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A Controlled Trial Of Erenumab For Episodic Migraine

Guidance And Search Strategy

Peter Goadsby, EAN 2018 Erenumab in difficult-to-treat episodic migraine: LIBERTY study

The study was conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses Extension Statement for network Meta-analyses guidelines . It was registered on the OSF platform .

We searched the MEDLINE, Cochrane CENTRAL, ClinicalTrials.gov, and embase bibliographic databases from inception until October 30, 2020 . No language limitations were applied. The following MeSH terms and free-text terms such as migraine,migraine headache,calcitonin gene-related peptide binding monoclonal antibody,eptinezumab,ALD403,erenumab,AMG334,fremanezumab,TEV-48125,galcanezumab,LY2951742, and randomized controlled trial were used to identify any eligible publications. Additional studies were identified by searching previous systematic reviews and meta-analyses and by searching the reference lists of the included trials.

Up To Half Of Aimovig

Percentage of Patients Achieving at Least a 50% Reduction From Baseline in MMDs1

50% response rate was the secondary endpoint in the phase 3, double-blind, randomized study.1,2

*Odds of achieving a 50% reduction were significantly higher for the Aimovig® 70 mg group than for the placebo group .1,2

Odds of achieving a 50% reduction were significantly higher for the Aimovig® 140 mg group than for the placebo group .1,2

In a phase 2 EM study

New Therapeutic Options Targeting The Cgrp And Its Receptors

Several emerging therapy options are targeting the CGRP and CGRP receptors. Currently, four monoclonal antibodies have been developed as migraine preventive therapies . Among four antibodies, eptinezumab, galcanezumab, and fremanezumab are anti-CGRP antibodies, and erenumab targets CGRP receptors . One thing worth noting is that galcanezumab also effective for prophylactic treatment of cluster headache .

Another option is CGRP receptor antagonists . The gepants has been investigated since 2000, but early trials stopped due to liver toxicity . Recently, the ubrogepant has been proven effective for relieving acute migraine attack without hepatoxicity . The monoclonal antibodies are nearly impossible to cross the blood-brain barrier , and the gepents has weak ability to cross the BBB; therefore, these medications affect peripherally accessible sites, not central targets .

Keaton S. Smetana PharmD, BCCCP, Casey C. May PharmD, BCCCP, in, 2019

Erenumab-aooe

Table 1. Adverse events occurring in ;2% of patients in the chronic migraine trial.

Adverse event

Nancy Sudak MD, Joseph Katzinger ND, in, 2020

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Strengths And Limitations Of The Study

Network meta-analysis allowed us to compare medication classes with placebo both directly and indirectly, which usually provides a more precise estimate of the relative efficacy and safety than pairwise analyses. A key strength of our study is the use of a network method to explore the relative effect of different types of CGRP monoclonal antibodies for migraine. By using network analysis, we were able to incorporate direct and indirect comparisons among various types of CGRP monoclonal antibodies to rank their efficacy and safety for migraine therapy. In addition, we reasonably used the GRADE method to judge the certainty of evidence for the primary estimates. These methods were useful for clinical decision making. We also provided more up-to-date information regarding the reported efficacy and safety of CGRP monoclonal binding antibody in treating adult patients with migraine. Indeed, this meta-analysis covered a greater number of recent trials, including the PROMISE-1 and CONQUER trials as well as the unpublished }NCT02959177 trial.

There are several limitations related to our study. First, the inclusion criteria varied in different trials. Some trials only included patients with episodic migraine, some included patients with chronic migraine, and some mixed these two subtypes of disease.

Second, several trials did not provide treatment-emerging adverse events; therefore, data on adverse events were used instead.

Clinical Trial Of Erenumab In Subjects With High

NEJM on Twitter: "Erenumab administered subcutaneously 1x ...

THIS STUDY IS BEING CONDUCTED TO OBTAIN MORE INFORMATION ON THE BENEFIT OF ERENUMAB TREATMENT, APART FROM THE EFFECT ON THE NUMBER OF MIGRAINE DAYS PER MONTH. THE STUDY WILL ASSESS MEASURES SUCH AS HEADACHE INTENSITY AND TIME SPENT WITH MODERATE OR SEVERE PAIN DURING TREATMENT. THIS STUDY IS ALSO BEING CONDUCTED TO OBTAIN MORE INFORMATION ON THE COMBINED EFFECT OF ERENUMAB AND TRIPTAN MEDICATION, SUCH AS THAT COMMONLY RECEIVED TO TREAT MIGRAINE ATTACKS.

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Inclusion And Exclusion Criteria

We included adult patients who were diagnosed with migraine according to the International Classification of Headache Disorders second edition , or the third edition , 2013). We defined intervention as the use of any type of monoclonal antibody against calcitonin gene-related peptide or its receptor at commercial doses, , 70;mg of erenumab , 100;mg of eptinezumab , or 225;mg of fremanezumab . The control group was defined as placebo or different types of CGRP monoclonal antibodies. We chose changes in the number of monthly migraine days from baseline to endpoint as the primary efficacy outcome measure and the proportion of participants who suffered treatment-emergent adverse events as the primary safety outcome measure. Additionally, the frequency of patients with at least 50 and 75% reductions in the days with migraine as well as the proportion of participants who suffered serious adverse events were assessed as secondary outcomes. We only included randomized controlled trials and excluded observational or cross-sectional studies.

Additionally, we excluded 1) trials that only compared different doses of a single CGRP monoclonal antibody, 2) trials that only compared a CGRP monoclonal antibody with other pharmacologically active drugs, and 3) trials that assessed calcitonin gene-related peptide binding monoclonal antibodies in pediatric migraine patients.

Efficacy And Tolerability Of Erenumab In Patients With Episodic Migraine In Whom Two

ClinicalTrials.gov-Kennung : NCT03096834

Kurzbeschreibung der Studie

ClinicalTrials.gov-Kennung : NCT03096834

Ergebnisse der Studie in der Übersicht

Between March 20, 2017, and Oct 27, 2017, 246 participants were randomly assigned, 121 to the;erenumab;group and 125 to the placebo group. 95 of 246 participants had previously unsuccessfully tried two preventive drugs, 93 had tried three, and 56 had tried four. At week 12, 36 patients in the;erenumab;had a 50% or greater reduction from baseline in the mean number of monthly;migraine;days, compared with 17 in the placebo group . The tolerability and safety profiles of;erenumab;and placebo were similar. The most frequent treatment-emergent adverse event was injection site pain, which occurred in seven participants in both groups.

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Comparison With Other Studies

From 2017 to 2020, several researchers conducted meta-analyses to evaluate treatment with GCRP monoclonal antibody in migraine patients . Though the meta-analyses were slightly different in design, they all used direct methods to compare the efficacy and safety of the medication with placebo. Their results remained similar in that CGRP-binding monoclonal antibodies significantly reduced the monthly migraine days without increasing the incidence of adverse events. Although they performed subgroup analyses of different types of GCRP monoclonal antibodies, the subgroup analyses did not show any significant difference. Their conclusions might be limited since most of the previous studies did not perform comprehensive literature searches and failed to show the comparative effectiveness of various types of CGRP monoclonal antibodies.

Availability Of Data And Materials

HER-MES study: erenumab versus topiramate in episodic migraine

Data may be shared with qualified external researchers, granting access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

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Review Of The Available Trials

Detailed information on patients with prior preventive treatment failures was available from 3 randomized controlled trials the NCT02066415, the Study to Evaluate the Efficacy and Safety of Erenumab in Migraine Prevention , and the 12-week Double-blind, Randomized, Multicenter Study Comparing the Efficacy and Safety of Once Monthly Subcutaneous AMG 334 Against Placebo in Adult Episodic Migraine Patients Who Have Failed Prophylactic Migraine Treatments – and their subgroup analyses or open-label extensions .

Table 1 Characteristics of the randomized controlled trials assessing the effect of prior preventive treatment failures on the treatment with erenumab for migraine prevention

The STRIVE trial considered 7 categories of preventive treatments, namely: 1) divalproex sodium, sodium valproate; 2) topiramate; 3) beta blockers; 4) tricyclic antidepressants; 5) serotonin-norepinephrine reuptake inhibitors; 6) flunarizine, verapamil; and 7) lisinopril, candesartan ; the NCT02066415 trial considered the same categories plus botulinum toxin , while the LIBERTY trial included in migraine prophylaxis treatments propranolol/metoprolol, topiramate, flunarizine, valproate/divalproex, amitriptyline, venlafaxine, lisinopril, candesartan, and locally approved products .

Patient Disposition Baseline Characteristics And Primary Results

Patients were randomized to receive erenumab 140 mg or placebo in the LIBERTY study. Of these, 240 completed the DBTP and entered the OLEP . A total of 36 patients discontinued OLEP before/on week 64: 17 patients from the continuous erenumab arm and 19 patients who switched from placebo to erenumab. The most common reasons for OLEP discontinuation were lack of efficacy , participant/guardian decision , and AEs .

    Proportion of Participants With Adverse Events and the Exposure-Adjusted Subject Rate per 100 Patient-Years in the DBTP and OLEP

    Treatment-emergent SAEs were reported in 16 patients of the overall population . This was nearly similar to the observations of DBTP . The most commonly reported SAE in both phases of the LIBERTY study was migraine, which occurred less frequently in the OLEP phase than in the DBTP .

    Treatment discontinuation due to treatment-emergent AEs was observed in 4 patients overall in the OLEP. The exposure-adjusted incidence rate of treatment-related AEs in the overall population was 30.1 per 100 patient-years in the OLEP. The corresponding values for treatment-related AEs in the DBTP were 21 with an incidence rate of 86.7 per 100 patient-years in erenumab arm and 24 with an incidence rate of 95.1 per 100 patient-years in the placebo arm, respectively. The incidence of treatment-related AEs decreased in the OLEP compared with the DBTP.

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    Standard Protocol Approvals Registrations And Patient Consents

    This study is registered with ClinicalTrials.gov . All processes were reviewed and approved by institutional review boards at the site of participation. All centers complied with local regulations, and patients provided written informed consent. This study was conducted in agreement with International Council for Harmonisation Good Clinical Practice guidelines.

    Risk Of Bias Judgment And Certainty Of Evidence Assessment

    A Controlled Trial of Erenumab for Episodic Migraine ...

    All included trials used adequate methods to generate random sequences and conceal allocation. Fifteen trials were judged as having an overall low risk of bias. The other three trials were regarded as having an unclear risk of bias. Two trials were judged as having an unclear risk of bias due to selective reporting bias; the other trial was judged as having an unclear risk of bias due to selective reporting bias and other biases. present the full details of the risk of bias assessment for each study. The quality of the evidence for primary outcomes is summarized in . In general, the certainty of evidence for each estimate was judged to be moderate to high.

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    The Em And Cm Studies

    The EM study was an international, randomized, double-blind, placebo-controlled, parallel-group, phase 3 pivotal regulatory trial of erenumab 70;mg and 140;mg administered monthly by subcutaneous injection in adult patients with EM where randomization was stratified by region and by preventive migraine medication use . The CM study was an international, randomized, double-blind, placebo-controlled, parallel-group pivotal regulatory trial in adult patients with CM where randomization was stratified by region and medication overuse . Detailed information on study designs, populations, and results are provided in the primary publications . The two studies were selected for post-hoc analyses on onset of efficacy given their design , sample size and the use of both doses of erenumab, 70;mg and 140;mg, across the two migraine categories, EM and CM.

    Fig. 1

    Erenumab For Preventing High

    Headache

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    Patients Experience More Migraine

    Change From Baseline in Mean MMDs Over Months 4 to 61,2,

    3.7;MORE MIGRAINE-FREE DAYS

    This was a phase 3 randomized, double-blind, placebo-controlled study of adult episodic migraine patients.1,2

    Study Information

    Aimovig® was evaluated for the prevention of episodic migraine in patients aged 18 to 65 years with 4 to 14 monthly migraine days in this multicenter, 24-week study.1

    *Earliest post-baseline prespecified assessment.2

    Least-square means are presented. For Aimovig® 70 mg, the difference from placebo was -1.4 . For Aimovig® 140 mg, the difference from placebo was -1.9 .1,2

    ATP = active treatment phase; DBTP = double-blind treatment phase; EM = episodic migraine; MMDs = monthly migraine days; Ph = phase.

    A Controlled Trial Of Erenumab For Episodic Migraine

    Erenumab in Migraine Therapy: Clinical Data

    METHODS: We randomly assigned patients to receive a subcutaneous injection of either;erenumab, at a dose of 70 mg or 140 mg, or placebo monthly for 6 months. The primary end point was the change from baseline to months 4 through 6 in the mean number of;migrainedays per month. Secondary end points were a 50% or greater reduction in mean;migraine;days per month, change in the number of days of use of acute;migraine-specific medication, and change in scores on the physical-impairment and everyday-activities domains of the;MigrainePhysical Function Impact Diary .

    ClinicalTrials.gov-Kennung :;NCT02456740

    Kurzbeschreibung der Studie

    METHODS: We randomly assigned patients to receive a subcutaneous injection of either;erenumab, at a dose of 70 mg or 140 mg, or placebo monthly for 6 months. The primary end point was the change from baseline to months 4 through 6 in the mean number of;migrainedays per month. Secondary end points were a 50% or greater reduction in mean;migraine;days per month, change in the number of days of use of acute;migraine-specific medication, and change in scores on the physical-impairment and everyday-activities domains of the;MigrainePhysical Function Impact Diary .

    ClinicalTrials.gov-Kennung :;NCT02456740

    Ergebnisse der Studie in der Übersicht

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    Erenumab For Migraine Prophylaxis In Adults

    ALEX M. SHREIBER, PharmD, Idaho State University, Pocatello, Idaho

    Am Fam Physician.;2019;Jun;15;99:781-782.

    Erenumab-aooe is a once-monthly injected monoclonal antibody labeled for migraine prophylaxis in adults. It is one of three biologic products that block the receptor of calcitonin generelated peptide, a vasodilatory neurotransmitter that accumulates during active migraine.1,2

    70 mg once monthly; select patients may benefit from 140 mg once monthly

    70-mg single-use prefilled autoinjector or prefilled syringe

    $600 for 70-mg dose

    *Estimated retail price for one month of treatment based on information obtained at .

    Drug

    70 mg once monthly; select patients may benefit from 140 mg once monthly

    70-mg single-use prefilled autoinjector or prefilled syringe

    $600 for 70-mg dose

    *Estimated retail price for one month of treatment based on information obtained at .

    Selection Process And Data Extraction

    After deleting duplicates, two reviewers manually filtered articles that were deemed ineligible by screening titles and abstracts. Then, the full texts of articles were reviewed and further screened based on the eligibility criteria mentioned above. Two reviewers independently completed this procedure together. Conflicts in study selection were resolved by comprehensive discussion or by consulting a third independent reviewer for help.

    The following data were extracted onto a modified table form of the data extraction template designed by the Cochrane Public Health Group: study characteristics such as primary author, year of publication, geographical location, numbers of centers that the study included, duration of follow-up, etc.; patient characteristics such as age, sex, condition of disease, etc.; and treatment characteristics such as type and dose of the drugs. Two reviewers worked in pairs to extract data from the eligible studies. In cases of incomplete or ambiguous data, we contacted the corresponding author of the article or the editor of the journal. Disagreements on data extraction were settled by comprehensive discussion or turned to a third independent reviewer for help.

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    Assessment Of Risk Of Bias And Quality Of Evidence

    The same two reviewers evaluated the risk of bias of each trial by using the tool designed by the Cochrane Statistical Methods Group across seven domains: allocation concealment, incomplete outcome data, blinding of study participants, random sequence generation, selective reporting, blinding of outcome assessment, and other potential risk of bias . The risk of bias in each domain was assessed as either low, unclear, or high. A trial was rated as having an overall low risk of bias if each domain was assessed to have a low risk of bias. Otherwise, it was judged as having an overall high risk of bias. We contacted the original study investigators for more information if necessary.

    Additionally, the certainty of evidence of the primary outcomes was assessed using a framework developed by the GRADE working group: Grading of Recommendations Assessment, Development, and Evaluation for rating the certainty of effect estimates . A total of five domains were evaluated: limitations in design, indirectness, imprecision, publication bias, and inconsistency. The overall quality of evidence was further rated high,moderate,low, or very low.

    Arise: A Phase 3 Randomized Trial Of Erenumab For Episodic Migraine

    Early onset of efficacy with erenumab in patients with ...

    In this randomized, double-blind, placebo-controlled, phase 3 study, 577 adults with episodic;migraine;were randomized to placebo or 70mg;erenumab; 570 patients were included in efficacy analyses. Primary endpoint was change in monthly;migraine;days. Secondary endpoints were 50% reduction in monthly;migraine;days, change in acute;migraine-specific medication treatment days, and 5-point reduction in Physical Impairment and Impact on Everyday Activities domain scores measured by the;Migraine;Physical Function Impact Diary. All endpoints assessed change from baseline at month 3.

    ClinicalTrials.gov-Kennung :;NCT02483585

    Kurzbeschreibung der Studie

    In this randomized, double-blind, placebo-controlled, phase 3 study, 577 adults with episodic;migraine;were randomized to placebo or 70mg;erenumab; 570 patients were included in efficacy analyses. Primary endpoint was change in monthly;migraine;days. Secondary endpoints were 50% reduction in monthly;migraine;days, change in acute;migraine-specific medication treatment days, and 5-point reduction in Physical Impairment and Impact on Everyday Activities domain scores measured by the;Migraine;Physical Function Impact Diary. All endpoints assessed change from baseline at month 3.

    ClinicalTrials.gov-Kennung :;NCT02483585

    Ergebnisse der Studie in der Übersicht

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