible studies. Besides, we ensured all relevant studies had been included in this meta-analysis by manually screening reference lists from RCTs and systematic reviews.

Inclusion And Exclusion Criteria

Inclusion criteria were as follows: (a) Study type: RCTs; (b) Language restriction: our study had no language restriction; (c) Participants: patients aged > 18 years with chronic or episodic migraine, and were allowed to use preventive medications or not; (d) Intervention: fremanezumab and placebo; (e) Outcomes: efficacy outcomes including mean monthly migraine days, mean monthly headache days and safety outcomes. Exclusion criteria were as follows: (a) study types: case reports, reviews, retrospective studies, post-hoc analyses studies and cohort studies;(b) patients who used onabotulinumtoxinA during 4 months before screening; patients who used interventions or devices for migraine during 2 months before screening; patients with previous exposure to a monoclonal antibody targeting the CGRP pathway.

Study Selection And Data Collection

All studies and reference lists of RCTs and reviews of systematic searches in electronic databases were evaluated separately on the mentioned inclusion and exclusion criteria. After several assessment and selection, the basic information of the included trails (first author, title, number of NCT, patient characteristics (age, sex, BMI, migraine classification, etc.), outcome measures were used to extract the data. (Table 1)

Table 1

Characteristics of the Included Studies and Outcome Events
Trials	Bigal, 2015 (NCT02021773)	Bigal, 2015 (NCT02025556)	Silberstein, 2017 (NCT02621931)	Dodick, 2018 (NCT02629861)	Ferrari, 2019 (NCT03308968)
Information of the Included Trials
Regions	Multy centers in USA	Multy centers in USA	Multy centers in nine countries	Multy centers in nine countries	Multy centers in fifteen countries
Phases	IIB/III	IIB/III	III	III	III
Publication	Lancet Neurology	Lancet Neurology	The New England Journal of Medicine	Jama	Lancet
Eligibility Criteria and Study Design
Inclusion Criteria	Chronic migraine Age:18–65 years old No more than 2 different preventive medications or interventions/devices used for migraine.	Episodic migraine Age:18–65 years old No more than 1 preventive medication or intervention/device used for migraine.	Chronic migraine Age:18–70 years old Up to 30% patients were permitted to use no more than 1 concomitant preventive medication	Episodic migraine Age:18–70 years old Up to 30% patients were permitted to use no more than 1 concomitant preventive medication	Chronic migraine and Episodic migraine Age: 18–70 years old Failure from 2–4 different preventive medications using
Exclusion Criteria	OnabotulinumtoxinA use more than 6 months before study. Opioids or barbiturate compounds use more than 4 days during the run-in phase.	Opioids or barbiturate compounds use for more than 4 days during the run-in phase	OnabotulinumtoxinA use more than 6 months before study. Opioids or barbiturate compounds use more than 4 days during the run-in phase.	OnabotulinumtoxinA use more than 6 months before study. Opioids or barbiturate compounds use more than 4 days during the run-in phase.	OnabotulinumtoxinA use more than 3 months before study. Opioids or barbiturate compounds use more than 4 days during the run-in phase.
Study Design	PBO/PBO/PBO Fremanezumab 675/225/225 mg Fremanezumab 900/900/900 mg	PBO/PBO/PBO Fremanezumab 225/225/225 mg Fremanezumab 675/675/675 mg	PBO/PBO/PBO Fremanezumab 675/PBO/PBO mg Fremanezumab 675/225/225 mg	PBO/PBO/PBO Fremanezumab 675/PBO/PBO mg Fremanezumab 225/225/225 mg	PBO/PBO/PBO Fremanezumab 675/PBO/PBO mg Fremanezumab 225/225/225 mg in EM 675/225/225 mg in CM
Outcomes Assessments
Primary outcomes	Mean change from headache hours of any severity, baseline to week 12	Mean change from migraine days, baseline to week 12	Mean change from monthly average headache days of at least moderate severity, baseline to week 12	Mean change from monthly average migraine days, baseline to week 12	Mean change from monthly average migraine days, baseline to week 12
Safety outcomes	Serious adverse events, Injection-site reactions, Headache, Infections,etc.	Serious adverse events, Injection-site reactions, Headache, Infections,etc.	At least one adverse event At least one adverse event related to the trial regimen At least one serious adverse event. Injection-site reactions, Infections, Dizziness, Nausea, etc.	At least one adverse event At least one adverse event related to the trial regimen At least one serious adverse event. Injection-site reactions, Infections, Gastrointestinal disorders, etc.	At least one adverse event At least one adverse event related to the trial regimen At least one serious adverse event. Injection-site reactions, Infections, Gastrointestinal disorders, etc.

Outcome Measures

The primary outcomes included mean monthly headache days, baseline to week 12 and mean monthly migraine days, baseline to week 12. Baseline means the days of headache or migraine of 28 days before study started. Secondary endpoints included ≥ 50% reduction in average number of migraine days per month, mean monthly days with any acute headache medication, baseline to week 12, mean monthly headache days, baseline to week 4 and mean monthly migraine days, baseline to week 4. Among them, a migraine day was defined as a calendar day with at least 4 consecutive hours of a migraine with or without aura as per ICHD-3 diagnostic criteria [2] (no more than one ICHD-3 migraine criterion missing), or a headache of any duration treated with migraine-specific acute medications (triptans or ergot compounds). A headache day was defined as a calendar day with at least 4 consecutive hours of headache at least moderate severity. The adverse events included at least one adverse event (AE) or AE related to the trial regimen or serious AE, injection-site reactions, infections and dizziness or nausea. Among them, injection-site reactions included erythema, induration, pain, bruising, paraesthesia, rash and warmth. Infections included nasopharyngitis, upper respiratory tract infection, influenza, gastroenteritis and urinary tract infection.

Summary Measures And Synthesis Of Results

Review manager 5.3 was used to assess the data. Estimated profit with mean difference and estimated proportions with the risk ratio (mean difference [MD] or relative risk [RR]; 95% confidence interval [CI]) were calculated using a random-effects model. The I² statistic was used to estimate the statistical heterogeneity as follows: I² < 30% represents “low heterogeneity”, 30% < I² < 50% means “moderate heterogeneity” and I² > 50% means “substantial heterogeneity”. Sensitivity analysis and subgroup analysis were used to explore the stability of the consolidated results. A less than 0.05 P value was considered to be significant for all analyses and tests are two-tailed.

Risk Of Bias

The Review manager 5.3 software was used to create the risk of bias summary in these studies. The Cochrane collaboration uniform criteria was used to assess the risk of bias of RCTs. Selection bias, performance bias, detection bias, attrition bias, reporting bias, and other possible biases were included in the criteria.

Search results

382 researches and abstracts from Pubmed (MEDLINE) and EMBASE, and 208 from Cochrane Library were identified. 376 researches were removed due to duplicates and 46 researches were removed because they were not directly relevant to the subject, such as research on other drugs or etiological analysis of migraine, etc. After removing duplicates and uncorrelated titles, 168 of these articles are directly related to the topic of interest. However, among them, there were 163 articles being excluded because they were case reports, meta-analyses, protocols and reviews. And so, at last, these 5 RCTs were included into our study. (Fig. 1)

Assessment Of Primary Outcomes

In this study, two primary outcomes were analyzed included mean monthly headache days, baseline to week 12 and mean monthly migraine days, baseline to week 12. The average mean monthly headache days during 12 weeks in fremanezumab group is 2.36 days less than that in placebo group. (95% CI, -3.17, -1.56, P < 0.0001, Fig. 2A) Also, the average mean monthly migraine days during 12 weeks in fremanezumab group is 2.21 days less than that in placebo group. (95% CI, -3.03, -1.38, P < 0.0001 Fig. 2B)

Assessment Of Secondary Outcomes

The number of patients who had ≥ 50% reduction in average number of migraine days per month had a significant increase than placebo. (RR = 2.22 95%CI, 1.60, 3.07, P < 0.00001 Fig. 3A) The average mean monthly days with any acute headache medication in fremanezumab group is 2.11 days less than that in placebo group. (95% CI, -3.01, -1.21, P < 0.00001, Fig. 3B) The average mean monthly headache days during 4 weeks in fremanezumab group is 2.65 days less than that in placebo group. (95% CI, -3.63, -1.66, P < 0.00001, Fig. 3C) The average mean monthly migraine days during 4 weeks in fremanezumab group is 2.49 days less than that in placebo group. (95% CI, -3.47, -1.51, P < 0.00001, Fig. 3D)

Assessment Of Adverse Events

The comprehensive analysis show that the proportion of patients with at least one adverse event in fremanezumab group is more than placebo group (RR = 1.10, 95% CI, 1.04, 1.17, P = 0.001 Fig. 4A). Then, our statistical analysis suggests that fremanezumab group is more likely to suffer from adverse events related to the trail regimen. (RR = 1.21, 95% CI, 1.09, 1.34, P = 0.0005 Fig. 4B) However, the proportion of patients with at least one serious adverse event in fremanezumab group has no significant difference from placebo group. (RR = 0.84 95% CI, 0.41, 1.73, P = 0.63 Fig. 4C)

We also analyzed several special adverse events, including injection-site reactions, infections and dizziness or nausea. In fremanezumab group, the incidence rate of injection-site reactions is higher than the control group, while the proportion of infections and dizziness or nausea have no significant difference. (Injection-site reactions: RR = 1.24, 95% CI, 1.07, 1.43 P = 0.003 Fig. 5A; Infections: RR = 0.81, 95% CI, 0.81, 1.20, P = 0.86 Fig. 5B; Dizziness or Nausea: RR = 0.93, 95% CI, 0.62, 1.40, P = 0.73 Fig. 5C).

Subgroup Analysis

Patients were divided into chronic migraine subgroup and episodic migraine subgroup according to migraine characteristics. In chronic migraine subgroup, the average mean monthly migraine days during 12 weeks in fremanezumab group is 2.43 days less than placebo group (95% CI, -3.70, -1.17, P = 0.0002 Fig. 6A), and in episodic migraine subgroup, the average mean monthly migraine days during 12 weeks in fremanezumab group is 2.36 days less than placebo group. (95% CI, -3.55, -1.17, P = 0.0001 Fig. 6A) When it comes to another primary outcome, in chronic migraine subgroup, the average mean monthly headache days during 12 weeks in fremanezumab group is 1.99 days less than placebo group (95% CI, -2.55, -1.43, P < 0.00001 Fig. 6B), and in episodic migraine subgroup, the average mean monthly headache days during 12 weeks in fremanezumab group is 1.90 days less than placebo group. (95% CI, -2.88, -0.92, P = 0.0001 Fig. 6B) However, differences between CM and EM subgroup are not statistically significant in both outcomes.(P = 0.93 and P = 0.88)

The subjects were divided into two different subgroups based on if they had used no more than 2 preventive medications or 2–4 kinds of preventive medications. In no more than 2 preventive medications subgroup, the average mean monthly migraine days during 12 weeks in fremanezumab group is 1.77 days less than placebo group (95% CI, -2.29 -1.25, P < 0.00001 Fig. 7A), and in 2–4 preventive medications subgroup, the average mean monthly migraine days during 12 weeks in fremanezumab group is 3.30 days less than placebo group. (95% CI, -4.08, -2.52, P < 0.00001 Fig. 7A) When it comes to another primary outcome, in no more than 2 preventive medications subgroup, the average mean monthly headache days during 12 weeks in fremanezumab group is 1.97 days less than placebo group (95% CI, -2.45, -1.48, P < 0.00001 Fig. 7B), and in 2–4 preventive medications subgroup, the average mean monthly headache days during 12 weeks in fremanezumab group is 3.40 days less than placebo group. (95% CI, -4.18, -2.62, P < 0.00001 Fig. 7B) What’s more, differences between no more than 2 preventive medications subgroup and 2–4 preventive medications subgroup are significant in both outcomes.(P = 0.001 and P = 0.002)

Risk Of Bias In Included Studies

The independent risk of bias of the five included RCTs is shown in Fig. 8 in detail. The risk for selective reporting bias is unclear in Ferrari’s study in 2019. In addition to the measure, other studies have low risks of bias.(Fig. 8)

Our meta-analysis concluded 3379 patients from 5 multi-center RCTs [9, 11–14] which provided high level of clinical reliability for assessing safety and efficacy of fremanezumab for the prevention of chronic and episodic migraine. According to results of this meta-analysis, fremanezumab was significantly more effective for the prevention of CM or EM versus placebo. By comparing two primary outcomes, the reduction from baseline in the mean monthly migraine or headache days during the 12 weeks after the first dose of fremanezumab was greater than placebo. After using fremanezumab, the number of patients who had ≥ 50% reduction in average number of migraine days per month had a significant increase than placebo. In addition, patients who used fremanezumab had a greater reduction of mean monthly days with acute headache medication than placebo group. In short-term effects, no matter migraine or headache days reduced more than placebo during four weeks after the first dose of fremanezumab. In terms of side effects, compared with placebo, fremanezumab may cause several mild trial-related or unrelated adverse events, but will not cause some serious adverse events. In these mild adverse events, injection-site reactions may be more common in patients who used fremanezumab than placebo. Whereas, infections, dizziness and nausea are not common.

Fremanezumab had a flexible dosing regimen in these previous clinical trials. For these dosing regimens, they can be roughly divided into quarterly and monthly administration. Although higher doses have been used in earlier studies, the dossing regimens of recent studies have been the same. The difference is that when administrating monthly, the first dose is 675 mg in patients with chronic migraine but 275 mg in patients with episodic migraine. In order to analyze efficacy and safety of fremanezumab conservatively, we combined different dosing regimens for analyzing. Migraine and headache attacks are the most bothersome symptoms for migraine patients. Since the terms of medication administration is 12 weeks, we identified mean monthly migraine days and headache days, baseline to week 12 as primary outcomes. The definitions of migraine day and headache day are the same as those in previous studies. Because patients’ sensitivity to fremanezumab may affect the results, in addition to two primary outcomes, we also analyzed patients who had ≥ 50% reduction in average number of migraine days per month as a secondary outcome. Also, mean monthly days of using acute headache medication was assessed as a secondary outcome in order to evaluate the improvement of migraine from another perspective. Not only long-term effect, but also the improvement of migraine in the short-term after using fremanezumab were needed to assess. Therefore, we also identified mean monthly migraine days and headache days, baseline to week 4 as secondary outcomes. After analysis, we found that no matter in which primary or secondary outcomes, fremanezumab was more effective than placebo. In summary, fremanezumab indeed had a significant effect on preventing migraine attacks.

However, it was found that in the primary and secondary endpoints, the heterogeneity of these RCTs was high, all greater than 50%. This may be due to the different characteristics of patients in these studies. Previous studies were performed for one of chronic migraine (CM) or episodic migraine (EM), however, Ferrari’s study in 2019 combined CM and EM for analysis. Our meta-analysis was based on Ferrari’s study, which analyzed chronic and episodic migraine together. Consequently, we performed a subgroup analysis for CM and EM to analyze the efficacy of fremanezumab in CM and EM separately. After subgroup analysis, we found that in both CM and EM, fremanezumab has a significant effect on the reduction of migraine days and headache days. There are no significant differences in effectiveness of fremanezumab for preventing migraine in patients with CM and EM. On the other hand, patients from Ferrari’s study were all failure from 2–4 preventive medications, whereas, patients from other 4 studies used no more than 2 preventive medications. In order to evaluate whether using preventive medications affects the effectiveness of fremanezumab. Another subgroup analysis was needed to perform. We divided patients into no more than 2 preventive medications subgroup and 2–4 preventive medications subgroup. After subgroup analysis, fremanezumab can reduce the mean monthly migraine and headache days in both subgroups. Regardless of how many kinds of preventive medications patients had used, fremanezumab can effectively prevent the occurrence of migraine. However, for patients who used 2–4 preventive medications, the effect of fremanezumab is better than that of patients who used less than 2 preventive medications before. Moreover, after subgroup analysis, the heterogeneity of data in each group was significantly reduced, which also showed that the sources of heterogeneity were the type of migraine and the use of preventive medications.

In the past, many studies have described the safety of fremanezumab. Bigal and Silberstein believed that the use of fremanezumab was generally safe. [15, 16] However, results regarding security were not consistent in these RCTs. After meta-analysis, we found fremanezumab does indeed not cause some serious adverse events or even death but may cause some mild adverse events especially injection-site reactions. Compared with the benefits of using fremanezumab, because fremanezumab dose not cause serious adverse events, the use of fremanezumab for preventing migraine is still feasible. However, evaluations of these studies on adverse events were limited to 12 weeks after first dose. Whether fremanezumab will produce long-term adverse events still needs further observation.

Our meta analysis also has several limitations. Because interventions in the included studies were all fremanezumab and placebo, we can only conclude that fremanezumab is more effective than placebo in prevention of migraine. Although patients in these studies had used more or less preventive medications before, all these studies lack a horizontal comparison of fremanezumab with other preventive measures. More researches are still needed in order to compare whether fremanezumab is better than other preventive medications. Another limitation is, in our meta analysis, it is hard to figure out which dosing regimen is more advantageous because our meta-analysis combines various dosing regimens. Since patients in Bigal’s two studies in 2015 were not divided into monthly and quarterly administration, meta-analysis of these two dosing regimen cannot be performed. There still needs further researches for assessing monthly and quarterly administration. What’s more, subjects of these five RCTs were roughly 40–45 years old non-Hispanic and non-Latino white women with the BMI about 25–27. Although our analysis found the efficacy of fremanezumab for the prevention of migraine is good in this kind of people, in order to prove that the scope of application of fremanezumab can be more extensive, more researches on migraine patients of different characteristics are still needed.

Fremanezumab has good efficacy and safety for the prevention of migraine. Fremanezumab is effective for preventing migraine attacks measured by mean monthly migraine and headache days during 12 weeks after drug ingestion versus placebo. In both CM and EM subgroup, fremanezumab has good efficacy in reduction of migraine days and headache days. No matter how many preventive medications used before, fremanezumab has good efficacy for preventing migraine. Fremanezumab showed better efficacy in patients with 2–4 preventive medications than patients with < 2 preventive medications before. The administration of fremanezumab may cause some mild adverse events especially injection-site reactions, but it is not related to significant increase in some serious adverse events.

CGRP: calcitonin gene-related peptide; RCT: random clinical trail; CM: chronic migraine; EM: episodic migraine; NCT: national clinical trail; AE: adverse events; MD: mean difference; RR: relative risk; CI: confidence interval

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Availability of data and material

All data generated or analyzed during this study are included in this review

Competing interests

The authors declare that they have no competing interests.

Funding

This work was supported by the Suzhou Health Talents Training Project (GSWS2019002).

Author contributions

ZW is the principal investigator. BG and NS designed the study and developed the analysis plan. MC and YS analyzed the data and performed meta-analysis. BG, YY and NS contributed in writing of the article. ZC and ZW revised the manuscript and polish the language.

Acknowledgements

Thanks for my senior fellow apprentice Zhouqing Chen for teaching me how to be a true man who does not give in to miserable life.

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Safety and Efficacy of Fremanezumab for the Prevention of Migraine: a Meta-analysis from Random Clinical Trails

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Abstract

Figures

Introduction

Methods

Search strategy

Inclusion And Exclusion Criteria

Study Selection And Data Collection

Outcome Measures

Summary Measures And Synthesis Of Results

Risk Of Bias

Results

Search results

Assessment Of Primary Outcomes

Assessment Of Secondary Outcomes

Assessment Of Adverse Events

Subgroup Analysis

Risk Of Bias In Included Studies

Discussion

Conclusion

Abbreviations

Declarations

References

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