Systematic review of outcomes and endpoints in acute migraine clinical trials

Carrie R. Houts; James S. McGinley; Tracy K. Nishida; Dawn C. Buse; R. J. Wirth; David W. Dodick; Peter J. Goadsby; Richard B. Lipton

doi:10.1111/head.14067

Systematic review of outcomes and endpoints in acute migraine clinical trials

Carrie R. Houts^*, James S. McGinley, Tracy K. Nishida, Dawn C. Buse, R. J. Wirth, David W. Dodick, Peter J. Goadsby, Richard B. Lipton

^*Corresponding author for this work

Research output: Contribution to journal › Review article › peer-review

27 Citations (Scopus)

Abstract

Background/Objective: To review the acute migraine clinical trial literature and provide a summary of the endpoints and outcomes used in such trials. Method: A systematic literature review, following a prespecified (but unregistered) protocol developed to adhere to recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, was conducted to understand endpoints and outcomes used in acute migraine clinical trials. Predefined terms were searched in PubMed to locate clinical trials assessing acute migraine treatments. Final database search was conducted on October 28, 2019. Identified publications were reviewed against established inclusion and exclusion criteria to determine eligibility. Data related to general trial design characteristics, sample characteristics, and outcomes and endpoints reported in each publication were extracted from eligible publications. Descriptive summaries of design features, sample characteristics, and the endpoints and outcomes employed across publications were constructed. Outcomes are presented within four broad categories: (a) pain-related outcomes (pain relief, pain freedom, etc.), (b) associated symptoms (nausea, photophobia, etc.), (c) disability/impairment/impact, (d) patient-reported outcome measures (PROMs, general health and migraine/headache-specific). Endpoint types were categorized within three broad categories: (a) change from baseline, (b) fixed timepoint, and (c) responder definitions (e.g., 50% reduction). This review focuses on a subset of recent (1998 or later) randomized and blinded publications evaluating drugs or medical devices. Results: Of 1567 publications found through the initial search and reference section reviews, 705 met criteria and were included for data extraction. Inter-rater agreement kappas for the descriptive variables extracted had an average kappa estimate of 0.86. The more recent, randomized and blinded pharmaceutical and medical device article subset includes 451 publications (451/705, 63.9%). The outcomes and endpoints varied substantially across trials, ranging from pain relief or freedom, freedom from or relief of migraine-associated symptoms, use of acute or rescue medication, and various other PROMs, including measures of satisfaction and quality of life. Within the recent randomized and blinded article subset, most articles examined ≥1 pain-related outcome (430/451, 95.3%). Of the publications that examined pain, outcomes most often used were pain relief (310/430, 72.1%), pain freedom (279/430, 64.9%), and headache recurrence (202/43,051, 47.0%) or rescue medication use (278/430, 64.9%). Associated symptoms such as nausea, photophobia, and phonophobia were more frequently measured (299/451, 66.3%) compared to most bothersome associated symptom (16/451, 3.5%), as it is a new addition to regulatory guidance. Over one-third of eligible publications examined disability/impairment (186/451, 41.2%) or ≥1 PROM (159/451, 35.3%). The definition of the endpoints used (e.g., change from baseline, fixed timepoint comparisons, categorization of “responders” to treatment based on wide variety of “responder definitions”) also differed substantially across publications. Conclusion: Acute migraine clinical trials exhibit a large amount of variability in outcomes and endpoints used, in addition to the variability in how outcomes and endpoints were used from trial-to-trial. There were some common elements across trials that align with guidance from the International Headache Society, the Food and Drug Administration and other regulatory agencies (e.g., assessing pain and associated symptoms, 2-hour post-treatment). Other aspects of acute migraine clinical trial design did not follow guidance. For example, multi-item PROMs intended to measure constructs (e.g., scales) are rarely used, the use of pain-related outcomes is inconsistent, some associated symptom assessments are idiosyncratic, and the timing of the assessment of primary endpoints is variable. The development of a core set of outcomes and endpoints for acute migraine clinical trials that are patient-centered and statistically robust could improve the conduct of individual trials, facilitate cross-trial comparisons, and better support informed treatment decisions by healthcare professionals and patients.

Original language	English
Pages (from-to)	263-275
Number of pages	13
Journal	Headache
Volume	61
Issue number	2
DOIs	https://doi.org/10.1111/head.14067
Publication status	Published - Feb 2021

Keywords

acute migraine
clinical outcome assessment
clinical trial design
endpoints
outcomes
patient-reported outcome measures

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10.1111/head.14067

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@article{6f7fcd777aa94e7ca44170e6c5a19efd,

title = "Systematic review of outcomes and endpoints in acute migraine clinical trials",

abstract = "Background/Objective: To review the acute migraine clinical trial literature and provide a summary of the endpoints and outcomes used in such trials. Method: A systematic literature review, following a prespecified (but unregistered) protocol developed to adhere to recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, was conducted to understand endpoints and outcomes used in acute migraine clinical trials. Predefined terms were searched in PubMed to locate clinical trials assessing acute migraine treatments. Final database search was conducted on October 28, 2019. Identified publications were reviewed against established inclusion and exclusion criteria to determine eligibility. Data related to general trial design characteristics, sample characteristics, and outcomes and endpoints reported in each publication were extracted from eligible publications. Descriptive summaries of design features, sample characteristics, and the endpoints and outcomes employed across publications were constructed. Outcomes are presented within four broad categories: (a) pain-related outcomes (pain relief, pain freedom, etc.), (b) associated symptoms (nausea, photophobia, etc.), (c) disability/impairment/impact, (d) patient-reported outcome measures (PROMs, general health and migraine/headache-specific). Endpoint types were categorized within three broad categories: (a) change from baseline, (b) fixed timepoint, and (c) responder definitions (e.g., 50% reduction). This review focuses on a subset of recent (1998 or later) randomized and blinded publications evaluating drugs or medical devices. Results: Of 1567 publications found through the initial search and reference section reviews, 705 met criteria and were included for data extraction. Inter-rater agreement kappas for the descriptive variables extracted had an average kappa estimate of 0.86. The more recent, randomized and blinded pharmaceutical and medical device article subset includes 451 publications (451/705, 63.9%). The outcomes and endpoints varied substantially across trials, ranging from pain relief or freedom, freedom from or relief of migraine-associated symptoms, use of acute or rescue medication, and various other PROMs, including measures of satisfaction and quality of life. Within the recent randomized and blinded article subset, most articles examined ≥1 pain-related outcome (430/451, 95.3%). Of the publications that examined pain, outcomes most often used were pain relief (310/430, 72.1%), pain freedom (279/430, 64.9%), and headache recurrence (202/43,051, 47.0%) or rescue medication use (278/430, 64.9%). Associated symptoms such as nausea, photophobia, and phonophobia were more frequently measured (299/451, 66.3%) compared to most bothersome associated symptom (16/451, 3.5%), as it is a new addition to regulatory guidance. Over one-third of eligible publications examined disability/impairment (186/451, 41.2%) or ≥1 PROM (159/451, 35.3%). The definition of the endpoints used (e.g., change from baseline, fixed timepoint comparisons, categorization of “responders” to treatment based on wide variety of “responder definitions”) also differed substantially across publications. Conclusion: Acute migraine clinical trials exhibit a large amount of variability in outcomes and endpoints used, in addition to the variability in how outcomes and endpoints were used from trial-to-trial. There were some common elements across trials that align with guidance from the International Headache Society, the Food and Drug Administration and other regulatory agencies (e.g., assessing pain and associated symptoms, 2-hour post-treatment). Other aspects of acute migraine clinical trial design did not follow guidance. For example, multi-item PROMs intended to measure constructs (e.g., scales) are rarely used, the use of pain-related outcomes is inconsistent, some associated symptom assessments are idiosyncratic, and the timing of the assessment of primary endpoints is variable. The development of a core set of outcomes and endpoints for acute migraine clinical trials that are patient-centered and statistically robust could improve the conduct of individual trials, facilitate cross-trial comparisons, and better support informed treatment decisions by healthcare professionals and patients.",

keywords = "acute migraine, clinical outcome assessment, clinical trial design, endpoints, outcomes, patient-reported outcome measures",

author = "Houts, {Carrie R.} and McGinley, {James S.} and Nishida, {Tracy K.} and Buse, {Dawn C.} and Wirth, {R. J.} and Dodick, {David W.} and Goadsby, {Peter J.} and Lipton, {Richard B.}",

note = "Funding Information: This publication was supported by the Food and Drug Administration (FDA) of the U.S. Department of Health and Human Services (HHS) as part of a financial assistance award (UG3FD006795) totaling $1,286,743 with 100 percent funded by FDA/HHS. Funding Information: CRH and TKN are full‐time employees of Vector Psychometric Group, LLC. JSM is a full‐time employee of Vector Psychometric Group, LLC and has received honoraria/payment/reimbursement from the journal Cephalalgia (biostatistics editor) and the American Headache Society (teaching course). JSM has also received research grants/support from Amgen, Inc. and the National Headache Foundation. RJW is a full‐time employee and partner of Vector Psychometric Group, LLC, a consulting company servicing numerous pharmaceutical and medical device companies. RJW has received research grant support from Amgen, Inc., the National Headache Foundation, and the US Food and Drug Administration. DCB is a part‐time employee of Vector Psychometric Group, LLC and has received grant support and honoraria from the Food and Drug Administration and the National Headache Foundation and grant support and honoraria from Allergan, Amgen, Biohaven, Lilly, Novartis and Promius/Dr. Reddys. She serves on the editorial board of Current Pain and Headache Reports. RBL has received grant support from the National Institutes of Health, the Food and Drug Administration, the National Headache Foundation, and the Migraine Research Fund. He serves as a consultant, serves as an advisory board member, has received honoraria from or conducted studies funded by Alder, Abbvie/Allergan, American Headache Society, Biohaven, Eli Lilly, eNeura Therapeutics, Lundbeck, Merck, Novartis, Pfizer, and Teva, Inc. He receives royalties from Wolff's Headache, 8th Edition (Oxford University Press, 2009). He holds stock options in eNeura Therapeutics and Biohaven. PJG reports, over the last 36 months, grants and personal fees from Amgen and Eli Lilly and Company, grant from Celgene, and personal fees from Alder Biopharmaceuticals, Aeon Biopharma, Allergan, Biohaven Pharmaceuticals Inc., Cerecin, Clexio, Electrocore LLC, eNeura, Epalex, GlaxoSmithKline, Impel Neuropharma, Lundbeck, MundiPharma, Novartis, Pfizer, Sanofi, Santara Therapeutics, Satsuma, Teva Pharmaceuticals, Trigemina Inc., WL Gore, and personal fees from MedicoLegal work, Massachusetts Medical Society, Up‐to‐Date, Oxford University Press, and Wolters Kluwer. DWD reports consulting: Amgen, Allergan, Abbvie, Eli Lilly, Novartis, Lundbeck, AEON, Clexio, Cerecin, Biohaven, Linpharma, Promius, eNeura, Impel, Theranica, WL Gore, Nocira, XoC, Zosano, Upjohn (Division of Pfizer), Pieris, Revance, Equinox. Honoraria: CME Outfitters, Curry Rockefeller Group, DeepBench, Global Access Meetings, KLJ Associates, Majallin LLC, Medlogix Communications, Miller Medical Communications, Southern Headache Society (MAHEC), WebMD Health/Medscape, Wolters Kluwer, Oxford University Press, Cambridge University Press. Research Support: Department of Defense, National Institutes of Health, Henry Jackson Foundation, Sperling Foundation, American Migraine Foundation, Patient Centered Outcomes Research Institute (PCORI). Stock Options/Shareholder/Patents/Board of Directors: Aural analytics (options), ExSano (options), Palion (options), Healint (Options), Theranica (Options), Second Opinion/Mobile Health (Options), Epien (Options/Board), Nocira (options), Ontologics (Options/Board), King‐Devick Technologies (Options/Board), Precon Health (Options/Board). Patent 17189376.1‐1466:vTitle: Botulinum Toxin Dosage Regimen for Chronic Migraine Prophylaxis. Funding Information: This publication was supported by the Food and Drug Administration (FDA) of the U.S. Department of Health and Human Services (HHS) as part of a financial assistance award (UG3FD006795) totaling $1,286,743 with 100 percent funded by FDA/HHS. We would like to thank Renee Benoit, MA, Ronit Fallek, MPA, Sabrina Howland, BA, Lindsay Olix, BA, and Julia Warren, MA, for assisting in the literature review process. Publisher Copyright: {\textcopyright} 2021 The Authors. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = feb,

doi = "10.1111/head.14067",

language = "English",

volume = "61",

pages = "263--275",

journal = "Headache",

issn = "0017-8748",

publisher = "Wiley-Blackwell",

number = "2",

}

TY - JOUR

T1 - Systematic review of outcomes and endpoints in acute migraine clinical trials

AU - Houts, Carrie R.

AU - McGinley, James S.

AU - Nishida, Tracy K.

AU - Buse, Dawn C.

AU - Wirth, R. J.

AU - Dodick, David W.

AU - Goadsby, Peter J.

AU - Lipton, Richard B.

N1 - Funding Information: This publication was supported by the Food and Drug Administration (FDA) of the U.S. Department of Health and Human Services (HHS) as part of a financial assistance award (UG3FD006795) totaling $1,286,743 with 100 percent funded by FDA/HHS. Funding Information: CRH and TKN are full‐time employees of Vector Psychometric Group, LLC. JSM is a full‐time employee of Vector Psychometric Group, LLC and has received honoraria/payment/reimbursement from the journal Cephalalgia (biostatistics editor) and the American Headache Society (teaching course). JSM has also received research grants/support from Amgen, Inc. and the National Headache Foundation. RJW is a full‐time employee and partner of Vector Psychometric Group, LLC, a consulting company servicing numerous pharmaceutical and medical device companies. RJW has received research grant support from Amgen, Inc., the National Headache Foundation, and the US Food and Drug Administration. DCB is a part‐time employee of Vector Psychometric Group, LLC and has received grant support and honoraria from the Food and Drug Administration and the National Headache Foundation and grant support and honoraria from Allergan, Amgen, Biohaven, Lilly, Novartis and Promius/Dr. Reddys. She serves on the editorial board of Current Pain and Headache Reports. RBL has received grant support from the National Institutes of Health, the Food and Drug Administration, the National Headache Foundation, and the Migraine Research Fund. He serves as a consultant, serves as an advisory board member, has received honoraria from or conducted studies funded by Alder, Abbvie/Allergan, American Headache Society, Biohaven, Eli Lilly, eNeura Therapeutics, Lundbeck, Merck, Novartis, Pfizer, and Teva, Inc. He receives royalties from Wolff's Headache, 8th Edition (Oxford University Press, 2009). He holds stock options in eNeura Therapeutics and Biohaven. PJG reports, over the last 36 months, grants and personal fees from Amgen and Eli Lilly and Company, grant from Celgene, and personal fees from Alder Biopharmaceuticals, Aeon Biopharma, Allergan, Biohaven Pharmaceuticals Inc., Cerecin, Clexio, Electrocore LLC, eNeura, Epalex, GlaxoSmithKline, Impel Neuropharma, Lundbeck, MundiPharma, Novartis, Pfizer, Sanofi, Santara Therapeutics, Satsuma, Teva Pharmaceuticals, Trigemina Inc., WL Gore, and personal fees from MedicoLegal work, Massachusetts Medical Society, Up‐to‐Date, Oxford University Press, and Wolters Kluwer. DWD reports consulting: Amgen, Allergan, Abbvie, Eli Lilly, Novartis, Lundbeck, AEON, Clexio, Cerecin, Biohaven, Linpharma, Promius, eNeura, Impel, Theranica, WL Gore, Nocira, XoC, Zosano, Upjohn (Division of Pfizer), Pieris, Revance, Equinox. Honoraria: CME Outfitters, Curry Rockefeller Group, DeepBench, Global Access Meetings, KLJ Associates, Majallin LLC, Medlogix Communications, Miller Medical Communications, Southern Headache Society (MAHEC), WebMD Health/Medscape, Wolters Kluwer, Oxford University Press, Cambridge University Press. Research Support: Department of Defense, National Institutes of Health, Henry Jackson Foundation, Sperling Foundation, American Migraine Foundation, Patient Centered Outcomes Research Institute (PCORI). Stock Options/Shareholder/Patents/Board of Directors: Aural analytics (options), ExSano (options), Palion (options), Healint (Options), Theranica (Options), Second Opinion/Mobile Health (Options), Epien (Options/Board), Nocira (options), Ontologics (Options/Board), King‐Devick Technologies (Options/Board), Precon Health (Options/Board). Patent 17189376.1‐1466:vTitle: Botulinum Toxin Dosage Regimen for Chronic Migraine Prophylaxis. Funding Information: This publication was supported by the Food and Drug Administration (FDA) of the U.S. Department of Health and Human Services (HHS) as part of a financial assistance award (UG3FD006795) totaling $1,286,743 with 100 percent funded by FDA/HHS. We would like to thank Renee Benoit, MA, Ronit Fallek, MPA, Sabrina Howland, BA, Lindsay Olix, BA, and Julia Warren, MA, for assisting in the literature review process. Publisher Copyright: © 2021 The Authors. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/2

Y1 - 2021/2

N2 - Background/Objective: To review the acute migraine clinical trial literature and provide a summary of the endpoints and outcomes used in such trials. Method: A systematic literature review, following a prespecified (but unregistered) protocol developed to adhere to recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, was conducted to understand endpoints and outcomes used in acute migraine clinical trials. Predefined terms were searched in PubMed to locate clinical trials assessing acute migraine treatments. Final database search was conducted on October 28, 2019. Identified publications were reviewed against established inclusion and exclusion criteria to determine eligibility. Data related to general trial design characteristics, sample characteristics, and outcomes and endpoints reported in each publication were extracted from eligible publications. Descriptive summaries of design features, sample characteristics, and the endpoints and outcomes employed across publications were constructed. Outcomes are presented within four broad categories: (a) pain-related outcomes (pain relief, pain freedom, etc.), (b) associated symptoms (nausea, photophobia, etc.), (c) disability/impairment/impact, (d) patient-reported outcome measures (PROMs, general health and migraine/headache-specific). Endpoint types were categorized within three broad categories: (a) change from baseline, (b) fixed timepoint, and (c) responder definitions (e.g., 50% reduction). This review focuses on a subset of recent (1998 or later) randomized and blinded publications evaluating drugs or medical devices. Results: Of 1567 publications found through the initial search and reference section reviews, 705 met criteria and were included for data extraction. Inter-rater agreement kappas for the descriptive variables extracted had an average kappa estimate of 0.86. The more recent, randomized and blinded pharmaceutical and medical device article subset includes 451 publications (451/705, 63.9%). The outcomes and endpoints varied substantially across trials, ranging from pain relief or freedom, freedom from or relief of migraine-associated symptoms, use of acute or rescue medication, and various other PROMs, including measures of satisfaction and quality of life. Within the recent randomized and blinded article subset, most articles examined ≥1 pain-related outcome (430/451, 95.3%). Of the publications that examined pain, outcomes most often used were pain relief (310/430, 72.1%), pain freedom (279/430, 64.9%), and headache recurrence (202/43,051, 47.0%) or rescue medication use (278/430, 64.9%). Associated symptoms such as nausea, photophobia, and phonophobia were more frequently measured (299/451, 66.3%) compared to most bothersome associated symptom (16/451, 3.5%), as it is a new addition to regulatory guidance. Over one-third of eligible publications examined disability/impairment (186/451, 41.2%) or ≥1 PROM (159/451, 35.3%). The definition of the endpoints used (e.g., change from baseline, fixed timepoint comparisons, categorization of “responders” to treatment based on wide variety of “responder definitions”) also differed substantially across publications. Conclusion: Acute migraine clinical trials exhibit a large amount of variability in outcomes and endpoints used, in addition to the variability in how outcomes and endpoints were used from trial-to-trial. There were some common elements across trials that align with guidance from the International Headache Society, the Food and Drug Administration and other regulatory agencies (e.g., assessing pain and associated symptoms, 2-hour post-treatment). Other aspects of acute migraine clinical trial design did not follow guidance. For example, multi-item PROMs intended to measure constructs (e.g., scales) are rarely used, the use of pain-related outcomes is inconsistent, some associated symptom assessments are idiosyncratic, and the timing of the assessment of primary endpoints is variable. The development of a core set of outcomes and endpoints for acute migraine clinical trials that are patient-centered and statistically robust could improve the conduct of individual trials, facilitate cross-trial comparisons, and better support informed treatment decisions by healthcare professionals and patients.

AB - Background/Objective: To review the acute migraine clinical trial literature and provide a summary of the endpoints and outcomes used in such trials. Method: A systematic literature review, following a prespecified (but unregistered) protocol developed to adhere to recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, was conducted to understand endpoints and outcomes used in acute migraine clinical trials. Predefined terms were searched in PubMed to locate clinical trials assessing acute migraine treatments. Final database search was conducted on October 28, 2019. Identified publications were reviewed against established inclusion and exclusion criteria to determine eligibility. Data related to general trial design characteristics, sample characteristics, and outcomes and endpoints reported in each publication were extracted from eligible publications. Descriptive summaries of design features, sample characteristics, and the endpoints and outcomes employed across publications were constructed. Outcomes are presented within four broad categories: (a) pain-related outcomes (pain relief, pain freedom, etc.), (b) associated symptoms (nausea, photophobia, etc.), (c) disability/impairment/impact, (d) patient-reported outcome measures (PROMs, general health and migraine/headache-specific). Endpoint types were categorized within three broad categories: (a) change from baseline, (b) fixed timepoint, and (c) responder definitions (e.g., 50% reduction). This review focuses on a subset of recent (1998 or later) randomized and blinded publications evaluating drugs or medical devices. Results: Of 1567 publications found through the initial search and reference section reviews, 705 met criteria and were included for data extraction. Inter-rater agreement kappas for the descriptive variables extracted had an average kappa estimate of 0.86. The more recent, randomized and blinded pharmaceutical and medical device article subset includes 451 publications (451/705, 63.9%). The outcomes and endpoints varied substantially across trials, ranging from pain relief or freedom, freedom from or relief of migraine-associated symptoms, use of acute or rescue medication, and various other PROMs, including measures of satisfaction and quality of life. Within the recent randomized and blinded article subset, most articles examined ≥1 pain-related outcome (430/451, 95.3%). Of the publications that examined pain, outcomes most often used were pain relief (310/430, 72.1%), pain freedom (279/430, 64.9%), and headache recurrence (202/43,051, 47.0%) or rescue medication use (278/430, 64.9%). Associated symptoms such as nausea, photophobia, and phonophobia were more frequently measured (299/451, 66.3%) compared to most bothersome associated symptom (16/451, 3.5%), as it is a new addition to regulatory guidance. Over one-third of eligible publications examined disability/impairment (186/451, 41.2%) or ≥1 PROM (159/451, 35.3%). The definition of the endpoints used (e.g., change from baseline, fixed timepoint comparisons, categorization of “responders” to treatment based on wide variety of “responder definitions”) also differed substantially across publications. Conclusion: Acute migraine clinical trials exhibit a large amount of variability in outcomes and endpoints used, in addition to the variability in how outcomes and endpoints were used from trial-to-trial. There were some common elements across trials that align with guidance from the International Headache Society, the Food and Drug Administration and other regulatory agencies (e.g., assessing pain and associated symptoms, 2-hour post-treatment). Other aspects of acute migraine clinical trial design did not follow guidance. For example, multi-item PROMs intended to measure constructs (e.g., scales) are rarely used, the use of pain-related outcomes is inconsistent, some associated symptom assessments are idiosyncratic, and the timing of the assessment of primary endpoints is variable. The development of a core set of outcomes and endpoints for acute migraine clinical trials that are patient-centered and statistically robust could improve the conduct of individual trials, facilitate cross-trial comparisons, and better support informed treatment decisions by healthcare professionals and patients.

KW - acute migraine

KW - clinical outcome assessment

KW - clinical trial design

KW - endpoints

KW - outcomes

KW - patient-reported outcome measures

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U2 - 10.1111/head.14067

DO - 10.1111/head.14067

M3 - Review article

AN - SCOPUS:85101080127

SN - 0017-8748

VL - 61

SP - 263

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JO - Headache

JF - Headache

IS - 2

ER -

Systematic review of outcomes and endpoints in acute migraine clinical trials

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