Systematic review of outcomes and endpoints in preventive migraine clinical trials

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

doi:10.1111/head.14069

Systematic review of outcomes and endpoints in preventive migraine clinical trials

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

^*Corresponding author for this work

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

36 Citations (Scopus)

Abstract

Background: Over the last six decades (earliest included publication from 1959), clinical trials of migraine preventive treatments have led to the regulatory approval of many medications and devices. Despite similar clinical goals, the outcomes and endpoints used in these trials are broad and not well standardized. Objective: To describe results from a systematic literature review focused on outcomes and endpoints used in preventive migraine clinical trials. Method: A systematic literature review, following a pre-specified (unregistered) protocol developed to adhere to recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, was conducted to characterize the endpoints and outcomes used in preventive migraine clinical trials. Predetermined terms were searched in PubMed on October 28, 2019. Data related to trial design, subject characteristics, outcomes, and endpoints reported in each publication were extracted. Descriptive summaries of these features were tabulated for the recent subset of publications, published during or after 1988, that were randomized, blinded, and focused on pharmacological or device therapies for the preventive treatment of migraine. Results: The initial literature search identified 1506 publications, of which 757 publications were eligible for data extraction. Of specific clinical interest were the recent subset of 268 articles (268/757, 35.4%) fulfilling the targeted criteria. Results showed that the outcomes used to define endpoints varied substantially across publications. For example, in the recent subset of publications, 68.7% (184/268) of the publications examined ≥1 migraine-specific outcome, 39.6% (106/268) examined ≥1 headache-specific outcome, 50.7% (136/268) examined ≥1 acute/rescue medication use outcome, 40.3% (108/268) examined ≥1 headache-related patient-reported outcome measure (PROM), and 22.0% (59/268) examined ≥1 non-headache-specific PROM. Furthermore, 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 across publications. Conclusion: Publications from clinical trials of preventive migraine pharmacologic and device treatments differed in terms of study design, endpoint definitions, and how endpoints and outcomes were measured. Although there were common outcomes and endpoints used across publications, no clear “standardized” set of endpoints and outcomes emerged. The inconsistencies in endpoints and outcomes within this literature suggest that the development of a uniform set of outcomes and endpoints could improve the clinical meaningfulness of clinical trial results, facilitate cross-trial comparisons and better inform patient care. This standard set of outcomes and endpoints should be statistically robust and informed by the priorities of various stakeholders, most importantly, the needs and preferences of people living with migraine.

Original language	English
Pages (from-to)	253-262
Number of pages	10
Journal	Headache
Volume	61
Issue number	2
DOIs	https://doi.org/10.1111/head.14069
Publication status	Published - Feb 2021

Keywords

clinical outcome assessment
clinical trial design
endpoints
outcomes
patient reported outcome measures
preventive migraine

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10.1111/head.14069

Cite this

@article{42c15ed35e134668a3b92bc66fde6f08,

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

abstract = "Background: Over the last six decades (earliest included publication from 1959), clinical trials of migraine preventive treatments have led to the regulatory approval of many medications and devices. Despite similar clinical goals, the outcomes and endpoints used in these trials are broad and not well standardized. Objective: To describe results from a systematic literature review focused on outcomes and endpoints used in preventive migraine clinical trials. Method: A systematic literature review, following a pre-specified (unregistered) protocol developed to adhere to recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, was conducted to characterize the endpoints and outcomes used in preventive migraine clinical trials. Predetermined terms were searched in PubMed on October 28, 2019. Data related to trial design, subject characteristics, outcomes, and endpoints reported in each publication were extracted. Descriptive summaries of these features were tabulated for the recent subset of publications, published during or after 1988, that were randomized, blinded, and focused on pharmacological or device therapies for the preventive treatment of migraine. Results: The initial literature search identified 1506 publications, of which 757 publications were eligible for data extraction. Of specific clinical interest were the recent subset of 268 articles (268/757, 35.4%) fulfilling the targeted criteria. Results showed that the outcomes used to define endpoints varied substantially across publications. For example, in the recent subset of publications, 68.7% (184/268) of the publications examined ≥1 migraine-specific outcome, 39.6% (106/268) examined ≥1 headache-specific outcome, 50.7% (136/268) examined ≥1 acute/rescue medication use outcome, 40.3% (108/268) examined ≥1 headache-related patient-reported outcome measure (PROM), and 22.0% (59/268) examined ≥1 non-headache-specific PROM. Furthermore, 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 across publications. Conclusion: Publications from clinical trials of preventive migraine pharmacologic and device treatments differed in terms of study design, endpoint definitions, and how endpoints and outcomes were measured. Although there were common outcomes and endpoints used across publications, no clear “standardized” set of endpoints and outcomes emerged. The inconsistencies in endpoints and outcomes within this literature suggest that the development of a uniform set of outcomes and endpoints could improve the clinical meaningfulness of clinical trial results, facilitate cross-trial comparisons and better inform patient care. This standard set of outcomes and endpoints should be statistically robust and informed by the priorities of various stakeholders, most importantly, the needs and preferences of people living with migraine.",

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

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

note = "Funding Information: CRH, TKN, and RJW 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). JSM has also received research grants/support from Amgen, Inc. and the National Headache Foundation. DCB is a part‐time employee of Vector Psychometric Group, LLC which has received a grant from the Food and Drug Administration for the MICOAS research project and has received grant support from 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 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. The contents are those of the authors and do not necessarily represent the official views of, nor an endorsement, by FDA/HHS, or the U.S. Government. Publisher Copyright: {\textcopyright}2021 Vector Psychometric Group, LLC. 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.14069",

language = "English",

volume = "61",

pages = "253--262",

journal = "Headache",

issn = "0017-8748",

publisher = "Wiley-Blackwell",

number = "2",

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TY - JOUR

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

AU - McGinley, James S.

AU - Houts, Carrie R.

AU - Nishida, Tracy K.

AU - Buse, Dawn C.

AU - Lipton, Richard B.

AU - Goadsby, Peter J.

AU - Dodick, David W.

AU - Wirth, R. J.

N1 - Funding Information: CRH, TKN, and RJW 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). JSM has also received research grants/support from Amgen, Inc. and the National Headache Foundation. DCB is a part‐time employee of Vector Psychometric Group, LLC which has received a grant from the Food and Drug Administration for the MICOAS research project and has received grant support from 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 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. The contents are those of the authors and do not necessarily represent the official views of, nor an endorsement, by FDA/HHS, or the U.S. Government. Publisher Copyright: ©2021 Vector Psychometric Group, LLC. 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: Over the last six decades (earliest included publication from 1959), clinical trials of migraine preventive treatments have led to the regulatory approval of many medications and devices. Despite similar clinical goals, the outcomes and endpoints used in these trials are broad and not well standardized. Objective: To describe results from a systematic literature review focused on outcomes and endpoints used in preventive migraine clinical trials. Method: A systematic literature review, following a pre-specified (unregistered) protocol developed to adhere to recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, was conducted to characterize the endpoints and outcomes used in preventive migraine clinical trials. Predetermined terms were searched in PubMed on October 28, 2019. Data related to trial design, subject characteristics, outcomes, and endpoints reported in each publication were extracted. Descriptive summaries of these features were tabulated for the recent subset of publications, published during or after 1988, that were randomized, blinded, and focused on pharmacological or device therapies for the preventive treatment of migraine. Results: The initial literature search identified 1506 publications, of which 757 publications were eligible for data extraction. Of specific clinical interest were the recent subset of 268 articles (268/757, 35.4%) fulfilling the targeted criteria. Results showed that the outcomes used to define endpoints varied substantially across publications. For example, in the recent subset of publications, 68.7% (184/268) of the publications examined ≥1 migraine-specific outcome, 39.6% (106/268) examined ≥1 headache-specific outcome, 50.7% (136/268) examined ≥1 acute/rescue medication use outcome, 40.3% (108/268) examined ≥1 headache-related patient-reported outcome measure (PROM), and 22.0% (59/268) examined ≥1 non-headache-specific PROM. Furthermore, 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 across publications. Conclusion: Publications from clinical trials of preventive migraine pharmacologic and device treatments differed in terms of study design, endpoint definitions, and how endpoints and outcomes were measured. Although there were common outcomes and endpoints used across publications, no clear “standardized” set of endpoints and outcomes emerged. The inconsistencies in endpoints and outcomes within this literature suggest that the development of a uniform set of outcomes and endpoints could improve the clinical meaningfulness of clinical trial results, facilitate cross-trial comparisons and better inform patient care. This standard set of outcomes and endpoints should be statistically robust and informed by the priorities of various stakeholders, most importantly, the needs and preferences of people living with migraine.

AB - Background: Over the last six decades (earliest included publication from 1959), clinical trials of migraine preventive treatments have led to the regulatory approval of many medications and devices. Despite similar clinical goals, the outcomes and endpoints used in these trials are broad and not well standardized. Objective: To describe results from a systematic literature review focused on outcomes and endpoints used in preventive migraine clinical trials. Method: A systematic literature review, following a pre-specified (unregistered) protocol developed to adhere to recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, was conducted to characterize the endpoints and outcomes used in preventive migraine clinical trials. Predetermined terms were searched in PubMed on October 28, 2019. Data related to trial design, subject characteristics, outcomes, and endpoints reported in each publication were extracted. Descriptive summaries of these features were tabulated for the recent subset of publications, published during or after 1988, that were randomized, blinded, and focused on pharmacological or device therapies for the preventive treatment of migraine. Results: The initial literature search identified 1506 publications, of which 757 publications were eligible for data extraction. Of specific clinical interest were the recent subset of 268 articles (268/757, 35.4%) fulfilling the targeted criteria. Results showed that the outcomes used to define endpoints varied substantially across publications. For example, in the recent subset of publications, 68.7% (184/268) of the publications examined ≥1 migraine-specific outcome, 39.6% (106/268) examined ≥1 headache-specific outcome, 50.7% (136/268) examined ≥1 acute/rescue medication use outcome, 40.3% (108/268) examined ≥1 headache-related patient-reported outcome measure (PROM), and 22.0% (59/268) examined ≥1 non-headache-specific PROM. Furthermore, 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 across publications. Conclusion: Publications from clinical trials of preventive migraine pharmacologic and device treatments differed in terms of study design, endpoint definitions, and how endpoints and outcomes were measured. Although there were common outcomes and endpoints used across publications, no clear “standardized” set of endpoints and outcomes emerged. The inconsistencies in endpoints and outcomes within this literature suggest that the development of a uniform set of outcomes and endpoints could improve the clinical meaningfulness of clinical trial results, facilitate cross-trial comparisons and better inform patient care. This standard set of outcomes and endpoints should be statistically robust and informed by the priorities of various stakeholders, most importantly, the needs and preferences of people living with migraine.

KW - clinical outcome assessment

KW - clinical trial design

KW - endpoints

KW - outcomes

KW - patient reported outcome measures

KW - preventive migraine

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U2 - 10.1111/head.14069

DO - 10.1111/head.14069

M3 - Review article

AN - SCOPUS:85100996770

SN - 0017-8748

VL - 61

SP - 253

EP - 262

JO - Headache

JF - Headache

IS - 2

ER -

Systematic review of outcomes and endpoints in preventive migraine clinical trials

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