Progressive improvements in efficacy and disability with fremanezumab in patients with medication overuse and inadequate response to multiple migraine preventive medication classes

Abstract Background Fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) selectively targets the calcitonin gene-related peptide and has proven efficacy for the preventive treatment of migraine. In this study, we evaluated the long-term efficacy, safety, and tolerability of monthly and quarterly fremanezumab. Methods Episodic migraine and chronic migraine patients completing the 12-week double-blind period of the FOCUS trial entered the 12-week open-label extension and received 3 monthly doses of fremanezumab (225 mg). Changes from baseline in monthly migraine days, monthly headache days of at least moderate severity, days of acute headache medication use, days with photophobia/phonophobia, days with nausea or vomiting, disability scores, and proportion of patients achieving a ≥50% or ≥75% reduction in monthly migraine days were evaluated. Results Of the 807 patients who completed the 12-week double-blind treatment period and entered the open-label extension, 772 patients completed the study. In the placebo, quarterly fremanezumab, and monthly fremanezumab dosing regimens, respectively, patients had fewer average monthly migraine days (mean [standard deviation] change from baseline: − 4.7 [5.4]; − 5.1 [4.7]; − 5.5 [5.0]), monthly headache days of at least moderate severity (− 4.5 [5.0]; − 4.8 [4.5]; − 5.2 [4.9]), days per month of acute headache medication use (− 4.3 [5.2]; − 4.9 [4.6]; − 4.8 [4.9]), days with photophobia/phonophobia (− 3.1 [5.3]; − 3.4 [5.3]; − 4.0 [5.2]), and days with nausea or vomiting (− 2.3 [4.6]; − 3.1 [4.5]; − 3.0 [4.4]). During the 12-week open-label extension, 38%, 45%, and 46% of patients, respectively, achieved a ≥50% reduction and 16%, 15%, and 20%, respectively, achieved a ≥75% reduction in monthly migraine days. Disability scores were substantially improved in all 3 treatment groups. There were low rates of adverse events leading to discontinuation (<1%). Conclusion Fremanezumab demonstrated sustained efficacy up to 6 months and was well tolerated in patients with episodic migraine or chronic migraine and documented inadequate response to multiple migraine preventive medication classes. Trial registration ClinicalTrials.gov NCT03308968 (FOCUS).

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Efficacy and safety of fremanezumab in patients with migraine and inadequate response to prior preventive treatment: subgroup analyses by country of a randomized, placebo-controlled trial

The Journal of Headache and Pain ◽

10.1186/s10194-021-01232-8 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Egilius L. H. Spierings ◽

Mikko Kärppä ◽

Xiaoping Ning ◽

Joshua M. Cohen ◽

Verena Ramirez Campos ◽

...

Keyword(s):

United States ◽

Czech Republic ◽

Adverse Events ◽

Least Squares ◽

The United States ◽

Inadequate Response ◽

Double Blind ◽

Monthly Average ◽

Preventive Medication ◽

Subgroup Analyses

Abstract Background The FOCUS study evaluated the efficacy of migraine preventive medications across different countries within the same patient population, particularly for patients with difficult-to-treat migraine. These prespecified subgroup analyses evaluated efficacy by country in the FOCUS study of fremanezumab in adults with episodic migraine or chronic migraine and documented inadequate response to 2 to 4 migraine preventive medication classes. Methods Overall, 838 participants were enrolled in the FOCUS study, a randomized, double-blind, placebo-controlled, parallel-group, phase 3b study performed at 104 sites. For 12 weeks of double-blind treatment, patients were randomized (1:1:1) to quarterly fremanezumab, monthly fremanezumab, or matched placebo. The primary efficacy endpoint was the mean change from baseline in monthly average migraine days over 12 weeks of double-blind treatment, evaluated by country in these subgroup analyses. Results Of 14 countries contributing data, the Czech Republic (n = 188/838; 22%), the United States (n = 120/838; 14%), and Finland (n = 85/838; 10%) enrolled the most patients. Changes from baseline in monthly average migraine days over 12 weeks were significantly greater with fremanezumab versus placebo for patients in these countries: Czech Republic (least-squares mean difference versus placebo [95% confidence interval]: quarterly fremanezumab, − 1.9 [− 3.25, − 0.47]; P = 0.009; monthly fremanezumab, − 3.0 [− 4.39, − 1.59]; P < 0.001), the United States (quarterly fremanezumab, − 3.7 [− 5.77, − 1.58]; P < 0.001; monthly fremanezumab, − 4.2 [− 6.23, − 2.13]; P < 0.001), and Finland (quarterly fremanezumab, − 3.0 [− 5.32, − 0.63]; P = 0.014; monthly fremanezumab, − 3.9 [− 6.27, − 1.44]; P = 0.002). Results were comparable for the remaining 9 countries, with the least-squares mean difference versus placebo ranging from – 5.6 to – 2.4 with quarterly fremanezumab and from − 5.3 to − 1.5 with monthly fremanezumab. Incidences of serious adverse events and adverse events leading to discontinuation were low and comparable across countries and treatment groups. Conclusions Monthly and quarterly fremanezumab significantly reduced the monthly average number of migraine days versus placebo regardless of country and continent (North America versus Europe) in migraine patients with documented inadequate response to 2 to 4 migraine preventive medication classes. Trial registration ClinicalTrials.gov Identifier: NCT03308968.

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New Daily Persistent Headache in a Pediatric Population

Journal of Child Neurology ◽

10.1177/08830738211004514 ◽

2021 ◽

pp. 088307382110045

Author(s):

Eric Strong ◽

Emily Linda Pierce ◽

Raquel Langdon ◽

Jeffery Strelzik ◽

William McClintock ◽

...

Keyword(s):

Pediatric Patients ◽

Medication Overuse ◽

Pediatric Population ◽

Medication Overuse Headache ◽

Activity Level ◽

New Daily Persistent Headache ◽

Tertiary Referral Center ◽

Preventive Medication ◽

Headache Clinic ◽

Persistent Headache

Introduction: New daily persistent headache (NDPH) is a primary headache disorder characterized by an intractable, daily, and unremitting headache lasting for at least 3 months. Currently, there are limited studies in the pediatric population describing the characteristics of NDPH. Objective: The objective of the current study is to describe the characteristics of NDPH in pediatric patients presenting to a headache program at a tertiary referral center. Methods: The participants in the current study were pediatric patients who attended the Headache Clinic at Children’s National Hospital between 2016 and 2018. All patients seen in the Headache Clinic were enrolled in an institutional review board–approved patient registry. Results: Between 2016 and 2018, NDPH was diagnosed in 245 patients, representing 14% of the total headache population. NDPH patients were predominantly female (78%) and white (72%). The median age was 14.8 years. The median pain intensity was 6 of 10 (standard deviation = 1.52). Most patients reported experiencing migrainous features, namely, photophobia (85%), phonophobia (85%), and a reduced activity level (88%). Overall, 33% of patients had failed at least 1 preventive medication, and 56% had failed at least 1 abortive medication. Furthermore, 36% of patients were additionally diagnosed with medication overuse headache. Conclusion: NDPH is a relatively frequent disorder among pediatric chronic headache patients. The vast majority of these patients experience migrainous headache characteristics and associated symptoms and are highly refractory to treatment—as evidenced by a strong predisposition to medication overuse headache and high rates of failed preventive management.

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Treatment of medication-overuse headache: A systematic review

Cephalalgia ◽

10.1177/0333102415593088 ◽

2015 ◽

Vol 36 (4) ◽

pp. 371-386 ◽

Cited By ~ 72

Author(s):

Chia-Chun Chiang ◽

Todd J Schwedt ◽

Shuu-Jiun Wang ◽

David W Dodick

Keyword(s):

Medication Overuse ◽

Medication Overuse Headache ◽

Treatment Strategies ◽

Preventive Treatment ◽

Early Discontinuation ◽

Level Of Evidence ◽

Preventive Medication ◽

Long Term Prognosis ◽

Acute Headache

Introduction The objective of this review is to provide an evidence-based discussion of different treatment strategies for medication-overuse headache (MOH). Method We searched PubMed for articles discussing the treatment and prognosis of MOH published between 2004 and August 2014. Titles, abstract and articles were reviewed systematically. The level of evidence provided by each study of the included articles was determined according to the American Academy of Neurology Clinical practice guideline manual. We discuss the level of evidence to support the early discontinuation/withdrawal of overused medications, the level of evidence to support the use of preventive treatment, the short- and long-term prognosis, and the outcome according to the class of drug overused in patients diagnosed with MOH. Results The initial search resulted in 1313 articles; 68 articles met our inclusion criteria and were discussed. The level of evidence to support early discontinuation of overused medications alone is low due to the absence of controlled studies. Adding preventive medication to early discontinuation led to a better outcome than early discontinuation alone. For patients with chronic migraine (CM) and medication overuse (MO), there are large randomized control trials supporting the use of onabotulinumtoxinA and topiramate without early discontinuation of overuse; however, the evidence is limited since data were obtained from post hoc analysis. Conclusion Considering current available evidence and the systemic toxicity of overusing acute headache medication, we suggest discontinuation of the overused medication with the addition of preventive medication. Appropriately sized, randomized controlled trials evaluating the safety and long-term efficacy of preventive medication plus early discontinuation of overuse vs preventive medication alone vs early discontinuation of overuse alone are needed.

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Medication Overuse and Headache Burden: Results From the CaMEO Study

Neurology Clinical Practice ◽

10.1212/cpj.0000000000001037 ◽

2021 ◽

pp. 10.1212/CPJ.0000000000001037

Author(s):

Todd J. Schwedt ◽

Dawn C. Buse ◽

Charles E. Argoff ◽

Michael L. Reed ◽

Kristina M. Fanning ◽

...

Keyword(s):

Logistic Regression ◽

Chronic Migraine ◽

Medication Overuse ◽

Medication Overuse Headache ◽

Urgent Care ◽

Systematic Sampling ◽

Factors Associated ◽

Link Type ◽

Increased Risk ◽

Preventive Medication

AbstractObjective:To estimate the relative frequency of acute medication overuse (AMO) among people with episodic migraine (EM) and chronic migraine (CM), to characterize the types of acute medications overused for migraine, and to identify factors associated with AMO.Methods:We analyzed data from the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study (ClinicalTrials.gov, NCT01648530), a cross-sectional and longitudinal Internet study that included a systematic sampling of the US population. From September 2012 to November 2013, the CaMEO Study respondents participated in different modules to collect data on the clinical course of migraine, family burden, barriers to care, endophenotypes, and comorbidities. Among people who met criteria for migraine consistent with the International Classification of Headache Disorders, 3rd edition (ICHD-3), we evaluated types and frequency of medications used for headache/migraine, selected comorbidities, and emergency department (ED) and urgent care (UC) use. AMO was defined by days/month of medication use as specified by ICHD-3 criteria for medication overuse headache (MOH) without the requirement for ≥15 monthly headache days (MHDs). Nested, multivariable binary logistic regression modeling was used to identify factors associated with increased risk of AMO.Results:Of 16,789 CaMEO respondents with migraine, 2,975 (17.7%) met AMO criteria. Approximately 67.9% (2,021/2,975) of AMO respondents reported <15 MHDs. Simple analgesics, combination analgesics, and opioids were the medication classes most commonly overused. Factors associated with AMO in the final multivariable logistic regression model included ≥15 MHDs, moderate to severe disability, severe migraine interictal burden, use of preventive medication, and an ED/UC visit for headache within 6 months.Conclusions:Approximately two-thirds of respondents with AMO reported <15 MHDs and therefore did not meet criteria for MOH. Those with AMO had greater disease burden and increased ED/UC utilization relative to people with migraine but not AMO.

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Economic benefits of treating medication-overuse headache – results from the multicenter COMOESTAS project

Cephalalgia ◽

10.1177/0333102418786265 ◽

2018 ◽

Vol 39 (2) ◽

pp. 274-285 ◽

Cited By ~ 9

Author(s):

Pernille Linde Jellestad ◽

Louise Ninett Carlsen ◽

Maria Lurenda Westergaard ◽

Signe Bruun Munksgaard ◽

Lars Bendtsen ◽

...

Keyword(s):

Health Care ◽

Health Care Costs ◽

Latin American ◽

Medication Overuse ◽

Medication Overuse Headache ◽

Total Study Population ◽

Preventive Medication ◽

Prospective Longitudinal ◽

The Impact ◽

Care Costs

Background Medication-overuse headache is a costly disease for individuals and society. Objective To estimate the impact of medication-overuse headache treatment on direct and indirect headache-related health care costs. Methods This prospective longitudinal study was part of the COMOESTAS project (COntinuous MOnitoring of Medication Overuse Headache in Europe and Latin America: development and STAndardization of an Alert and decision support System). Patients with medication-overuse headache were included from four European and two Latin American headache centers. Costs of acute medication, costs of health care services, and measurements of productivity were calculated at baseline and at 6-month follow-up Treatment consisted of overused drug withdrawal with optional preventive medication. Results A total of 475 patients (71%) completed treatment and were followed up for 6 months. Direct health care costs were on average reduced significantly by 52% ( p < 0.001) for the total study population. Significant reductions were seen in both number of consumed tablets (−71%, p < 0.001) and number of visits to physicians (−43%, p < 0.001). Fifty percent of patients reduced their number of consumed tablets ≥ 80%. Headache-related productivity loss, calculated either as absence from work or ≥ 50% reduction of productivity during the workday, were reduced by 21% and 34%, respectively ( p < 0.001). Conclusion Standardized treatment of medication-overuse headache in six countries significantly reduced direct health care costs and increased productivity. This emphasizes the importance of increasing awareness of the value of treating medication-overuse headache. Trial registration The trial was registered at ClinicalTrials.gov (no. NCT02435056)

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Odds ratios for response to fremanezumab in migraine patients with inadequate response TO 2-4 migraine preventive medication classes: Results of the focus phase 3B study

Journal of the Neurological Sciences ◽

10.1016/j.jns.2019.10.338 ◽

2019 ◽

Vol 405 ◽

pp. 64-65

Author(s):

H.C. Diener ◽

X. Ning ◽

M. Galic ◽

J.M. Cohen ◽

V. Ramirez-Campos ◽

...

Keyword(s):

Inadequate Response ◽

Odds Ratios ◽

Preventive Medication

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Factors associated to chronic migraine with medication overuse: A cross-sectional study

Cephalalgia ◽

10.1177/0333102418761047 ◽

2018 ◽

Vol 38 (14) ◽

pp. 2045-2057 ◽

Cited By ~ 4

Author(s):

Michele Viana ◽

Sara Bottiroli ◽

Grazia Sances ◽

Natascia Ghiotto ◽

Marta Allena ◽

...

Keyword(s):

Multivariate Analysis ◽

Chronic Migraine ◽

Medication Overuse ◽

Episodic Migraine ◽

Cross Sectional Study ◽

Sectional Study ◽

Cross Sectional ◽

Factors Associated ◽

Preventive Medication ◽

History Of

Background and aim Factors implicated in the evolution of episodic migraine into chronic migraine are largely elusive. Medication overuse is considered to be one of the main determinants, but other possible clinical and psychological factors can play a role. The aim of this study is to identify factors that are associated with chronic migraine with medication overuse. Method We enrolled consecutive migraine patients, subdividing them in two groups: Subjects with a long history of episodic migraine and subjects with chronic migraine and medication overuse. We then compared their clinical and psychological variables in a cross-sectional study. Results Three hundred and eighteen patients were enrolled, of which 156 were episodic migraine and 162 were chronic migraine and medication overuse patients. The mean age was 42.1 ± 10.3, 80.8% were female. The duration of migraine was 24.6 years in episodic migraine and 24.0 years in chronic migraine and medication overuse ( p = 0.57). After the multivariate analysis, the factors associated to chronic migraine and medication overuse were: Marital status (married vs. unmarried, OR 3.65, 95% CI 1.63–8.19, p = 0.002; separated/divorced/widowed vs. unmarried, OR 4.19, 95% CI 1.13–15.47, p = 0.031), physical activity (OR 0.42, 95% CI 0.19–0.91, p = 0.029), age at onset of migraine (OR 0.94, 95% CI 0.89–0.98, p = 0.016), use of at least one migraine preventive medication (OR 2.36, 95% CI 1.18–4.71, p = 0.014), history of depression (OR 2.91, 95% CI 1.25–6.73, p = 0.012), insomnia associated with the use of hypnotics (OR 5.59, 95% CI 1.65–18.93, p = 0.006), traumatic head injuries (OR 3.54, 95% CI 1.57–7.99, p = 0.002), snoring (OR 2.24, 95% CI 1.05–4.79, p = 0.036), previous and/or actual use of combined oral contraceptives (OR 3.38, 95% CI 1.10–10.3, p = 0.031) and higher scores in the Childhood Trauma questionnaire (OR 1.48, 95% CI 1.09–2.02, p = 0.012). Conclusion We considered several aspects that may be involved in the development of chronic migraine and medication overuse. A multivariate analysis identified 10 factors belonging to five different areas, to suggest that chronic migraine and medication overuse onset is likely influenced by a complex mixture of factors. This information is useful when planning strategies to prevent and manage chronic migraine and medication overuse.

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Impact of age and sex on the efficacy of fremanezumab in patients with difficult-to-treat migraine: results of the randomized, placebo-controlled, phase 3b FOCUS study

The Journal of Headache and Pain ◽

10.1186/s10194-021-01336-1 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Antoinette MaassenVanDenBrink ◽

Gisela M. Terwindt ◽

Joshua M. Cohen ◽

Steve Barash ◽

Verena Ramirez Campos ◽

...

Keyword(s):

Primary Endpoint ◽

Age Groups ◽

Medication Use ◽

Study Drug ◽

Inadequate Response ◽

Double Blind ◽

Link Type ◽

Acute Medication ◽

Preventive Medication ◽

Age And Sex

Abstract Background Migraine prevalence is age and sex dependent, predominating in women in early and middle adulthood; however, migraine also represents a substantial burden for men and adults of all ages. Thus, understanding this burden and the efficacy of migraine preventive medications in both sexes and across age groups is critical. The randomized, placebo-controlled, double-blind, phase 3b FOCUS study demonstrated the safety and efficacy of fremanezumab, a fully humanized monoclonal antibody (IgG2∆a) that selectively targets calcitonin gene-related peptide as a migraine preventive treatment for individuals with migraine and prior inadequate response to 2 to 4 migraine preventive medication classes. Here, we assessed the efficacy of fremanezumab in participants from FOCUS subgrouped by age (18–45 years and > 45 years) and sex. Methods In the FOCUS study, eligible participants were randomized (1:1:1) to 12 weeks of double-blind treatment with quarterly fremanezumab, monthly fremanezumab, or matched monthly placebo. In this post hoc analysis, we evaluated changes from baseline in monthly migraine days (primary endpoint of FOCUS) and other secondary and exploratory efficacy outcomes in prespecified age (18–45 and > 45 years) and sex subgroups. Results The modified intention-to-treat population (received ≥ 1 dose of study drug and had ≥ 10 days of postbaseline efficacy assessments for the primary endpoint) totaled 837 participants (18–45 years, n = 373; > 45 years, n = 464; male, n = 138; female, n = 699). Consistent reductions in monthly average number of migraine days during 12 weeks were observed, regardless of age (18–45 years: quarterly fremanezumab, − 4.1 days; monthly fremanezumab, − 4.7 days; placebo, − 0.9 days; P < 0.001; > 45 years: quarterly fremanezumab, − 3.6 days; monthly fremanezumab, − 3.7 days; placebo, − 0.3 days; P < 0.001) and sex (male: quarterly fremanezumab, − 4.1 days; monthly fremanezumab, − 4.6 days; placebo, − 0.3 days; P < 0.001; female: quarterly fremanezumab, − 3.6 days; monthly fremanezumab, − 3.9 days; placebo, − 0.6 days; P < 0.001). Fremanezumab also reduced monthly headache days of at least moderate severity, monthly days of acute medication use, and improved Migraine Disability Assessment scores across subgroups. Conclusions These results demonstrate the efficacy of fremanezumab in patients with difficult-to-treat migraine for reducing migraine and headache days, acute medication use, and disability, regardless of age or sex. Trial registration ClinicalTrials.gov Identifier NCT03308968 (FOCUS), registered October 13, 2017.

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