CAM 50129

Monoclonal Antibody Therapies for Migraine Prevention

Category:Medicine   Last Reviewed:March 2019
Department(s):Medical Affairs   Next Review:March 2020
Original Date:March 2019    

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 3 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 8 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 2 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  

Brand Name Generic Name Manufacturer Distributor BLA Approval Date
Aimovig

erenumab

Amgen

Novartis

761077

5/17/2018

Ajovy™

fremanezumab

Teva

Teva

761089

9/14/2018

Emgality™

galcanezumab

Arteus

Eli Lilly

761063

9/27/2018
 

eptizumab

Alder Bros

     

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 for the preventive treatment of episodic or chronic migraine under the following conditions:

  • The patient is ≥ 18 years of age; AND
  • Has ≥ 4 migraine headache days per month; AND
  • Has failed a trial (e.g., not effective or not tolerated) from ≥ 3 classes of prophylactic pharmacologic therapies (e.g., anti-depressants, anticonvulsants, and beta-blockers, if not contraindicated) AND;
  • Has not received botulinum toxin headache prophylaxis in the past 4 months.

Treatment with monoclonal antibodies for calcitonin gene-related peptide is considered INVESTIGATIONAL 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 a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function -- including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to 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 a technology, 2 domains are examined: the relevance and the 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 is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events 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
Clinical Context and Therapy Purpose
The purpose of mAbs for the calcitonin gene-related peptide receptor in patients who have episodic migraine 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?

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

Patients
The relevant population of interest is patients with episodic migraine.

Interventions
The therapy being considered is a mAbs for the CGRP molecule or the GCRP receptor. Subcutaneous injections in the abdomen, thigh, or upper arm are self-administered with prefilled syringes or automatic injectors. The CGRP target and dosing are described in Table 2. Higher doses are obtained by using 2 prefilled syringes or auto-injectors. 

Table 2. Humanized Monoclonal Antibodies for CGRP

Brand Name

Generic Name

Target

FDA-Approved Dose

Route

Aimovig™

erenumab

CGRP receptor

70 or 140 mg once monthly

Subcutaneous

Ajovy™

fremanezumab

CGRP molecule

225 mg monthly or 675 mg every three months

Subcutaneous

Emgality™

galcanezumab

CGRP molecule

240 mg loading dose followed by 120 mg monthly

Subcutaneous

 

eptizumab

 

 

Intravenous

CGRP: calcitonin gene-related peptide  

Comparators
The following therapies are currently used for migraine prevention:

Oral medications approved by the U.S. Food and Drug Administration (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 quality of life (see Table 3). The most common outcome measures are 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. 

Table 3. Patient-Reported Outcome Measures

Outcome Measure

Abbreviation

Description

Monthly Migraine Days

MMD

The average number of days that there is onset or continuation of a migraine headache. Outcomes are typically reported as a decrease in MMD.

50% Decrease in MMD

50% MMD

The proportion of people who achieve a decrease of 50% in MMD. Also frequently reported are 75% and 100% decrease in MMD.

Migraine Physical Function Impact Diary3

MPFID

Impact of migraine on function. This is an electronic diary developed and validated by Amgen and used in the erenumab trials.

Migraine Disability Assessment4

MIDAS

Report of the number of days that a headache has impacted function at home, work, or school.

Headache Impact Test5

HIT-6

Six-item measure of the impact of headache on social, role, and cognitive function and psychological distress.

Migraine Specific Quality of Life Questionnaire6

MSQL

Migraine specific quality of life questionnaire.

Timing
The acute effect of mAbs on migraine severity and frequency should be measured over 3 to 6 months. Safety and long-term efficacy may be observed at 1 to 2 years.

Setting
The setting is outpatient care by a specialist in migraine headache (e.g., neurologist).

Randomized Controlled Trials
Five multi-center pivotal trials with over 4,000 adults with episodic migraine have been published for erenumab, fremanezumab, and galcanezumab (see Table 4). The average number of migraine days per month ranged from 8.3 to 9.1 in these studies (see Table 5). 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 2 or 3 classes of preventive treatments.

Table 4. Summary of Key RCT Characteristics

Study; Trial

Countries

Sites

Dates

Participants

Interventions

 

 

 

 

 

Active

Comparator

Dodick et al. (2018)7; ARISE

U.S., EU

69

2015-2016

577 adults with episodic migraine occurring on 4 to 14 days per month

n=286 Erenumab 70 mg/monthly subcutaneous injection

n=291 Placebo monthly subcutaneous injection

Goadsby et al. (2017)8; STRIVE

U.S., EU

121

2015-2016

955 adults with episodic migraine occurring on 4 to 14 days per month

Erenumab 70 mg (n=317) or 140 mg (n=319) monthly subcutaneous injection

n=319 Placebo monthly subcutaneous injection

Dodick et al. (2018)9

U.S., EU, Canada, Israel, Japan, Russia

123

2016 -2017

875 adults with episodic migraine occurring on 6 to 14 days per month

Fremanezumab 225 mg (n=290) monthly or 675 mg (n=291) single subcutaneous injection

n=294 Placebo monthly subcutaneous injection

Stauffer et al. (2018)10; EVOLVE-1

U.S. and Canada

90

2016-2017

858 adults with episodic migraine headache occurring on 4 to 14 days per month

Galcanezumab 120 mg (n=213) or 240 mg (n=212) monthly subcutaneous injection

n=433 Placebo monthly subcutaneous injection

Skljarevski et al. (2018) EVOLVE-211

U.S., EU, Israel, Asia, Central America, South America

109

2016-2017

915 adults with episodic migraine headache occurring on 4 to 14 days per month

Galcanezumab 120 mg (n=226) or 240 mg (n=239) monthly subcutaneous injection

n=450 Placebo monthly subcutaneous injection

RCT: randomized controlled trial.

Table 5. Summary of Clinical Characteristics

Study; Trial

Age

Migraine Preventative Medication Use %

History of Preventive Treatment Failure %

Migraine Days per Month (SD)

Key Exclusion Criteria

 

 

None

Previous

Current

 

 

 

Dodick et al. (2018)7; ARISE

18-65

50.9

43.0

6.1

40.2

8.3 (2.6)

Failure of 3 classes of preventive treatments

Goadsby et al. (2017)8; STRIVE

18-65

56.5

40.6

2.8

38.7

8.3 (2.5)

Failure of 3 classes of preventive treatments

Dodick et al. (2018)9

18-70

 

19.2a

21

 

9.1 (2.6)

Failure of 2 classes of preventive treatments

Stauffer et al. (2018)10; EVOLVE-1

18-65

 

60.0

0

18.5

9.1 (3.0)

Failure of 3 classes of preventive treatments

Skljarevski et al. (2018) EVOLVE-211

18-65

 

65.5

0

14.3

9.1 (2.9)

Failure of 3 classes of preventive treatments

aReported only for prior topiramate use

Patients receiving injections of a GCRP 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 adverse events ranged from 1.9% to 2.5%.

Table 6. Summary of Key RCT Results

Study

Change in Monthly Migraine Days (SE)

>50% Reduction in Monthly Migraine Days n (%)

Change in Monthly Acute Migraine-Specific Medication Days (SE or 95% CI)

Physical Impairment and Quality of Life (SE or 95% CI)

Grade 3 or Serious Adverse Events n (%)

Dodick et al. (2018)7; ARISE

 

 

 

MPFID-PI≥5-point Reduction

 

N

570

570

570

570

572

Erenumab

-2.9

112 (39.7)

-1.2

93 (33.0%)

6 (2.1)

Placebo

-1.8

85 (29.5)

-0.6

78 (27.1%)

8 (2.8)

Diff/OR (95% CI)

Diff -1.0 (-1.6 to -0.5)

OR: 1.59 (1.12, 2.27)

Diff: -0.6 (-1.0to -0.2)

OR: 1.33 (0.92 to 1.90)

 

P Value

<0.001

0.010

0.002

0.13

 

Goadsby et al. (2017)8; STRIVE

 

 

 

MPFID-PIChange from Baseline (SE)

 

Erenumab 70 mg

-3.2 (0.2)

135 (43.3)

-1.1 (0.1)

−4.8 (0.4)

8 (2.5)

Erenumab 140 mg

-3.7 (0.2)

159 (50.0)

-1.6 (0.1)

−4.2 (0.4)

6 (1.9)

Placebo

-1.8 (0.2)

84 (26.6)

-0.2 (0.1)

−2.4 (0.4)

7 (2.2)

Diff/OR (95%CI) for 70 mg

−1.4 (−1.9 to −0.9)

2.1 (1.5 to 3.0)

−0.9 (−1.2 to −0.6)

−1.9 (−3.0 to −0.8)

 

Diff/OR (95%CI) for 140 mg

−1.9 (−2.3 to −1.4)

2.8 (2.0 to 3.94)

−1.4 (−1.7 to −1.1)

−2.4 (−3.5 to −1.4)

 

P Value

<0.001

<0.001

<0.001

<0.001

 

Dodick et al. (2018)

 

 

 

 

 

N

865

865

865

865

874

Fremanezumab 225 mg monthly

−3.7 (−4.2 to −3.2)

137 (47.7)

−3.0 (−3.4 to −2.6)

−24.6 (−27.7 to −21.5)

3 (1.0)

Fremanezumab 675 mg once

−3.4 (−3.9 to −3.0)

128 (44.4)

−2.9 (−3.3 to −2.5)

−23.0 (−26.1 to −19.8)

3 (1.0)

Placebo

−2.2 (−2.7 to −1.7)

81 (27.9)

−1.6 (−2.0 to −1.2)

−17.5 (−20.6 to −14.5)

7 (2.4)

Diff for 225 mg

−1.5 (−2.0 to −0.9)

19.8 (12.0 to 27.6)

−1.4 (−1.8 to −0.9)

−7.0 (−10.5 to −3.5)

 

Diff for 675 mg

−1.3 (−1.8 to −0.7)

16.5 (8.9 to 24.1)

−1.3 (−1.8 to −0.8)

−5.4 (−8.9 to −1.9)

 

P Value

<0.001

<0.001

<0.001

<0.001

 

Stauffer et al. (2018) EVOLVE-1

 

 

 

MSQRFR

 

Galcanezumab 120 mg

-4.7

62.3

−4.0

32.4

6 (2.9)

Galcanezumab 240 mg

-4.6

60.9

−3.8

32.1

0

Placebo

-2.8

38.6

−2.2

24.7

5 (1.2)

Diff/OR for 120 mg

−1.9 (−2.5 to −1.4)

2.6 (2.0-3.4)

−1.8 (−2.3 to −1.3)

7.7 (5.2-10.3)

 

Diff/OR for 240 mg

−1.8 (−2.3 to −1.2)

2.5 (1.9-3.2)

−1.6 (−2.1 to −1.1)

7.4 (4.8-10.0)

 

P Value

<.001

<.001

<.001

<.001

 

Skljarevski et al. (2018) EVOLVE-211

 

 

 

MSQRFR

 

N

896

896

896

896

 

Galcanezumab 120 mg

-4.3 (-4.8 to -3.8)

59.3 (55 to 64)

-3.7 (-4.1 to -3.2)

-28.5 (26.2 to 30.7)

5 (2.2)

Galcanezumab 240 mg

-4.2 (-4.7 to -3.7)

56.5 (52 to 61)

-3.6 (-4.1 to -3.2)

-27.0 (24.7 to 29.3)

7 (3.1)

Placebo

-2.3

36 (33 to 39)

-1.9 (-2.2 to -1.5)

-19.7 (17.9 to 21.5)

5 (1.1)

Diff vs 120 mg

-2.0

23.3

-1.8

-8.8

 

P Value

<0.001

<0.001

<0.001

<0.001

 

Range

-1.0 to -2.0 days compared to placebo

Placebo: 27.9 to 38.6

mAbs: 39.7 to 62.3%

-0.6 to -1.8 days compared to placebo

 

Placebo: 1.1% to 2.4% mAbs:1.0% to 3.1%

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

No major gaps were identified in study design and conduct. A gap in relevance for these studies is the short-term follow-up for a treatment that might be given indefinitely, with uncertainty for long-term benefits and harms (see Table 7). Some trials may have ongoing follow-up of patients after the double-blind phase.

Table 7. Relevance Gaps

Study

Populationa

Interventionb

Comparatorc

Outcomesd

Follow-Upe

Dodick et al. (2018)7; ARISE

 

 

 

 

1, 2, 3 mo follow-up is insufficient to establish long-term efficacy or harms

Goadsby et al. (2017)8; STRIVE

 

 

 

 

1, 2, 6 mo follow-up is insufficient to establish long-term efficacy or harms

Dodick et al. (2018)9

 

 

 

 

1, 2, 3 mo follow-up is insufficient to establish long-term efficacy or harms

Stauffer et al. (2018)10; EVOLVE-1

 

 

 

 

1, 2, 6 mo follow-up is insufficient to establish long-term efficacy or harms

Skljarevski et al. (2018)EVOLVE-211

 

 

 

 

1, 2, 6 mo follow-up is insufficient to establish long-term efficacy or harms

The evidence gaps stated in this table are those notable in the current review; this is not a comprehensive gaps 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 established 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
Pivotal trials with over 4,000 adults have been published with CGRP mAbs for the treatment of episodic migraine. All of the studies excluded patients who had failed at least 2 or 3 classes of preventive treatments. Patients receiving injections of a GCRP mAb had an average decrease of 2.9 to 4.7 monthly migraine days, while the placebo group had a decrease in an average of 1.8 to 2.8 monthly migraine days. This resulted in an improvement of 1.0 to 2.0 monthly migraine days with the CGRP mAbs. The odds ratio for a 50% decrease in monthly migraine days ranged from 1.6 to 2.8. The most common adverse event was injection site pain. Because of the short follow-up of the trials to date, there is uncertainty regarding long-term benefits and harms; serious adverse events during the study periods were similar to placebo (1.0% to 3.1%).

Episodic Migraine not responsive to standard pharmacologic preventive therapy
Clinical Context and Therapy Purpose
The purpose of human monoclonal antibody for the calcitonin gene-related peptide 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 GCRP mAbs improve health outcomes in patients who have episodic migraine not responsive to standard pharmacologic preventive therapy?

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

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

Interventions
The therapy being considered is a CGRP mAb 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 therapy.

Outcomes
The general outcomes of interest are migraine intensity and frequency, the effect of the migraines or treatment on quality of life as measured by instruments such as the SF-12, hospitalizations due to migraine, and adverse effects of the monoclonal antibody (see Table 3).

Timing
Migraine severity and frequency are measured over 3 to 6 months.

Setting
The setting is outpatient care by a specialist in migraine headache (e.g., neurologist).

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). 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 placebo (-3.5, p=0.003).

Table 8. Summary of Key RCT Characteristics

Study; Trial

Countries

Sites

Dates

Participants

Interventions

 

 

 

 

 

Active

Comparator

Reuter et al. (2018)12; LIBERTY

Australia, EU

59

March - October 2017

246 patients with 4 to 14 migraine days per month and failure of 2 to 4 preventive treatments

n=121 erenumab 140 mg monthly subcutaneous injection for 12 weeks

n=125 placebo subcutaneous injections (2 filled syringes once per month)

RCT: randomized controlled trial.

Table 9. Summary of Clinical Characteristics

Study; Trial

Age

Failure of 2 Preventive Treatments %

Failure of 3 Preventive Treatments %

Failure of 4 Preventive Treatments %

Migraine Days per Month (SD)

Reuter et al. (2018)12; LIBERTY

18-65

39

38

23

9.3 (2.7)

Table 10. Summary of Key RCT Results 

Study

>50% Reduction in Monthly Migraine Days n (%)

>75% Reduction in Monthly Migraine Days n (%)

Change in Monthly Migraine Days n (SE)

MPFID Physical Impairment (SE)

Grade 3or Serious Adverse Events n (%)

Reuter et al. (2018)12; LIBERTY

 

 

 

 

 

N

243

243

243

243

 

Erenumab

36 (30%)

14 (12%)

-1.8 (0.4)

-1.9 (0.8)

2 (2)

Placebo

17 (14%)

5 (4%)

-0.2 (0.2)

1.6 (0.8)

1 (1)

OR/DIFF (95% CI)

OR 2.7 ( 1.4-5.2)

OR 3.2 (1.1-9.0)

DIF: -1.6 (-2.7 to -0.5)

DIFF -3.5 (-5.7 to -1.2)

 

P Value

0.002

0.025

0.004

0.003

 

CI: confidence interval; HR: hazard ratio; MPFID: Migraine Physical Function Impact Diary; NNT: number needed to treat; OR: odds ratio; RCT: randomized controlled trial; RR: relative risk.
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. 

Gaps in relevance and design and conduct of this trial are described in Tables 11 and 12.

Table 11. Relevance Gaps

Study

Populationa

Interventionb

Comparatorc

Outcomesd

Follow-Upe

Reuter et al. (2018)12; LIBERTY

 

 

 

 

1, 2, 3 months is insufficient to establish long-term efficacy or harms 

The evidence gaps stated in this table are those notable in the current review; this is not a comprehensive gaps 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 2 to 4 other preventive 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 placebo. A limitation of this body of evidence is that only one trial with 246 patients specifically evaluated GCRP mAbs for treatment-resistant migraines. Other trials, however, included some proportion of patients who had failed up to 3 other preventive treatments. In ARISE and STRIVE, about 40% of patients had a history of preventive treatment failure.

Chronic Migraine
Clinical Context and Therapy Purpose
The purpose of human monoclonal antibody for the calcitonin gene-related peptide receptor in patients who have chronic migraine 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 monoclonal antibody for CGRP improve health outcomes in patients who have chronic migraine?

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

Patients
The relevant population of interest is patients with chronic migraine.

Interventions
The therapy being considered is mAbs for GCRP (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 U.S. Food and Drug Administration (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 quality of life (see Table 3). The most common outcome measures are 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.

Timing
Migraine severity and frequency are measured on the last month of 3 to 6 months of treatment.

Setting
The setting is outpatient care by a specialist in migraine headache (e.g., neurologist).

Randomized Controlled Trials
Three multicenter RCTs with 3 different mAbs, two of which had over 1,000 patients, have been identified on GCRP 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 2 or 3 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 GCRP 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).

Table 13. Summary of Key RCT Characteristics

Study; Trial

Countries

Sites

Dates

Participants2

Interventions1

Tepper et al. (2017)13

U.S., Canada, EU

69

2014-2016

667 patients with chronic migraine ≥15 days/month

Erenumab 70 mg (n=191), or erenumab 140 mg (n=190) monthly

n=286 Placebo injections monthly

Silberstein et al. (2017)14

U.S., EU

132

2016-2017

1,130 patients with chronic migraine ≥15 days/month

Fremanezumab 225 mg monthly (n=379), frenamezumab 675 mg quarterly (n=276)

n=375 Placebo injections monthly

Emgality Study-3 (2018)15

 

 

 

1,113 patients with chronic migraine ≥15 days/month

Galcanezumab 120 mg (n=252), galcanezumab 240 (n=367) mg monthly

n=494 Placebo injections monthly

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

Table 14. Summary of Clinical Characteristics

Study; Trial

Age

Migraine Preventive Medication Use %

History of Preventive Treatment Failure %

Migraine Days per Month (SD)

Key Exclusion Criteria

 

 

None

Previous

Current

 

 

 

Tepper et al. (2017)13

18-65

33

67

 

49% failed ≥ 2 drugs

18.0 (4.6)

Failure of >3 classes of preventive treatments

Silberstein et al. (2017)14

18-70

 

30a

21

 

16.2 (5.1)

Failure of ≥2 classes of preventive treatments

Emgality study-3 (2018)15

18-65

 

 

15

 

19.5

 

aPrevious use of topiramate

Table 15. Summary of Key RCT Results

Study

Change in Monthly Migraine Days (SE)

>50% Reduction in Monthly Migraine Days n (%)

Change in Monthly Acute Migraine-Specific Medication Days (SE or 95% CI)

Function

Grade 3 or Serious Adverse Events %

Tepper et al. (2017)13,

 

 

 

 

 

N

656

656

656

 

 

Erenumab 70 mg

-6.6 (0.4)

75 (40)

-3.5 (0.3)

 

3

Erenumab 140 mg

-6.6 (0.4)

77 (41)

-4.1 (0.3)

 

1

Placebo

-4.2 (0.4)

66 (23)

-1.6 (0.2)

 

2

Diff/OR vs 70 mg

-2.5 (-3.5 to -1.4)

2.2 (1.5 to 3.3)

-1.9 (-2.6 to -1.1)

 

 

Diff/OR vs 140 mg

-2.5 (-3.5 to -1.4)

2.3 (1.6 to 3.5)

-2.6 (-3.3 to -1.8)

 

 

P Value

<0.001

<0.001

<0.001

 

 

Silberstein et al. (2017)14,

 

 

 

Change in HIT-6 Score (SE)

 

N

1121

1121

1121

1121

 

Fremanezumab monthly

-4.6 (0.3)

153 (41)

-4.2 (0.3)

-6.8 (0.4)

1

Fremanezumab quarterly

-4.3 (0.3)

141 (38)

-3.7 (0.3)

-6.4 (0.5)

<1

Placebo

-2.5 (0.3)

67 (18)

-1.9 (0.3)

-4.5 (0.5)

2

Diff monthly (SE)

-2.1 (0.3)

 

-2.3 (0.3)

-2.4 (0.5)

 

Diff quarterly (95% CI)

-1.8 (0.3)

 

-1.8 (0.3)

-1.9 (0.5)

 

P Value

<0.001

<0.001

<0.001

 

 

Emgality study-3 (2018)15,

 

 

 

MSQL Role Function

 

Galcanezumab

-4.8

28

-4.7

21.8

 

Placebo

-2.7

15

-2.2

16.8

 

Diff

-2.1

13

-2.5

5.0

 

P Value

<0.001

<0.001

<0.001

<0.001

 

Summary Range

-2.1 to -2.5

13 to 23

-1.8 to -2.6

 

1 to 3

CI: confidence interval; HIT-6: Headache Impact Test; MSQL: Migraine-specific quality of life; NNT: number needed to treat; OR: odds ratio; RCT: randomized controlled trial; RR: relative risk.

No major gaps were identified in study design and conduct. The major gap in relevance of these studies is the short-term follow-up for a treatment that might be given indefinitely (see Table 16), with uncertainty regarding long-term benefits and harms. 

Table 16. Relevance Gaps

Study

Populationa

Interventionb

Comparatorc

Outcomesd

Follow-Upe

Tepper et al. (2017)13

 

 

 

 

1, 2, 3 mo follow-up is insufficient to establish long-term efficacy or harms

Silberstein et al. (2017)14

 

 

 

 

1, 2, 3 mo follow-up is insufficient to establish long-term efficacy or harms

Emgality Study-3 (2018)15

 

 

 

 

1, 2, 3 mo follow-up is insufficient to establish long-term efficacy or harms

The evidence gaps stated in this table are those notable in the current review; this is not a comprehensive gaps 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 established 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
Three multicenter RCTs, with a total of nearly 3,000 adult patients, have been identified on GCRP mAbs for the preventive treatment of chronic migraine. Compared to controls, GCRP 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. Serious adverse events during the study period were low. There is uncertainty, however, regarding long-term benefits and harms due to the short follow-up to date.

Chronic Migraine not responsive to standard pharmacologic preventive therapy
Clinical Context and Therapy Purpose
The purpose of human monoclonal antibody 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 PICOTS were used to select literature to inform this review.

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

Interventions
The therapy being considered is a human monoclonal antibody 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 quality of life as measured by instruments such as the SF-12, hospitalizations due to migraine, and adverse effects of the treatment (see Table 3).

Timing
Migraine severity and frequency are measured over 6 to 12 months.

Setting
The setting is outpatient care by a specialist in migraine headache (e.g., neurologist).

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).13

Section Summary: Chronic Migraine Not Responsive to Standard Pharmacologic Preventive Therapy
No trials were identified that included only patients with chronic migraine not responsive to standard pharmacologic preventive therapy. The high percentage of patients who had failed pharmacologic therapies in the chronic migraine trials suggests that mAbs would be effective in patients who have failed 2 to 3 classes of pharmacologic treatment.

Summary of Evidence
For individuals who have episodic migraine who receive CGRP mAbs, the evidence includes pivotal 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 FDA 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 who failed 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 FDA 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 3 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.

Practice Guidelines and Position Statements 
American Academy of Neurology American Headache Society and
In 2012, the American Academy of Neurology and the American Headache Society (AAN/AHA) published guidelines on therapies for migraine prevention.16 Recommended pharmacologic treatments for episodic migraine prevention are described in Table 17. These guidelines were reaffirmed in 2015. 

Table 17. Recommended Pharmacologic Treatments for Episodic Migraine Prevention

Class

Drugs

LOE

Recommendation

Antidepressants

Amitriptyline and venlafaxine

B

Probably Effective

Antieleptics

Divalproex sodium, sodium valproate, and topiramate

A

Established as Effective

Beta-Blockers

Metoprolol, propranolol, and timolol

A

Established as Effective

 

Atenolol and nadolol

B

Probably Effective

Triptans

Fovatriptan for MAMs

A

Established as Effective

 

Naratriptan and zolmitriptan for MAMs

B

Probably Effective

MAM: menstrually associated migraines

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 18.

Table 18. Summary of Key Trials

NCT No.

Trial Name

Planned Enrollment

Completion Date

Ongoing

 

 

 

NCT02614261a

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of LY2951742 [galcanezumab] in Patients With Chronic Migraine - the REGAIN Study

1,113

May 2021

NCT02638103a

A Multicenter, Randomized, Double-Blind, Parallel-Group Study Evaluating the Long-Term Safety, Tolerability, and Efficacy of Subcutaneous Administration of TEV-48125 [fremanezumab] for the Preventive Treatment of Migraine

1,890

Dec 2018

Unpublished

 

 

 

NCT02621931a

A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study Comparing the Efficacy and Safety of 2 Dose Regimens of Subcutaneous Administration of TEV-48125 [fremanezumab] Versus Placebo for the Preventive Treatment of Chronic Migraine

1,130

Apr 2017 (Completed)

NCT02559895a

A Parallel Group, Double-Blind, Randomized, Placebo-Controlled, Trial to Evaluate the Efficacy and Safety of ALD403 [eptizezumab] Administered Intravenously in Patients With Frequent Episodic Migraines (PROMISE 1)

900

Dec 2017 (Completed)

NCT02974153 a

A Parallel Group, Double-Blind, Randomized, Placebo-Controlled Phase 3 Trial to Evaluate the Efficacy and Safety of ALD403 [eptizezumab] Administered Intravenously in Patients With Chronic Migraine (PROMISE 2)

1,121

Apr 2018 (Completed)

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

References 

  1. Burch R, Rizzoli P, Loder E. The Prevalence and Impact of Migraine and Severe Headache in the United States: Figures and Trends From Government Health Studies. Headache. Apr 2018;58(4):496-505. PMID 29527677
  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. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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
  13. 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
  14. 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
  15. U.S. Food and Drug Administration. Emgality label. 2018; https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761063s000lbl.pdf. Accessed November 12, 2018.
  16. 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

Coding Section  

Codes

Number

Description

CPT

No code

 

HCPCS

 

See Policy Guidelines

 

J3031 (effective 10/01/19 

Injection, fremanezumab-vfrm, 1 mg (code may be used for Medicare when drug administered under the direct supervision of a physician, not for use when drug is self-administered) 

ICD-10-CM

G43.001-G43.919

Migraine Diagnosis Range

ICD-10-PCS

 

ICD-10-PCS codes are only used for inpatient services. There is no specific ICD-10-PCS code for this procedure

Type of Service

Medicine

 

Place of Service

Outpatient/Home

 

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each Policy. They may not be all-inclusive.  

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association.  All Rights Reserved" 

History From 2018 Forward     

10/03/2019 

Updating coding. No other changes made. 

03/19/2019

New Policy


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