Migraine day frequency in migraine prevention: longitudinal modelling approaches

Abstract

Background: Health economic models are critical tools to inform reimbursement agencies on health care interventions. Many clinical trials report outcomes using the frequency of an event over a set period of time, for example, the primary efficacy outcome in most clinical trials of migraine prevention is mean change in the frequency of migraine days (MDs) per 28 days (monthly MDs [MMD]) relative to baseline for active treatment versus placebo. Using these cohort-level endpoints in economic models, accounting for variation among patients is challenging. In this analysis, parametric models of change in MMD for migraine preventives were assessed using data from erenumab clinical studies.

Methods: MMD observations from the double-blind phases of two studies of erenumab were used: one in episodic migraine (EM) (NCT02456740) and one in chronic migraine (CM) (NCT02066415). For each trial, two longitudinal regression models were fitted: negative binomial and beta binomial. For a thorough comparison we also present the fitting from the standard multilevel Poisson and the zero inflated negative binomial.

Results: Using the erenumab study data, both the negative binomial and beta-binomial models provided unbiased estimates relative to observed trial data with well-fitting distribution at various time points.

Conclusions: This proposed methodology, which has not been previously applied in migraine, has shown that these models may be suitable for estimating MMD frequency. Modelling MMD using negative binomial and beta-binomial distributions can be advantageous because these models can capture intra- and inter-patient variability so that trial observations can be modelled parametrically for the purposes of economic evaluation of migraine prevention. Such models have implications for use in a wide range of disease areas when assessing repeated measured utility values.

Keywords: Beta-binomial; Erenumab; Migraine; Migraine frequency; Modelling; Negative binomial.

Conflict of interest statement

Ethics approval and consent to participate

As previously reported, the two trials used in this study were registered with Consent for publication

Not applicable

Competing interests

JP and GLDT are both Amgen employees.

RBL is the Edwin S. Lowe Professor of Neurology at the Albert Einstein College of Medicine in New York. He receives research support from the NIH: 2PO1 AG003949 (Program Director), 5 U10 NS077308 (PI), 1RO1 AG042595 (Investigator), RO1 NS082432 (Investigator), K23 NS09610 (Mentor), K23AG049466 (Mentor). He also receives support from the Migraine Research Foundation and the National Headache Foundation. He serves on the editorial board of Neurology, is an associate editor of Cephalalgia, and as senior advisor to Headache. He has reviewed for the NIA and NINDS, holds stock options in eNeura Therapeutics and Biohaven Holdings; serves as consultant, advisory board member, or has received honoraria from: American Academy of Neurology, Alder, Allergan, American Headache Society, Amgen, Autonomic Technologies, Avanir, Biohaven, Biovision, Boston Scientific, Dr. Reddy’s, Electrocore, Eli Lilly, eNeura Therapeutics, GlaxoSmithKline, Merck, Pernix, Pfizer, Supernus, Teva, Trigemina, Vector, Vedanta. He receives royalties from Wolff’s Headache, 8th Edition, Oxford Press University, 2009, Wiley and Informa.

AB has research grants from NIHR, PHE, NIH (US), and DH, and receives consulting fees from Amgen, GSK, RTI, TeamDRG.

SP receives consulting fees from Amgen.

SS and GV are employed by Amgen and have stock in Amgen.

AJH was an employee of BresMed Health Solutions when the study was conducted, which received consulting fees from Amgen.

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Figures

Fig. 1

Estimated and actual MMD distributions in the EM study at weeks 0, 4, 12 and 24

Fig. 2

Estimated and actual MMD distributions in the CM study at weeks 0, 4, 8 and 12

Fig. 3

MMDs over 24 weeks of the EM study: negative binomial and beta-binomial longitudinal regression estimates and observed data. neg, negative. 95% confidence intervals for the negative and beta-binomials indicated by the shaded grey (placebo) and red (erenumab)

Fig. 4

MMDs over 12 weeks of the CM study: negative binomial and beta-binomial longitudinal regression estimates and observed data. neg, negative. 95% confidence intervals for the negative and beta-binomials indicated by the shaded grey (placebo) and red (erenumab)