Effect of Fremanezumab Compared With Placebo for Prevention of Episodic Migraine: A Randomized Clinical Trial

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; 225 mg at baseline, week 4, and week 8); a single higher dose of fremanezumab, as intended to support a quarterly dose regimen (n = 291; 675 mg 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 point was 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.

Trial registration: clinicaltrials.gov Identifier: NCT02629861.

Figure 1.. Flow of Participants in a Randomized Clinical Trial of Fremanezumab vs Placebo for Prevention of Episodic Migraine

^aThe 1036 patients with chronic migraine were enrolled in a separate clinical trial of fremanezumab in patients with chronic migraine. ^bIneligible patients included those who met the following exclusion criteria: onabotulinumtoxinA use within 4 months of screening (n=6); opioid or barbiturate use >4 d/mo (n=29); ≥2 medication clusters previously failed (n=14); intervention or device use within 2 months of screening (n=4); clinically significant other disease (at discretion of investigator) (n=31); evidence or history of significant psychiatric issues (n=46); history of significant cardiovascular disease (n=21); known infection or history of infectious disease (n=9); cancer (current or past 5 years) (n=4); pregnant or nursing (n=5); history of hypersensitivity to injected proteins (n=1); participation in clinical study within 2 months or 5 half-lives (n=3); prior exposure to monoclonal antibody targeting calcitonin gene-related peptide pathway (n=2); clinically significant 12-lead electrocardiogram finding (n=13); clinically significant laboratory abnormality (n=16); hepatic enzymes >1.5 times upper limit of normal range or Hy’s law (presence of 3 components: aspartate aminotransferase or alanine aminotransferase ≥3 times upper limit of normal; total bilirubin ≥2 times upper limit of normal; and no other reason to explain these increases (eg, viral hepatitis A, B, or C; liver disease; or drug capable of causing injury) (n=24); serum creatinine >1.5 times upper limit of normal, clinically significant proteinuria, or renal disease (n=11); alcohol or drug abuse in past 2 years or dependence in past 5 years (n=14); unable to participate or complete study (n=16); study center or sponsor employee or relative of such an employee (n=7). Ineligible patients also included those who did not meet the following inclusion criteria: male or female aged 18-70 years with migraine onset at ≤50 years (n=5); provide written informed consent (n=2); history of migraine for ≥12 months (n=32); confirmed episodic migraine during pretreatment period (n=279); not using preventive medications or one with stable dose for ≥2 months (n=38); body mass index 17.5-37.5 and total body weight 45-120 kg (n=37); nonchildbearing potential (n=22); women of childbearing potential with negative pregnancy test result (n=3); about 85% electronic headache diary adherence (n=80); in overall good health (n=36); willing and able to adhere to study restrictions, remain at clinic during study period, and return to clinic for follow-up evaluation (n=111). ^cThe primary analysis included all patients who were randomized, received at least 1 dose of study drug, and had at least 10 days of postbaseline efficacy assessments for the primary end point.

Figure 2.. Effect of Fremanezumab vs Placebo on Migraine Outcomes

Panel A shows the change in mean number of monthly migraine days from baseline to week 12, analyzed via mixed-effects repeated measures. Error bars represent 95% confidence intervals. LSM indicates least-squares mean. Differences from placebo were significant for both fremanezumab treatment groups at each time point. For the primary analysis (analysis of covariance) of mean migraine days per month from baseline to week 12, the difference vs placebo for the fremanezumab monthly dosing group was –1.5 days (95% CI, –2.01 to –0.93 days; P<.001) and for the fremanezumab single-higher-dose group was –1.3 days (95% CI, –1.79 to –0.72 days; P<.001). Panel B shows the percentage of patients with at least a 50% reduction in mean number of monthly migraine days during the 12 weeks following the first administration of the study drug. The overall difference vs placebo for the fremanezumab monthly dosing group was 19.8% (95% CI, 12.0%-27.6%; P<.001) and for the fremanezumab single-higher-dose group was 16.5% (95% CI, 8.9%-24.1%; P<.001).