Description
Migraine is a headache disorder characterized by recurrent moderate to severe headaches with associated symptoms. For patients who experience more than four migraine days per month, preventive treatment may be recommended. Evidence implicates calcitonin gene-related peptide (CGRP) in migraines, and monoclonal antibodies (mAbs) for the CGRP receptor and molecule have been developed for migraine prophylaxis.

For individuals who have episodic migraine who receive CGRP mAbs, the evidence includes pivotal randomized controlled trials (RCTs). The relevant outcomes are symptoms, change in disease status, quality of life, and treatment-related morbidity. Five RCTs with over 4,000 adults showed a reduction of 1 to 2 monthly migraine days with the CGRP mAbs compared to placebo. This is similar to oral medications that have been approved by the U.S. Food and Drug Administration for the prophylaxis of migraine headaches. Serious/Grade 3 adverse events during the three- to six-month study periods were similar to placebo and reported in the range of 1.0% to 3.1%; there is uncertainty regarding long-term benefits and harms for a treatment that could be given indefinitely. Studies on the long-term safety, efficacy, and tolerability of CGRP mAbs are ongoing. Results of these studies are needed to determine the place of CGRP mAbs among available preventive therapies. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have episodic migraine not responsive to standard pharmacologic therapy who receive CGRP mAbs, the evidence includes one RCT and some of the participants in the pivotal RCTs. The relevant outcomes are symptoms, change in disease status, quality of life, and treatment-related morbidity. One multicenter RCT (n = 246) was identified on erenumab for the prevention of migraine in patients whofailed 2 to 4 other preventive treatments. In this treatment-resistant group, mAbs reduced monthly migraine days by 1.6 days compared to placebo. In addition, the pivotal trials on episodic migraine that were submitted for Food and Drug Administration approval included patients who had failed other treatments. For example, in the pivotal trials of erenumab, about 40% of patients had a history of preventive treatment failure. These trials also showed a reduction of one to two monthly migraine days compared to placebo. These studies indicate that in adults who have failed pharmacologic preventive therapy, CGRP mAbs is an effective second-line option. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have chronic migraine who receive CGRP mAbs, the evidence includes multicenter RCTs. The relevant outcomes are symptoms, change in disease status, quality of life, and treatment-related morbidity. Nearly 3,000 adult patients in three trials have been included in studies of CGRP mAbs for the preventive treatment of chronic migraine. Compared to the placebo-treated groups, CGRP mAbs decreased the mean number of migraine days by as much as 2.5 days. More patients treated with the mAbs had greater than 50% reduction in migraines, with an odds ratio of 2.3. Serious/Grade 3 adverse events reported during the three-month study periods were similar to placebo and in the range of 1% to 3%; there is uncertainty regarding long-term benefits and harms for a treatment that could be given indefinitely. Studies on the long-term safety, efficacy, and tolerability of CGRP mAbs are needed to determine the place of CGRP mAbs among available preventive therapies. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have chronic migraine not responsive to standard pharmacologic therapy who receive CGRP mAbs, the evidence includes multicenter RCTs. The relevant outcomes are symptoms, change in disease status, quality of life, and treatment-related morbidity. No trials were identified that included only patients with chronic migraine not responsive to standard pharmacologic preventive therapy. However, a high percentage of patients in the pivotal chronic migraine trials had failed pharmacologic therapies. These results indicate that CGRP mAbs would be a reasonable second-line option in adults with chronic migraine who have failed two to three classes of pharmacologic treatment. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Background
Migraine
Migraine is a headache disorder characterized by recurrent moderate to severe headaches with associated symptoms. Approximately 15% of the population have migraines, with a higher prevalence in women than in men.¹ The typical migraine headache is throbbing, unilateral, and aggravated by motion. Migraines are frequently associated with nausea, vomiting, photophobia, and phonophobia, although other neurological symptoms may occur. Migraine attacks can last from several hours to several days and are often preceded by transient neurological symptoms (e.g., visual disturbance) known as migraine aura. 

Migraines are categorized as episodic or chronic depending on the frequency of attacks. Episodic migraine is defined as migraine or headache for less than 15 days per month and accounts for more than 90% of cases of migraine. Chronic migraine is defined as 15 or more headache days each month, of which at least eight are migraine days. 

Migraine was previously thought to be primarily vascular, but recent evidence suggests that sensitization of pain pathways in the central nervous system may be involved.² At least three messenger molecules are thought to be involved during migraine attacks: nitric oxide, 5-hydroxytryptamine (5-HT) and CGRP. CGRP is produced in both peripheral and central neurons and is a potent vasodilator. Some preclinical studies suggest that during a migraine, sensory neurons in the trigeminal ganglion release CGRP from their peripherally projecting nerve endings in the meninges. 

Treatment
Symptomatic treatment is available for migraine attacks. Other medications such as triptans (5-HT agonists) taken at the onset of a migraine may reduce the severity and duration of the attack. For patients who experience more than 4 migraine days per month, preventive treatment may be recommended. Most of the pharmaceutical agents that reduce migraine attack frequency and severity are antidepressants, anticonvulsants or antihypertensives, and were not developed specifically to prevent migraine. Oral medications approved by the U.S. Food and Drug Administration (FDA) for migraine prophylaxis include topiramate, propranolol, timolol, and valproate. All of these medications have contraindications and side effects that limit their use. Botulinum toxin injections in the head or neck may also be used (see evidence review no. 501050). 

This evidence review addresses humanized monoclonal antibodies (mAbs) that bind to the CGRP receptor or CGRP molecule and are designed specifically for the prevention of migraine (see Table 1). Unlike oral drug therapy, monoclonal antibodies are not metabolized by the liver and can remain in the body for weeks or months.

Regulatory Status
In May 2018, Aimovig (erenumab) was approved by the FDA for use in the preventive treatment of migraine in adults. Post-marketing requirements include two randomized controlled trials (RCTs) in pediatric patients, and 2 cohort studies to evaluate pregnancy exposure. Other monoclonal antibodies targeting CGRP were subsequently approved (see Table 1).

Table 1. Regulatory Status of Humanized Monoclonal Antibodies for CGRP  

CGRP: calcitonin gene-related peptide  

Related Policies
50105  Botulinum Toxin  

Policy 
FDA-approved monoclonal antibodies for calcitonin gene-related peptide may be considered MEDICALLY NECESSARY when the following criteria is met: 

• Patient has diagnosis of episodic:
  • Patient has four to 14 migraine days per month, but no more than 14 headache days per month OR
• Patient has diagnosis of chronic migraine:
  • Patient has greater than or equal to 15 headache days per month, of which at least eight must be migraine days for at least three months
• Patient has diagnosis episodic cluster headache (Emgality Only):
  • Patient has experienced at least two cluster periods lasting from seven days to 365 days, separated by pain-free periods lasting at least three months
• Medication overuse headache has been considered and potentially offending medication(s) have been discontinued
• The patient is ≥ 18 years of age;  
• Has failed a trial (e.g., not effective or not tolerated) at least two of the following prophylactic pharmacologic therapies (amitriptyline, venlafaxine, divalproex sodium, topiramate, atenolol, propranolol, nadolol, timolol, or metoprolol) if not contraindicated
• Has not received botulinum toxin headache prophylaxis in the past four months.

Continuation of calcitonin gene-related peptide may be considered MEDICALLY NECESSARY when:

• Patient has experienced a positive response to therapy, demonstrated by a reduction in headache frequency and/or intensity
• Use of acute migraine medications (e.g., NSAIDs, triptans) has decreased since the start of CGRP therapy

Treatment with monoclonal antibodies for calcitonin gene-related peptide is considered investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY in all other situations.

Policy Guidelines 
Botulinum toxin is an approved treatment for migraine headache prophylaxis (see policy No. 50105). Evidence is limited/lacking on combined treatment with botulinum toxin and monoclonal antibodies for calcitonin gene-related peptide.

Pharmacologic therapies that have demonstrated efficacy in the preventive treatment of migraine are described in the Supplemental Information section.

Coding:
There is currently no specific code for these drugs. They would probably be billed with the unlisted code J3590 - Unclassified biologics.

Benefit Application
BlueCard/National Account Issues
State or federal mandates (e.g., Federal Employee Program) may dictate that certain U.S. Food and Drug Administration-approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity. 

Rationale 
Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life (QOL), and ability to function — including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms. 

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, two domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical uses of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events (AEs) and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice. 

Episodic Migraine Who Are Eligible To Receive Standard Pharmacologic Preventative Therapy
Clinical Context and Therapy Purpose
The purpose of monoclonal antibodies (mAbs) for the calcitonin gene-related peptide receptor (CGRP) in patients who have episodic migraine who are eligible to receive standard pharmacologic preventative therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Do humanized mABs for CGRP improve health outcomes in patients who have episodic migraine who are eligible to receive standard pharmacologic preventative therapy?

The following PICOs were used to select literature to inform this review.

Patients
The relevant population of interest are patients with episodic migraine who are eligible to receive standard pharmacologic preventative therapy.

Interventions
The therapy being considered is a mAbs for the CGRP molecule or the CGRP receptor. Subcutaneous injections in the abdomen, thigh, or upper arm are self-administered with prefilled syringes or automatic injectors. The U.S. Food and Drug Administration (FDA) approved CGRP antagonists are described in Table 1.

Comparators
The following therapies are currently used for migraine prevention: oral medications approved by the FDA for migraine prophylaxis include topiramate, propranolol, timolol, and valproate. The decrease in migraine days per month with oral prophylactic treatments ranges from 1.2 to 1.8 after subtracting the placebo response.^2,

For patients who have failed or cannot tolerate oral prophylactic treatments, management involves supportive care.

Outcomes
The general outcomes of interest are migraine intensity and frequency, and the effect on function and QOL (see Table 2). The most common outcome measures are a decrease in migraine/headache days per month compared with baseline and the proportion of responders to the treatment (typically 12 weeks treatment duration), defined as those patients who report more than a 50%, 75% or 100% decrease in migraine days per month compared to pre-treatment. The acute effect of mAbs on migraine severity and frequency should be measured over three to six months. Safety and long-term efficacy may be observed at one to two years.

Table 2. Patient-Reported Outcome Measures

Randomized Controlled Trials
We did not identify any studies comparing mAbs for CGRP with FDA approved treatments in head-to-head trials. Five multicenter pivotal trials with over 4000 adults with episodic migraine have been published that compared erenumab, fremanezumab, and galcanezumab (see Table 3) with placebo. The average number of migraine days per month ranged from 8.3 to 9.1 in these studies (see Table 4). In ARISE and STRIVE, about 40% of patients had a history of preventive treatment failure, while in EVOLVE-1 18% of patients had failed preventive treatment. All of the studies excluded patients who had failed at least two or three classes of preventive treatments.

Meta-analysis
The Institute for Clinical and Economic Review conducted a network meta-analysis that included 18 trials: 8 placebo-controlled trials of CGRP inhibitors and 10 trials assessing oral preventive therapies.⁸ Overall, there were greater reductions in monthly migraine days, higher odds of 50% response, and greater reductions in days using acute medication per month for all interventions including CGRP inhibitors vs placebo. Results comparing CGRP inhibitors to oral preventive therapies were not statistically different. Compared to placebo, reduction in monthly migraine days with erunemab was 1.3 (70 mg monthly) to 1.9 days (140 mg monthly), fremanezumab 1.2 (675 mg quarterly) to 1.6 days (225 mg monthly), galcenuzemab 1.8 days (120 as well as 240 mg monthly), topiramate 1.2 (100 mg/day) to 1.0 (200 mg/day), amitriptyline 1.1 days (25-100 mg/day) and 1.2 days (160 mg/day).

Across the CGRP trials, there were no differences in the meta-analyzed odds of discontinuing for any cause, discontinuing due to AEs, or experiencing serious AEs with the CGRP inhibitors vs other preventive therapies. The most commonly reported AEs involved injection-site events (injection pain and injection-site reactions including erythema, induration, and pruritus) in up to 30% of patients at 12 or 24 weeks. In the trials of other preventive therapies, the most commonly reported AEs were fatigue, cognitive symptoms (including cognitive difficulties, difficulty with memory, concentration, language), paresthesia, taste perversion, and weight change. These AEs were not frequently observed in the CGRP inhibitor trials.

Table 3. Summary of Key RCT Characteristics

RCT: randomized controlled trial.

Table 4. Summary of Clinical Characteristics

SD: standard deviation.
^aReported only for prior topiramate use

Patients receiving injections of a CGRP mAb had an average decrease of 2.9 to 4.7 monthly migraine days, while the placebo group had a decrease of an average of 1.8 to 2.8 monthly migraine days (see Table 6). This resulted in an improvement of 1.0 to 2.0 monthly migraine days with the mAbs. The odds ratio for a 50% decrease in monthly migraine days ranged from 1.6 to 2.8. The decrease in monthly migraine-specific medication days was 0.6 to 1.8 days greater with mAB treatment. The most common adverse event was injection site pain. Serious AEs ranged from 1.9% to 2.5%.

Table 5. Summary of Key RCT Results

CI: confidence interval; Diff: difference; OR: odds ratio; mAbs: monoclonal antibody; MPFID: Migraine Physical Function ImpactDiary; MSQRFR, Migraine Specific Quality of Life questionnaire, version 2.1, Role-Function Restrictive; RCT: randomized controlled trial; SE: standard error.

No major limitations were identified in the study design and conduct (see Table 6). All trials had comparable arms at baseline, did not have differential attrition, were patient and physician/investigator blinded, had clear definitions of intervention and outcomes, and used an intent-to-treat analysis or a modified version. In terms of relevance limitations of this evidence base, the trials compared CGRP inhibitors to placebo, restricted the patient population to those for whom no more than two or three other preventive therapies had failed, and were short-term in duration. QOLoutcomes measures are considered critical in migraine and patients seek improvement in the QOL measures. However, such QOL measures were reported infrequently in the trials and when reported, the follow-up period was short. Generalizability of the results generated from the RCTs is limited and may not apply to many patients who are likely be treated with CGRP inhibitors, such as those who have tried more than three preventive therapies, those with comorbidities and other groups of patients such as children, older adults, and women during pregnancy and lactation. Further, as these agents have a novel mechanism of action, the short-term trials limit our certainty about the durability of benefit as well safety, particularly those AEs which may manifest after a longer duration of treatment such as cardiovascular or those that are rare. CGRP is involved in multiple physiological processes and some concerns exist about the long-term effects of continuous blocking of CGRP or its receptor due to CGRP’s cardiovascular protective role.^14,15,16

Table 6. Relevance Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive limitations assessment.
^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3.Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Section Summary: Episodic Migraine Who Are Eligible to Receive Standard Pharmacologic Therapy
No head-to-head studies comparing CGRP inhibitors with oral therapies for prophylaxis of episodic migraine were identified. Five placebo-controlled RCTs with over 4000 adults showed a reduction of 1 to 2 monthly migraine days with the CGRP mAbs. A network meta-analysis showed no statistical difference in reduction in monthly migraine days or a 50% decrease in monthly migraine days when CGRP inhibitors were compared to oral preventive therapies. The most commonly reported AEs with CGRP inhibitors involved injection-site events (injection pain and injection-site reactions including erythema, induration, and pruritus) in up to 30% of patients at 12 or 24 weeks. In the trials of oral preventive therapies, the most commonly reported AEs were fatigue, cognitive symptoms (including cognitive difficulties, difficulty with memory, concentration, and language), paresthesia, taste perversion, and weight change. Such adverse events were not observed with CGRP inhibitors. Evidence of CGRP inhibitors is lacking in a certain group of patients such as children, older adults, and women during pregnancy and lactation as they were excluded from the pivotal RCTs. Given the lack of head-to-head trials of CGRP inhibitors with currently available oral preventive therapies, lack of superiority of CGRP inhibitors vs oral preventive therapies in network meta-analysis and limited long-term data on efficacy and safety of CGRP inhibitors,the ability to ascertain the incremental benefit of CGRP inhibitors in patients who are eligible to receive standard oral pharmacologic preventative therapy is limited.

Episodic Migraine Not Responsive to Standard Pharmacologic Preventive Therapy.
Clinical Context and Therapy Purpose
The purpose of a human mAbs for the CGRP receptor in patients who have episodic migraine not responsive to standard pharmacologic preventive therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Do CGRP mAbs improve health outcomes in patients who have episodic migraine not responsive to standard pharmacologic preventive therapy?

The following PICOs were used to select literature to inform this review.

Patients
The relevant population of interest are patients with episodic migraine not responsive to standard pharmacologic preventive therapy

Interventions
The therapy being considered is a CGRP mAbs as shown in Table 2. Subcutaneous injections in the abdomen, thigh, or upper arm are self-administered with prefilled syringes or automatic injectors.

Comparators
The following therapies are currently used for episodic migraine not responsive to standard pharmacologic preventive therapy: supportive care

Outcomes
The general outcomes of interest are migraine intensity and frequency, the effect of the migraines or treatment on QOL as measured by instruments such as the 12-Item Short Form Health Survey, hospitalizations due to migraine, and adverse effects of the mAbs (see Table 3). Migraine severity and frequency are measured over three to six months.

Randomized Controlled Trials
One multicenter RCT (n = 246) was identified on erenumab for the prevention of migraine in patients who had failed 2 to 4 other preventative treatments (see Table 8). The characteristics of the patients are shown in Table 9. More patients in the mAb group had a 50% or greater and 75% or greater reduction in monthly migraine days compared to the placebo group (see Table 10), with an odds ratio of 2.7 (p = 0.002) and 3.2 (p = 0.025), respectively. The mAb treated group had a reduction of 1.8 monthly migraine days compared to a 0.2 day reduction in the placebo group (p = 0.004). Patient-reported physical impairment on the MPFID was significantly reduced compared to a placebo (-3.5, p = 0.003).

Table 7. Summary of Key RCT Characteristics

RCT: randomized controlled trial.

Table 8. Summary of Clinical Characteristics

SD: standard deviation.

Table 9. Summary of Key RCT Results

CI: confidence interval; HR: hazard ratio; MPFID: Migraine Physical Function Impact Diary; OR: odds ratio; RCT: randomized controlled trial; SE: standard error.
¹ Include number analyzed, effect in each group, and measure of effect (absolute or relative) with CI,
² Describe the range of sample sizes, effects, and other notable features in text.

Relevance and design and conduct limitations of this trial are described in Tables 10 and 11. QOL outcomes measures are considered critical in migraine and patients seek improvement in the QOL measures. However, such QOL measures were not reported. Generalizability of the results generated from the RCTs is limited and may not apply to many patients groups such as children, older adults, and women during pregnancy and lactation. Further, as these agents have a novel mechanism of action, the short-term trials limit our certainty about the durability of benefit as well safety, particularly those AEs which may manifest after a longer duration of treatment such as cardiovascular or those that are rare. CGRP is involved in multiple physiological processes and some concerns exist about the long-term effects of continuous blocking of CGRP or its receptor due to CGRP’s cardiovascular protective role.^14,15,16,

Table 10. Relevance Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive limitations assessment.
^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3.Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 11. Study Design and Conduct Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive limitations assessment.
^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3.Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

Section Summary: Episodic Migraine Not Responsive to Standard Pharmacologic Preventive Therapy
One multicenter RCT was identified on erenumab for the prevention of migraine in patients who had failed two to four other preventative treatments. More patients in the CGRP mAb group had a reduction in monthly migraine days compared to the placebo group, with an odds ratio of 2.7 to 3.2. In this treatment-resistant group, mAb reduced monthly migraine days by 1.6 days compared to a placebo. A limitation of this body of evidence is that only one trial with 246 patients specifically evaluated CGRP mAbs for treatment-resistant migraines. Other trials, however, included some proportion of patients who had failed up to three other preventive treatments. In ARISE and STRIVE, about 40% of patients had a history of preventive treatment failure. However, subgroup analysis of such patients is not available. While there are uncertainties about the durability of efficacy as well as safety, the observed magnitude of benefit observed in a single RCT represents a potential benefit to patients who have exhausted other preventive treatment options.

Chronic Migraine Who Are Eligible To Receive Standard Pharmacologic Preventative Therapy
Clinical Context and Therapy Purpose
The purpose of a human mAbs for the CGRP receptor in patients who have chronic migraine who are eligible to receive standard pharmacologic preventative therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does human mAbs for CGRP improve health outcomes in patients who have chronic migraine who are eligible to receive standard pharmacologic preventative therapy?

The following PICO were used to select literature to inform this review.

Patients
The relevant population of interest are patients with chronic migraine who are eligible to receive standard pharmacologic preventative therapy.

Interventions
The therapy being considered is mAbs for CGRP (see Table 2). Subcutaneous injections in the abdomen, thigh, or upper arm are self-administered with prefilled syringes or automatic injectors.

The following therapies are currently used for migraine prevention:

Oral medications approved by the FDA for migraine prophylaxis include topiramate, propranolol, timolol, and valproate. The decrease in migraine days per month with oral prophylactic treatments ranges from 1.2 to 1.8 after subtracting the placebo response.²

For patients who have failed or cannot tolerate oral prophylactic treatments, management involves supportive care.

Outcomes
The general outcomes of interest are migraine intensity and frequency, the effect of the migraines or treatment on function and QOL (see Table 3). The most common outcome measures are a decrease in migraine/headache days per month compared with baseline and the proportion of responders to the treatment (typically 12 weeks treatment duration), defined as those patients who report more than a 50%, 75% or 100% decrease in migraine days per month compared to pre-treatment. Migraine severity and frequency are measured in the last month of three to six months of treatment.

Randomized Controlled Trials
Three multicenter RCTs with 3 different mAbs, 2 of which had over 1,000 patients, have been identified on CGRP mAbs for the preventive treatment of chronic migraine (see Table 13). The mean number of migraine days per month ranged from 16.2 to 19.5 days at baseline (see Table 14). Two of the studies specified exclusion of patients who had failed two or three or more classes of preventive treatments; details were not available in the FDA summary of the Emgality Study-3. Two of the studies allowed concurrent use of prophylactic medications. Compared to placebo injections, mAbs for GCGRP resulted in a decrease of 2.1 to 2.5 monthly migraine days, a higher percentage of patients (13% to 23% higher) who had greater than 50% reduction in monthly migraine days, and a decrease of 1.8 to 2.6 migraine-specific medication days compared to patients treated with placebo (all p < 0.001, see Table 15).

Meta-analysis
The Institute for Clinical and Economic Review conducted a network meta-analysis that included 11 trials: 3 placebo-controlled trials of CGRP inhibitors and 8 trials assessing onabotulinum toxin A or topiramate.^8, Overall, there were greater reductions in monthly migraine days, higher odds of 50% response, and greater reductions in days using acute medication per month for all interventions including CGRP inhibitors vs placebo. Results comparing CGRP inhibitors to other preventive therapies were not statistically different. Compared to placebo, reduction in monthly migraine days with erunemab was 2.4 days (70 or 140 mg monthly) and fremanezumab 1.3 (675 mg quarterly) to 1.7 days (675/225 mg monthly), topiramate 1.7 (100 mg/day) and onabotulinum toxin A 2.0 days (155U quarterly). Results comparing CGRP inhibitors to active therapies were not statistically different.

Table 12. Summary of Key RCT Characteristics

RCT: randomized controlled trial.
¹ Number randomized; intervention; mode of delivery; dose (frequency/duration).
² Key eligibility criteria.

Table 13. Summary of Clinical Characteristics

SD: standard deviation.
^aPrevious use of topiramate.

Table 14. Summary of Key RCT Results

CI: confidence interval; Diff: difference; HIT-6: Headache Impact Test; MSQL: Migraine-specific quality of lfe;NNT: number needed to treat; OR: odds ratio; RCT: randomized controlled trial; SE: standard error.

No major limitations were identified in study design and conduct. In terms of relevance limitations of this evidence base, the trials compared CGRP inhibitors to placebo, restricted the patient population to those for whom no more than two or three other preventive therapies had failed, and were short-term in duration (See Table 16). QOL outcomes measures are considered critical in migraine and patients seek improvement in the QOL measures. However, such QOLmeasures were reported infrequently in the trials and when reported, the follow-up period was short. Generalizability of the results generated from the RCTs is limited and may not apply to many patients who are likely be treated with CGRP inhibitors, such as those who have tried more than three preventive therapies, those with comorbidities and other groups of patients such as children, older adults, and women during pregnancy and lactation. Further, as these agents have a novel mechanism of action, the short-term trials limit our certainty about the durability of benefit as well safety, particularly those AEs which may manifest after a longer duration of treatment such as cardiovascular or those that are rare. CGRP is involved in multiple physiological processes and some concerns exist about the long-term effects of continuous blocking of CGRP or its receptor due to CGRP’s cardiovascular protective role.^14,15,16

Table 15. Relevance Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive limitations assessment.
^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use. 
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3.Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Section Summary: Chronic Migraine Who Are Eligible To Receive Standard Pharmacologic Preventative Therapy 
No head-to-head studies comparing CGRP inhibitors with oral therapies for prophylaxis of chronic migraine were identified. Three multicenter RCTs, with a total of nearly 3000 adult patients, have been identified on CGRP mAbs for the preventative treatment of chronic migraine. Compared to controls, CGRP mAbs decreased the mean number of migraine days by up to 2.5 days. More patients treated with the mAbs had greater than 50% reduction in migraines, with an odds ratio of 2.3. The most commonly reported AEs with CGRP inhibitors involved injection-site events. A network meta-analysis showed no statistical difference in reduction in monthly migraine days or 50% decrease in monthly migraine days when CGRP inhibitors were compared to active therapies (onabotulinum toxin A or topiramate). Given the lack of head-to-head trials of CGRP inhibitors with currently available oral preventive therapies, lack of superiority of CGRP inhibitors vs oral preventive therapies in network meta-analysis and limited long term data on efficacy and safety of CGRP inhibitors, it is difficult to ascertain incremental benefit of CGRP inhibitors in patients who are eligible to receive standard oral pharmacologic preventative therapy.

Chronic Migraine Not Responsive to Standard Pharmacologic Preventive Therapy
Clinical Context and Therapy Purpose
The purpose of a human mAbs for CGRP in patients who have chronic migraine not responsive to standard pharmacologic preventive therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does mAbs for CGRP improve health outcomes in patients who have chronic migraine not responsive to standard pharmacologic preventive therapy?

The following PICOs were used to select literature to inform this review.

Patients
The relevant population of interest are patients with chronic migraine not responsive to standard pharmacologic preventive therapy

Interventions
The therapy being considered is a human mAbs for the calcitonin gene-related peptide receptor (see Table 2). Subcutaneous injections in the abdomen, thigh, or upper arm are self-administered with prefilled syringes or automatic injectors.

Comparators
The following therapies are currently used for chronic migraine not responsive to standard pharmacologic preventive therapy: supportive care.

Outcomes
The general outcomes of interest are migraine intensity and frequency, the effect of the migraines or treatment on QOL as measured by instruments such as the 12-Item Short Form Health Survey, hospitalizations due to migraine, and adverse effects of the treatment (see Table 3). Migraine severity and frequency are measured over 6 to 12 months.

Randomized Controlled Trials
No trials were identified on mAbs for the treatment of chronic migraine that included only patients not responsive to standard pharmacologic preventive therapy. However, in the trial by Tepper et al. (2017; described above), 49% of patients had failed 2 to 3 classes of migraine preventive therapies (see Table 14).¹⁸

Section Summary: Chronic Migraine Not Responsive to Standard Pharmacologic Preventive Therapy
No trials were identified that exclusively included patients with chronic migraine not responsive to standard pharmacologic preventive therapy. However, the pivotal trials conducted in patients with chronic migraine included a substantial proportion of patients who had failed pharmacologic therapies. However, subgroup analysis of such patients is not available. While there are uncertainties about the durability of efficacy as well as safety, the observed magnitude of benefit observed in pivotal trials that included patients who failed standard pharmacological preventive therapy represents a potential benefit to patients.

Episodic Cluster Headache 
Clinical Context and Therapy Purpose 
The purpose of a human mAbs for CGRP in patients who have episodic cluster headache is to provide a treatment option that is an alternative to or an improvement on existing therapies. 

The question addressed in this evidence review is: Does mAbs for CGRP improve health outcomes in patients who have episodic cluster headaches?

The following PICOs were used to select literature to inform this review.

Patients
The relevant population of interest are patients with episodic cluster headache.

Interventions
The therapy being considered is the human mAbs galcanezumab. Subcutaneous injections in the abdomen, thigh, or upper arm are self-administered with prefilled syringes or automatic injectors.

Comparators
The following therapies are currently used for episodic cluster headache: oral and intranasal triptans, and high flow oxygen. Verapamil and lithium have been used for prophylaxis, although they are associated with many side effects.²¹

Outcomes
The general outcomes of interest are cluster headache intensity and frequency and the effect of the cluster headaches or treatment on QOL on a self-reported basis.

Randomized Controlled Trials
One multicenter RCT (n = 106) randomized 106 adults who met the International Classification of Headache Disorders 3rd edition (beta version) diagnostic criteria for episodic cluster headache and had a maximum of 8 attacks per day, a minimum of 1 attack every other day, and at least 4 attacks during the prospective 7-day baseline period. All patients were randomized in a 1:1 ratio to receive once-monthly subcutaneous injections of galcanezumab 300 mg or placebo. Patients were allowed to use certain specified acute/abortive cluster headache treatments, including triptans, oxygen, acetaminophen, and NSAIDs during the study. The study excluded patients on other treatments intended to reduce the frequency of cluster headache attacks; patients with medication overuse headache; patients with ECG abnormalities compatible with an acute cardiovascular event or conduction delay; and patients with a history of myocardial infarction, unstable angina, percutaneous coronary intervention, coronary artery bypass grafting, deep vein thrombosis, or pulmonary embolism within six months of screening. In addition, patients with any history of stroke, intracranial or carotid aneurysm, intracranial hemorrhage, or vasospastic angina; clinical evidence of peripheral vascular disease; or diagnosis of Raynaud’s disease were excluded. The primary efficacy endpoint was the mean change from baseline in weekly cluster headache attack frequency across weeks one to three. A secondary endpoint was the percentage of patients who achieved a response (defined as a reduction from baseline of 50% or greater in the weekly cluster headache attack frequency) at week 3. Out of 106 patients randomized, 90 patients completed the 8-week double-blind phase. There was a greater decrease in the least-squares mean from baseline in the weekly frequency of cluster headache attacks across weeks one to three (see Table 18) in the treatment group compared to placebo. The percentage of patients with a reduction of at least 50% in the weekly frequency of cluster headaches at week 3 was greater in the treatment group compared to placebo. Beginning at week four and through the remainder of the eight-week double-blind period, there was no difference in the outcomes between galcanezumab and placebo arm suggesting spontaneous improvement or remission (reflecting the typical course of a bout of cluster headache) or that the treatment effect with galcanezumab no longer differed substantially from that with placebo at those time points. The incidence of discontinuation of the trial regimen was higher in the placebo group (21%) than in the galcanezumab group (8%), whereas the incidence of discontinuation due to an adverse event did not differ substantially between the groups.

Table 16. Summary of Key RCT Characteristics

RCT: randomized controlled trial.

Table 17. Summary of Key RCT Results

CI: confidence interval; RCT: randomized controlled trial; SD: standard deviation.

No major limitations were identified in study design and conduct. In terms of relevance limitations of this evidence base, the trials compared CGRP inhibitors to placebo and were short-term in duration (See Table 19). QOL outcomes measures are considered critical in episodic cluster headache and patients seek improvement in the QOL measures. However, such QOL measures were not reported. Generalizability of the results is limited and may not apply to many patients such as patients with cardiovascular comorbidities, children and pregnant women. Further, as these agents have a novel mechanism of action, the short-term trials limit our certainty about the durability of benefit as well safety, particularly those AEs which may manifest after a longer duration of treatment such as cardiovascular or those that are rare. CGRP is involved in multiple physiological processes and some concerns exist about the long-term effects of continuous blocking of CGRP or its receptor due to CGRP’s cardiovascular protective role.^14,15,16

Table 18. Relevance Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive limitations assessment.
^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3.Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Section Summary: Episodic Cluster Headache
No head-to-head studies comparing CGRP inhibitors with oral therapies for episodic cluster headache were identified. One RCT with 106 adult patients reported a reduction in the frequency of weekly cluster headache attacks by 8.7 days among those treated galcanezumab vs. 5.2 in the placebo arr over weeks 1 to 3. The proportion of patients with ≥ 50% reduction in weekly cluster headache attacks at week 3 was 71% and 53% respectively. The most commonly reported AEs with galcanezumab involved injection-site events. Given the lack of head-to-head trials of CGRP inhibitors with currently available oral therapies and limited long-term data on efficacy and safety of galcanezumab, it is difficult to ascertain the incremental benefit of galcanezumab in patients who are eligible to receive standard oral pharmacologic preventative therapy. However, it may be considered a reasonable second-line option in patients who fail to respond or in whom the standard oral pharmacologic agents are contraindicated.

Chronic Cluster Headache
Clinical Context and Therapy Purpose
The purpose of a human mAbs for CGRP in patients who have chronic cluster headache is to provide a treatment option that is an alternative existing therapy.

The question addressed in this evidence review is: Does mAbs for CGRP improve health outcomes in patients who have chronic cluster headaches?

The following PICOs were used to select literature to inform this review.

Patients
The relevant population of interest are patients with chronic cluster headache.

Interventions
The therapy being considered is the human mAbs galcanezumab. Subcutaneous injections in the abdomen, thigh, or upper arm are self-administered with prefilled syringes or automatic injectors.

Comparators
The following therapies are currently used for chronic cluster headache: verapamil and lithium ³

Outcomes
The general outcomes of interest are cluster headache intensity and frequency and the effect of the cluster headaches or treatment on QOL on a self-reported basis.

Randomized Controlled Trials
No published trials were identified on mAbs for the treatment of chronic cluster headache. Results of a recently completed RCT published on ClinicalTrials.gov reports a reduction in the number of weekly chronic cluster headaches. However, the results were not statistically significant.

Section Summary: Chronic Cluster Headache
No trials were identified that included a significant difference in chronic cluster headache response from galcanezumab compared to placebo.

Summary of Evidence
For individuals who have episodic migraine who are eligible to receive standard pharmacologic preventative therapy who receive CGRP mAbs, the evidence includes multiple randomized controlled trials (RCTs) and one network meta-analysis. The relevant outcomes are symptoms, change in disease status, quality of life (QOL), and treatment-related morbidity. No head-to-head studies comparing CGRP inhibitors with oral therapies for prophylaxis of episodic migraine were identified. Five placebo-controlled RCTs with over 4,000 adults showed a reduction of one to two monthly migraine days with the CGRP mAbs. A network meta-analysis showed no statistical difference in reduction in monthly migraine days or a 50% decrease in monthly migraine days when CGRP inhibitors were compared to oral preventive therapies. The most commonly reported adverse events (AEs) with CGRP inhibitors involved injection-site events (injection pain and injection-site reactions including erythema, induration, and pruritus) in up to 30% of patients at 12 or 24 weeks. In the trials of oral preventive therapies, the most commonly reported AEs were fatigue, cognitive symptoms (including cognitive difficulties, difficulty with memory, concentration, and language), paresthesia, taste perversion, and weight change. Such AEs were not observed with CGRP inhibitors. Evidence of CGRP inhibitors is lacking in a certain group of patients such as children, older adults, and women during pregnancy and lactation as they were excluded from the pivotal RCTs. Given the lack of head-to-head trials of CGRP inhibitors with currently available oral preventive therapies, lack of superiority of CGRP inhibitors vs. oral preventive therapies in network meta-analysis and limited long-term data on efficacy and safety of CGRP inhibitors, it is difficult to ascertain incremental benefit of CGRP inhibitors in patients who are eligible to receive standard oral pharmacologic preventative therapy. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have episodic migraine not responsive to standard pharmacologic therapy who receive CGRP mAbs, the evidence includes one RCT and some of the participants in the pivotal RCTs. The relevant outcomes are symptoms, change in disease status, QOL, and treatment-related morbidity. One multicenter RCT (n = 246) was identified on erenumab for the prevention of migraine in patients who failed two to four other preventive treatments. In this treatment-resistant group, mAbs reduced monthly migraine days by 1.6 days compared to placebo. In addition, the pivotal trials on episodic migraine that were submitted for Food and Drug Administration approval included patients who had failed other treatments. For example, in the pivotal trials of erenumab, about 40% of patients had a history of preventive treatment failure. These trials also showed a reduction of one to two monthly migraine days compared to placebo. However, subgroup analysis of such patients is not available. While there are uncertainties about long-term efficacy as well as safety, the observed magnitude of benefit observed in a single RCT represents a potential benefit to patients who have exhausted other preventive treatment options and as such CGRP mAbs may be an effective second-line option in these patients. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have chronic migraine who are eligible to receive standard pharmacologic preventative therapy who receive CGRP mAbs, the evidence includes multicenter RCTs. The relevant outcomes are symptoms, change in disease status, QOL, and treatment-related morbidity. Nearly 3,000 adult patients in three trials have been included in studies of CGRP mAbs for the preventive treatment of chronic migraine. Compared to the placebo-treated groups, CGRP mAbs decreased the mean number of migraine days by as much as 2.5 days. More patients treated with the mAbs had greater than 50% reduction in migraines, with an odds ratio of 2.3. Serious/Grade 3 AEs reported during the three month study periods were similar to placebo and in the range of 1% to 3%; there is uncertainty regarding long-term benefits and harms for a treatment that could be given indefinitely. Studies on the long-term safety, efficacy, and tolerability of CGRP mAbs are needed to determine the place of CGRP mAbs among available preventive therapies. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have chronic migraine not responsive to standard pharmacologic therapy who receive CGRP mAbs, the evidence includes multicenter RCTs. The relevant outcomes are symptoms, change in disease status, QOL, and treatment-related morbidity. No trials were identified that exclusively included patients with chronic migraine not responsive to standard pharmacologic preventive therapy. However, the pivotal trials conducted in patients with chronic migraine included a substantial proportion of patients who had failed pharmacologic therapies. However, subgroup analysis of such patients is not available. While there are uncertainties about the durability of efficacy as well safety, the observed magnitudeof benefit observed in pivotal trials that included patients who failed standard pharmacological preventive therapy indicate that CGRP mAbs would be a reasonable second-line option in adults with chronic migraine who have failed two to three classes of pharmacologic treatment. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have episodic cluster headache who receive CGRP mAbs, the evidence includes one multicenter RCT. The relevant outcomes are symptoms, change in disease status, QOL, and treatment-related morbidity. No head-to-head studies comparing CGRP inhibitors with oral therapies for episodic cluster were identified. One RCT with 106 adult patients reported a reduction in the frequency of weekly cluster headaches by 8.7 days among those treated galcanezumab vs. 5.2 in the placebo arm over week 1 to 3. The proportion of patients with ≥ 50% reduction in weekly cluster headache attacks at week 3 was 71% and 53%, respectively. The most commonly reported AEs with galcanezumab involved injection-site events. Given the lack of head-to-head trials of CGRP inhibitors with currently available oral therapies and limited long term data on efficacy and safety of galcanezumab, it is difficult to ascertain incremental benefit of galcanezumab in patients who are eligible to receive standard oral pharmacologic preventative therapy. However, galcanezumab may be considered a reasonable second-line option in patients who fail to respond or in whom the standard oral pharmacologic agents are contraindicated. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have chronic cluster headache who receive CGRP mAbs, the evidence includes an unpublished, multicenter RCT. The relevant outcomes are symptoms, change in disease status, QOL, and treatment-related morbidity. No published trials were identified on mAbs for the treatment of chronic cluster headache. Results of a recently completed RCT published on ClinicalTrials.gov reports a reduction in the number of weekly chronic cluster headaches. However, the results were not statistically significant. The evidence is insufficient to determine the effects of the technology on health outcomes.

Practice Guidelines and Position Statements
American Academy of Neurology American Headache Society
The American Academy of Neurology and the American Headache Society (2012) published guidelines on therapies for migraine prevention.²² Recommended pharmacologic treatments for episodic migraine prevention are described in Table 19. These guidelines were reaffirmed in 2015.

Table 19. Recommended Pharmacologic Treatments for Episodic Migraine Prevention

MAM: menstrually associated migraines

Institute for Clinical and Economic Review
The ICER assessed the comparative clinical effectiveness and value of CGRP inhibitors as preventive treatments for patients with episodic or chronic migraine.⁸

• Among patients with chronic migraine who are eligible to receive preventive therapy, ICER Report rated the evidence on the net benefit of erenumab and fremanezumab as insufficient (“I”) compared to oral agents or to onabotulinum toxin A.
• Among patients with chronic migraine for whom prior preventive therapy has failed, ICER Report rated the net benefit of erenumab and fremanezumab as comparable or better (“C+”) compared to no treatment, weighing uncertainties about potential harms of CGRP inhibitors against the need for therapy in patients with frequent migraine and no other preventive treatment options.
• Among patients with episodic migraine who are eligible to receive preventive therapy, ICER Report rated the evidence on the net benefit of erenumab, fremanezumab, and galcanezumab as insufficient (“I”) compared to oral agents.
• Among patients with episodic migraine for whom oral preventive therapies have failed, ICER Report rated the net benefit of erenumab and fremanezumab as promising but inconclusive (“P/I”) compared to no treatment, again weighing uncertainties about potential harms of CGRP inhibitors against the need for therapy in patients without other preventive treatment options but with less frequent migraine than in the chronic migraine population.

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed in Table 20.

Table 20. Summary of Key Trials

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.

References 

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2. Mitsikostas DD, Reuter U. Calcitonin gene-related peptide monoclonal antibodies for migraine prevention: comparisons across randomized controlled studies. Current opinion in neurology. Jun 2017;30(3):272-280. PMID 28240610
3. Beck et al. Management of Cluster Headache. American Academy of Family Physicians.February 1 2005. 71(4):717-724.
4. Kawata AK, Hsieh R, Bender R, et al. Psychometric Evaluation of a Novel Instrument Assessing the Impact of Migraine on Physical Functioning: The Migraine Physical Function Impact Diary. Headache. Oct 2017;57(9):1385-1398. PMID 28857154
5. Stewart WF, Lipton RB, Kolodner KB, Sawyer J, Lee C, Liberman JN. Validity of the Migraine Disability Assessment (MIDAS) score in comparison to a diary-based measure in a population sample of migraine sufferers. Pain. Oct 2000;88(1):41-52. PMID 11098098
6. Yang M, Rendas-Baum R, Varon SF, Kosinski M. Validation of the Headache Impact Test (HIT-6) across episodic and chronic migraine. Cephalalgia : an international journal of headache. Feb 2011;31(3):357-367. PMID 20819842
7. Martin BC, Pathak DS, Sharfman MI, et al. Validity and reliability of the migraine-specific quality of life questionnaire (MSQ Version 2.1). Headache. Mar 2000;40(3):204-215. PMID 10759923
8. Calcitonin Gene-Related Peptide (CGRP) Inhibitors as Preventive Treatments for Patients with Episodic or Chronic Migraine: Effectiveness and Value Final Evidence Report July 3, 2018. https://icer-review.org/wp-content/uploads/2017/11/ICER_Migraine_Final_Evidence_Report_070318.pdf Accessed on Nov 14, 2019
9. Dodick DW, Ashina M, Brandes JL, et al. ARISE: A Phase 3 randomized trial of erenumab for episodic migraine. Cephalalgia : an international journal of headache. May 2018;38(6):1026-1037. PMID 29471679
10. Goadsby PJ, Reuter U, Hallstrom Y, et al. A Controlled Trial of Erenumab for Episodic Migraine. The New England journal of medicine. Nov 30 2017;377(22):2123-2132. PMID 29171821
11. Dodick DW, Silberstein SD, Bigal ME, et al. Effect of Fremanezumab Compared With Placebo for Prevention of Episodic Migraine: A Randomized Clinical Trial. Jama. May 15 2018;319(19):1999-2008. PMID 29800211
12. Stauffer VL, Dodick DW, Zhang Q, Carter JN, Ailani J, Conley RR. Evaluation of Galcanezumab for the Prevention of Episodic Migraine: The EVOLVE-1 Randomized Clinical Trial. JAMA neurology. Sep 1 2018;75(9):1080-1088. PMID 29813147
13. Skljarevski V, Matharu M, Millen BA, Ossipov MH, Kim BK, Yang JY. Efficacy and safety of galcanezumab for the prevention of episodic migraine: Results of the EVOLVE-2 Phase 3 randomized controlled clinical trial. Cephalalgia : an international journal of headache. Jul 2018;38(8):1442-1454. PMID 29848108
14. Loder EW, Robbins MS. Monoclonal Antibodies for Migraine Prevention: Progress, but Not a Panacea.. JAMA, 2018 May 26;319(19). PMID 29800193
15. Deen M, Correnti E, Kamm K et al. Blocking CGRP in migraine patients - a review of pros and cons.. J Headache Pain, 2017 Sep 28;18(1). PMID 28948500
16. MaassenVanDenBrink A, Meijer J, Villaln CM et al. Wiping Out CGRP: Potential Cardiovascular Risks.. Trends Pharmacol. Sci., 2016 Jun 25;37(9). PMID 27338837
17. Reuter U, Goadsby PJ, Lanteri-Minet M, et al. Efficacy and tolerability of erenumab in patients with episodic migraine in whom two-to-four previous preventive treatments were unsuccessful: a randomised, double-blind, placebo-controlled, phase 3b study. Lancet (London, England). Oct 22 2018. PMID 30360965
18. Tepper S, Ashina M, Reuter U, et al. Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial. The Lancet Neurology. Jun 2017;16(6):425-434. PMID 28460892
19. Silberstein SD, Dodick DW, Bigal ME, et al. Fremanezumab for the Preventive Treatment of Chronic Migraine. The New England journal of medicine. Nov 30 2017;377(22):2113-2122. PMID 29171818
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22. Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. Apr 24 2012;78(17):1337-1345. PMID 22529202

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