Effect of Fremanezumab compared with placebo for prevention of episodic migraine a randomized clinical trial

David William Dodick, Stephen D. Silberstein, Marcelo E. Bigal, Paul P. Yeung, Peter J. Goadsby, Tricia Blankenbiller, Melissa Grozinski-Wolff, Ronghua Yang, Yuju Ma, Ernesto Aycardi

Research output: Contribution to journalArticle

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Abstract

Importance: Fremanezumab, a fully humanized monoclonal antibody that targets calcitonin gene-related peptide, may be effective for treating episodic migraine. Objective: To assess the efficacy of fremanezumab compared with placebo for prevention of episodic migraine with a monthly dosing regimen or a single higher dose. Design and setting: Randomized, double-blind, placebo-controlled, parallel-group trial conducted at 123 sites in 9 countries from March 23, 2016 (first patient randomized), to April 10, 2017, consisting of a screening visit, 28-day pretreatment period, 12-week treatment period, and final evaluation at week 12. Participants: Study participants were aged 18 to 70 years with episodic migraine (6-14 headache days, with at least 4 migraine days, during 28-day pretreatment period). Patients who had previous treatment failure with 2 classes of migraine-preventive medication were excluded. Interventions: Patients were randomized 1:1:1 to receive subcutaneous monthly dosing of fremanezumab (n = 290; 225mg at baseline, week 4, and week 8); a single higher dose of fremanezumab, as intended to support a quarterly dose regimen (n = 291; 675mg of fremanezumab at baseline; placebo at weeks 4 and 8); or placebo (n = 294; at baseline, week 4, and week 8). Main outcomes and measures: The primary end pointwas mean change in mean number of monthly migraine days during the 12-week period after the first dose. Results: Among 875 patients who were randomized (mean age, 41.8 [SD, 12.1] years; 742 women [85%]), 791 (90.4%) completed the trial. From baseline to 12 weeks, mean migraine days per month decreased from 8.9 days to 4.9 days in the fremanezumab monthly dosing group, from 9.2 days to 5.3 days in the fremanezumab single-higher-dose group, and from 9.1 days to 6.5 days in the placebo group. This resulted in a difference with monthly dosing vs placebo of -1.5 days (95%CI, -2.01 to -0.93 days; P > .001) and with single higher dosing vs placebo of -1.3 days (95%CI, -1.79 to -0.72 days; P > .001). The most common adverse events that led to discontinuation were injection site erythema (n = 3), injection site induration (n = 2), diarrhea (n = 2), anxiety (n = 2), and depression (n = 2). Conclusions and relevance: Among patients with episodic migraine in whom multiple medication classes had not previously failed, subcutaneous fremanezumab, compared with placebo, resulted in a statistically significant 1.3-to 1.5-day reduction in the mean number of monthly migraine days over a 12-week period. Further research is needed to assess effectiveness against other preventive medications and in patients in whom multiple preventive drug classes have failed and to determine long-term safety and efficacy.

Original languageEnglish (US)
Pages (from-to)1999-2008
Number of pages10
JournalJAMA - Journal of the American Medical Association
Volume319
Issue number19
DOIs
StatePublished - May 15 2018

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Migraine Disorders
Randomized Controlled Trials
Placebos
Antibodies, Monoclonal, Humanized
Injections
Calcitonin Gene-Related Peptide
Erythema
Treatment Failure
Headache
Diarrhea
Anxiety
Outcome Assessment (Health Care)
Depression
Safety
Research
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Medicine(all)

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Effect of Fremanezumab compared with placebo for prevention of episodic migraine a randomized clinical trial. / Dodick, David William; Silberstein, Stephen D.; Bigal, Marcelo E.; Yeung, Paul P.; Goadsby, Peter J.; Blankenbiller, Tricia; Grozinski-Wolff, Melissa; Yang, Ronghua; Ma, Yuju; Aycardi, Ernesto.

In: JAMA - Journal of the American Medical Association, Vol. 319, No. 19, 15.05.2018, p. 1999-2008.

Research output: Contribution to journalArticle

Dodick, DW, Silberstein, SD, Bigal, ME, Yeung, PP, Goadsby, PJ, Blankenbiller, T, Grozinski-Wolff, M, Yang, R, Ma, Y & Aycardi, E 2018, 'Effect of Fremanezumab compared with placebo for prevention of episodic migraine a randomized clinical trial', JAMA - Journal of the American Medical Association, vol. 319, no. 19, pp. 1999-2008. https://doi.org/10.1001/jama.2018.4853
Dodick, David William ; Silberstein, Stephen D. ; Bigal, Marcelo E. ; Yeung, Paul P. ; Goadsby, Peter J. ; Blankenbiller, Tricia ; Grozinski-Wolff, Melissa ; Yang, Ronghua ; Ma, Yuju ; Aycardi, Ernesto. / Effect of Fremanezumab compared with placebo for prevention of episodic migraine a randomized clinical trial. In: JAMA - Journal of the American Medical Association. 2018 ; Vol. 319, No. 19. pp. 1999-2008.
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abstract = "Importance: Fremanezumab, a fully humanized monoclonal antibody that targets calcitonin gene-related peptide, may be effective for treating episodic migraine. Objective: To assess the efficacy of fremanezumab compared with placebo for prevention of episodic migraine with a monthly dosing regimen or a single higher dose. Design and setting: Randomized, double-blind, placebo-controlled, parallel-group trial conducted at 123 sites in 9 countries from March 23, 2016 (first patient randomized), to April 10, 2017, consisting of a screening visit, 28-day pretreatment period, 12-week treatment period, and final evaluation at week 12. Participants: Study participants were aged 18 to 70 years with episodic migraine (6-14 headache days, with at least 4 migraine days, during 28-day pretreatment period). Patients who had previous treatment failure with 2 classes of migraine-preventive medication were excluded. Interventions: Patients were randomized 1:1:1 to receive subcutaneous monthly dosing of fremanezumab (n = 290; 225mg at baseline, week 4, and week 8); a single higher dose of fremanezumab, as intended to support a quarterly dose regimen (n = 291; 675mg of fremanezumab at baseline; placebo at weeks 4 and 8); or placebo (n = 294; at baseline, week 4, and week 8). Main outcomes and measures: The primary end pointwas mean change in mean number of monthly migraine days during the 12-week period after the first dose. Results: Among 875 patients who were randomized (mean age, 41.8 [SD, 12.1] years; 742 women [85{\%}]), 791 (90.4{\%}) completed the trial. From baseline to 12 weeks, mean migraine days per month decreased from 8.9 days to 4.9 days in the fremanezumab monthly dosing group, from 9.2 days to 5.3 days in the fremanezumab single-higher-dose group, and from 9.1 days to 6.5 days in the placebo group. This resulted in a difference with monthly dosing vs placebo of -1.5 days (95{\%}CI, -2.01 to -0.93 days; P > .001) and with single higher dosing vs placebo of -1.3 days (95{\%}CI, -1.79 to -0.72 days; P > .001). The most common adverse events that led to discontinuation were injection site erythema (n = 3), injection site induration (n = 2), diarrhea (n = 2), anxiety (n = 2), and depression (n = 2). Conclusions and relevance: Among patients with episodic migraine in whom multiple medication classes had not previously failed, subcutaneous fremanezumab, compared with placebo, resulted in a statistically significant 1.3-to 1.5-day reduction in the mean number of monthly migraine days over a 12-week period. Further research is needed to assess effectiveness against other preventive medications and in patients in whom multiple preventive drug classes have failed and to determine long-term safety and efficacy.",
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T1 - Effect of Fremanezumab compared with placebo for prevention of episodic migraine a randomized clinical trial

AU - Dodick, David William

AU - Silberstein, Stephen D.

AU - Bigal, Marcelo E.

AU - Yeung, Paul P.

AU - Goadsby, Peter J.

AU - Blankenbiller, Tricia

AU - Grozinski-Wolff, Melissa

AU - Yang, Ronghua

AU - Ma, Yuju

AU - Aycardi, Ernesto

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N2 - Importance: Fremanezumab, a fully humanized monoclonal antibody that targets calcitonin gene-related peptide, may be effective for treating episodic migraine. Objective: To assess the efficacy of fremanezumab compared with placebo for prevention of episodic migraine with a monthly dosing regimen or a single higher dose. Design and setting: Randomized, double-blind, placebo-controlled, parallel-group trial conducted at 123 sites in 9 countries from March 23, 2016 (first patient randomized), to April 10, 2017, consisting of a screening visit, 28-day pretreatment period, 12-week treatment period, and final evaluation at week 12. Participants: Study participants were aged 18 to 70 years with episodic migraine (6-14 headache days, with at least 4 migraine days, during 28-day pretreatment period). Patients who had previous treatment failure with 2 classes of migraine-preventive medication were excluded. Interventions: Patients were randomized 1:1:1 to receive subcutaneous monthly dosing of fremanezumab (n = 290; 225mg at baseline, week 4, and week 8); a single higher dose of fremanezumab, as intended to support a quarterly dose regimen (n = 291; 675mg of fremanezumab at baseline; placebo at weeks 4 and 8); or placebo (n = 294; at baseline, week 4, and week 8). Main outcomes and measures: The primary end pointwas mean change in mean number of monthly migraine days during the 12-week period after the first dose. Results: Among 875 patients who were randomized (mean age, 41.8 [SD, 12.1] years; 742 women [85%]), 791 (90.4%) completed the trial. From baseline to 12 weeks, mean migraine days per month decreased from 8.9 days to 4.9 days in the fremanezumab monthly dosing group, from 9.2 days to 5.3 days in the fremanezumab single-higher-dose group, and from 9.1 days to 6.5 days in the placebo group. This resulted in a difference with monthly dosing vs placebo of -1.5 days (95%CI, -2.01 to -0.93 days; P > .001) and with single higher dosing vs placebo of -1.3 days (95%CI, -1.79 to -0.72 days; P > .001). The most common adverse events that led to discontinuation were injection site erythema (n = 3), injection site induration (n = 2), diarrhea (n = 2), anxiety (n = 2), and depression (n = 2). Conclusions and relevance: Among patients with episodic migraine in whom multiple medication classes had not previously failed, subcutaneous fremanezumab, compared with placebo, resulted in a statistically significant 1.3-to 1.5-day reduction in the mean number of monthly migraine days over a 12-week period. Further research is needed to assess effectiveness against other preventive medications and in patients in whom multiple preventive drug classes have failed and to determine long-term safety and efficacy.

AB - Importance: Fremanezumab, a fully humanized monoclonal antibody that targets calcitonin gene-related peptide, may be effective for treating episodic migraine. Objective: To assess the efficacy of fremanezumab compared with placebo for prevention of episodic migraine with a monthly dosing regimen or a single higher dose. Design and setting: Randomized, double-blind, placebo-controlled, parallel-group trial conducted at 123 sites in 9 countries from March 23, 2016 (first patient randomized), to April 10, 2017, consisting of a screening visit, 28-day pretreatment period, 12-week treatment period, and final evaluation at week 12. Participants: Study participants were aged 18 to 70 years with episodic migraine (6-14 headache days, with at least 4 migraine days, during 28-day pretreatment period). Patients who had previous treatment failure with 2 classes of migraine-preventive medication were excluded. Interventions: Patients were randomized 1:1:1 to receive subcutaneous monthly dosing of fremanezumab (n = 290; 225mg at baseline, week 4, and week 8); a single higher dose of fremanezumab, as intended to support a quarterly dose regimen (n = 291; 675mg of fremanezumab at baseline; placebo at weeks 4 and 8); or placebo (n = 294; at baseline, week 4, and week 8). Main outcomes and measures: The primary end pointwas mean change in mean number of monthly migraine days during the 12-week period after the first dose. Results: Among 875 patients who were randomized (mean age, 41.8 [SD, 12.1] years; 742 women [85%]), 791 (90.4%) completed the trial. From baseline to 12 weeks, mean migraine days per month decreased from 8.9 days to 4.9 days in the fremanezumab monthly dosing group, from 9.2 days to 5.3 days in the fremanezumab single-higher-dose group, and from 9.1 days to 6.5 days in the placebo group. This resulted in a difference with monthly dosing vs placebo of -1.5 days (95%CI, -2.01 to -0.93 days; P > .001) and with single higher dosing vs placebo of -1.3 days (95%CI, -1.79 to -0.72 days; P > .001). The most common adverse events that led to discontinuation were injection site erythema (n = 3), injection site induration (n = 2), diarrhea (n = 2), anxiety (n = 2), and depression (n = 2). Conclusions and relevance: Among patients with episodic migraine in whom multiple medication classes had not previously failed, subcutaneous fremanezumab, compared with placebo, resulted in a statistically significant 1.3-to 1.5-day reduction in the mean number of monthly migraine days over a 12-week period. Further research is needed to assess effectiveness against other preventive medications and in patients in whom multiple preventive drug classes have failed and to determine long-term safety and efficacy.

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