Results

Study population
A total of 1130 patients with CM were randomized to receive fremanezumab quarterly (n = 376), fremanezumab monthly (n = 379), or placebo (n = 375). The criteria for CM with MO at baseline were met by 201 (53.6%), 198 (52.8%), and 188 (50.7%) of the evaluable patients in the fremanezumab quarterly, fremanezumab monthly, and placebo groups, respectively. The demographics and clinical characteristics of patients in each subgroup (with MO and without MO) differed from each other in several ways, most notably age, years since initial diagnosis, current preventive medication use, current use of triptans or ergots, prior topiramate use, prior onabotulinumtoxinA use, headache days of at least moderate severity, migraine days, and days of acute headache medication use, although statistical significance of differences between subgroups in individual characteristics was not tested (Table 1).
Table 1 Demographics and baseline characteristics with and without MOa
CM With MO CM Without MO
Fremanezumab Fremanezumab
Quarterly (n = 201) Monthly (n = 198) Placebo (n = 188) Quarterly (n = 174) Monthly(n = 177) Placebo(n = 183)
Age, mean (SD), y 44.6 (11.6) 44.8 (10.9) 45.0 (10.8) 39.0 (12.6) 36.2 (11.5) 37.7 (12.1)
Sex, female, n (%) 183 (91) 173 (87) 168 (89) 147 (84) 154 (87) 158 (86)
BMI, mean (SD), kg/m2 26.4 (5.3) 26.4 (5.0) 26.0 (5.0) 26.9 (5.5) 26.7 (5.3) 26.9 (5.1)
Disease history
 Years since initial migraine diagnosis, mean (SD) 21.0 (12.7) 22.8 (12.3) 23.2 (13.8) 18.3 (12.9) 17.1 (11.0) 16.7 (11.0)
 Current preventive medication use, n (%) 47 (23.4) 54 (27.3) 38 (20.2) 30 (17.2) 31 (17.5) 39 (21.3)
 Current use of triptans or ergots, n (%) 141 (70.1) 138 (69.7) 128 (68.1) 67 (38.5) 49 (27.7) 64 (35.0)
 Prior topiramate use, n (%) 65 (32.3) 72 (36.4) 77 (41.0) 41 (23.6) 43 (24.3) 40 (21.9)
 Prior onabotulinumtoxinA use, n (%) 38 (18.9) 34 (17.2) 32 (17.0) 28 (16.1) 16 (9.0) 17 (9.3)
Disease characteristics during the 28-day pretreatment period
 Number of headache days of at least moderate severity,b mean (SD) 15.5 (5.0) 14.9 (5.4) 14.8 (5.4) 10.5 (4.8) 10.5 (5.3) 11.7 (5.8)
 Number of migraine days,c mean (SD) 17.2 (4.6) 17.5 (4.9) 17.3 (5.0) 15.0 (4.9) 14.3 (5.0) 15.4 (5.1)
 Number of days of acute medication use, mean (SD) 18.1 (4.0) 18.4 (4.5) 18.2 (4.4) 7.4 (4.4) 7.1 (4.5) 7.7 (4.5)
 HIT-6 score, mean (SD) 64.5 (5.1) 65.3 (4.4) 63.8 (5.2) 64.0 (4.3) 63.9 (4.3) 64.3 (4.4)
 PHQ-9 score, mean (SD) 4.3 (5.5) 5.9 (6.7) 3.7 (5.7) 4.1 (5.6) 4.0 (5.6) 4.0 (5.6)
MSQoL domain scores
 RFR, mean (SD) 49.1 (18.9) 46.8 (19.7) 49.7 (20.5) 48.2 (18.3) 49.7 (18.7) 48.8 (19.2)
 RFP, mean (SD) 67.5 (21.1) 63.2 (23.5) 67.5 (22.9) 67.1 (20.4) 68.7 (20.6) 67.4 (21.7)
 EF, mean (SD) 58.4 (26.2) 54.3 (27.1) 58.0 (27.5) 55.8 (26.9) 60.4 (25.1) 57.7 (25.4)
BMI Body mass index, CM Chronic migraine, EF Emotional function, HIT-6 Six-item Headache Impact Test, MO Medication overuse, MSQoL Migraine-Specific Quality of Life, RFP Role function−preventive, RFR Role function−restrictive, SD Standard deviation
aMO was defined as use of acute headache medication on ≥ 15 days, migraine-specific acute medication on ≥ 10 days, or combination medication for headache on ≥ 10 days during the 28-day pretreatment period. bA headache day of at least moderate severity was defined as a calendar day in which headache pain lasted at least 4 consecutive hours and had a peak severity of at least a moderate level, or a day in which acute migraine-specific medication (triptan or ergot) was used to treat a headache of any severity or duration. cA migraine day was defined as a calendar day in which headache pain lasted at least 4 consecutive hours and met criteria for migraine (with or without aura) or probable migraine (subtype in which only one migraine criterion is absent), or a day in which acute migraine-specific medication (triptan or ergot) was used to treat a headache of any duration.

Monthly average number of headache days of at least moderate severity with and without MO
Among patients with MO at baseline, the placebo-adjusted LS mean (95% confidence interval [CI]) change from baseline in the monthly average number of headache days of at least moderate severity during the 12-week treatment period was significantly greater with fremanezumab quarterly (− 2.2 [− 3.1 to − 1.2]; P < 0.0001) and monthly (− 2.7 [− 3.7 to − 1.8]; P < 0.0001) (Fig. 1a). Similar results were seen in patients without MO at baseline (quarterly − 1.4 [− 2.3 to − 0.5], P = 0.0026; monthly − 1.4 [− 2.3 to − 0.6], P = 0.0017 vs placebo) (Fig. 1a). Fremanezumab-treated patients with MO had numerically greater reductions in the monthly average number of headache days of at least moderate severity than patients without MO and demonstrated a larger treatment effect over placebo than those with MO.
Fig. 1 Change in days with (a) headache, (b) migraine, and (c) medication use in patients with CM by MO. Values shown are the mean changes from baseline in the monthly average number of (a) headache days of at least moderate severity, (b) migraine days, and (c) acute headache medication use during the 12-week treatment period with and without MO. CM, chronic migraine; LSM, least-squares mean; MO, medication overuse; SE, standard error

Monthly average number of migraine days with and without MO
The placebo-adjusted LS mean (95% CI) reduction from baseline in monthly average number of migraine days in patients with MO at baseline was significantly greater with fremanezumab quarterly (− 2.0 [− 3.1 to − 1.0], P = 0.0002) and monthly (− 2.4 [− 3.5 to − 1.4], P < 0.0001) (Fig. 1b). Similar results were seen in patients without MO at baseline (quarterly − 1.4 [− 2.5 to − 0.3], P = 0.0132; monthly − 1.3 [− 2.4 to − 0.2], P = 0.0249 vs placebo]) (Fig. 1b). Numerically greater reductions in monthly average number of migraine days from baseline and a larger treatment difference over placebo were seen in fremanezumab-treated patients with MO compared with patients without MO.

Acute headache medication use days with and without MO
Treatment with fremanezumab resulted in significantly greater reductions in the monthly average number of days of any acute headache medication use compared with placebo among patients with MO at baseline (LS mean difference [95% CI]: quarterly − 1.8 [− 2.9 to − 0.8], P = 0.0006; monthly − 2.4 [− 3.5 to − 1.4], P < 0.0001; Fig. 1c) and patients without MO at baseline (quarterly − 1.6 [− 2.4 to − 0.9], monthly − 2.3 [− 3.1 to − 1.6]; P < 0.0001 for both (Fig. 1c). Reductions from baseline in monthly average number of days with any acute headache medication use and treatment difference over placebo were numerically greater in fremanezumab-treated patients with MO than in patients without MO.

≥ 50% reduction in the monthly average number of headache days
The proportion of patients with a ≥ 50% reduction in the monthly average number of headache days of at least moderate severity was significantly greater among fremanezumab quarterly and fremanezumab monthly groups compared with placebo, regardless of MO at baseline (with MO: quarterly 70/201 [34.8%, P < 0.0001], monthly 78/198 [39.4%, P < 0.0001] vs placebo 26/188 [13.8%]; without MO: quarterly 71/174 [40.8%, P = 0.0003], monthly 75/177 [42.4%, P < 0.0001] vs placebo 41/183 [22.4%, Fig. 2). The odds of achieving a ≥ 50% reduction (odds ratio [95% CI]) was greater with fremanezumab versus placebo in both patients with MO (quarterly 3.33 [2.01 to 5.52], monthly 4.08 [2.47 to 6.75]) and without MO (quarterly 2.37 [1.50 to 3.76], monthly 2.53 [1.60 to 4.00]).
Fig. 2 Proportion of patients with CM with ≥ 50% response (a) with MO and (b) without MO. A ≥ 50% response was defined as ≥ 50% reduction from baseline in the monthly average number of headache days of at least moderate severity over 12 weeks. CM, chronic migraine; MO, medication overuse

Patient-reported outcomes with and without MO
During the 12-week treatment period, the LS mean (standard error) change from baseline in HIT-6 scores was significantly greater with fremanezumab versus placebo, regardless of MO at baseline (with MO: quarterly LS mean − 6.0 [0.7], monthly − 6.9 [0.6] vs placebo − 4.5 [0.7]; Table 2; without MO: quarterly − 7.0 [0.7], monthly − 6.8 [0.6] vs placebo − 4.5 [0.6]; Table 2).
Table 2 Change from baseline in patient-reported outcome measures with and without MO
CM With MO CM Without MO
Fremanezumab Fremanezumab
Quarterly(n = 201) Monthly(n = 198) Placebo(n = 188) Quarterly(n = 174) Monthly(n = 177) Placebo(n = 188)
HIT-6
 LSM (SE) −6.0 (0.7) −6.9 (0.6) −4.5 (0.7) −7.0 (0.7) − 6.8 (0.64) −4.5 (0.6)
  LSMD (SE) − 1.5 (0.7) −2.4 (0.7) −2.4 (0.7) − 2.3 (0.7)
  P value 0.0356 0.0009 0.0006 0.0012
MSQoL, RFR
 LSM (SE) 19.6 (1.8) 21.4 (1.8) 14.7 (1.9) 21.9 (2.0) 21.6 (2.0) 14.5 (1.9)
  LSMD (SE) 4.9 (2.0) 6.7 (2.0) 7.4 (2.1) 7.1 (2.1)
  P value 0.0142 0.0008 0.0005 0.0008
MSQoL, RFP
 LSM (SE) 17.5 (1.7) 18.4 (1.6) 14.2 (1.7) 16.4 (1.7) 14.2 (1.7) 10.2 (1.7)
  LSMD (SE) 3.2 (1.8) 4.2 (1.8) 6.2 (1.8) 3.9 (1.8)
  P value 0.0696 0.0200 0.0007 0.0290
MSQoL, EF
 LSM (SE) 20.2 (2.0) 22.0 (1.9) 17.3 (2.0) 22.4 (2.1) 19.7 (2.1) 16.7 (2.1)
  LSMD (SE) 2.9 (2.2) 4.7 (2.2) 5.7 (2.3) 3.0 (2.3)
  P value 0.1833 0.0305 0.0118 0.1873
PHQ-9
 LSM (SE) −2.8 (0.4) −2.3 (0.4) −2.4 (0.4) −2.6 (0.4) −2.3 (0.4) −1.6 (0.4)
  LSMD (SE) −0.5 (0.4) 0.0 (0.4) −1.0 (0.4) −0.7 (0.4)
  P value 0.2679 0.9678 0.0155 0.0922
CM Chronic migraine, EF Emotional function, HIT-6 Six-item Headache Impact Test, LSM Least-squares mean, LSMD Least-squares mean difference, MO Medication overuse, MSQoL Migraine-Specific Quality of Life, RFP Role function–preventive, RFR Role function–restrictive, PHQ-9 Patient Health Questionnaire-9, SE Standard error
LSMD was determined in comparison to placebo
Improvement in MSQoL domain scores was observed in patients with MO (RFR: quarterly 19.6 [1.8], monthly 21.4 [1.8] vs placebo 14.7 [1.9]; RFP: quarterly 17.5 [1.7], monthly 18.4 [1.6] vs placebo 14.2 [1.7]; EF: quarterly 20.2 [2.0], monthly 22.0 [1.9] vs placebo 17.3 [2.0]; Table 2). In the fremanezumab quarterly with MO group, the RFR domain score change from baseline compared with placebo was significant; the RFP and EF domain score changes were not significantly different from placebo (Table 2). All changes from baseline in MSQoL domain scores in the fremanezumab monthly group were significantly different compared with placebo (Table 2). Similarly, in patients without MO, improvements in MSQoL domain scores were observed (RFR: quarterly 21.9 [2.0], monthly 21.6 [2.0] vs placebo 14.5 [1.9]; RFP: quarterly 16.4 [1.7], monthly 14.2 [1.7] vs placebo 10.2 [1.7]; EF: quarterly 22.4 [2.1], monthly 19.7 [2.1] vs placebo 16.7 [2.1]; Table 2). All MSQoL domain scores in the fremanezumab quarterly without MO group were significantly different compared with placebo (Table 2). In the fremanezumab monthly without MO group, RFR and RFP domain score changes from baseline were significant compared with placebo; no significant difference in the EF domain score was observed (Table 2).
Reductions in PHQ-9 scores were observed, regardless of MO at baseline (with MO: quarterly − 2.8 [0.4], monthly − 2.3 [0.4] vs placebo − 2.4 [0.4]; without MO: quarterly − 2.6 [0.4], monthly − 2.3 [0.4] vs placebo − 1.6 [0.4]; Table 2). Numerically larger reductions were generally observed in the fremanezumab-treated groups compared with placebo; however, the only significant difference was observed in patients without MO in the fremanezumab quarterly group compared with placebo (Table 2).

Reversion from MO to no MO
Among CM patients with baseline MO, significantly greater proportions of patients treated with fremanezumab quarterly or monthly reverted to no MO during the 12-week treatment period (quarterly 111/201 [55.2%], P = 0.0389; monthly 120/198 [60.6%], P = 0.0024) than those who received placebo (87/188 [46.3%]) (Fig. 3). This effect was present by week 4 (quarterly 102/201 [50.7%], monthly 107/198 [54.0%] vs placebo 73/188 [38.8%]).
Fig. 3 Proportion of patients with CM who reverted from MO to no MO during the 12-week treatment period. CM, chronic migraine; MO, medication overuse
Similar baseline mean (standard deviation) monthly average number of days of acute headache medication use were observed across treatment arms within the subgroup of patients who reverted from MO (quarterly 16.6 [3.4], monthly 16.7 [3.6], placebo 16.6 [3.3]) and the subgroup of patients who continued MO (quarterly 19.9 [3.9], monthly 21.0 [4.5], placebo 19.5 [4.8]), though numerically greater numbers were observed among patients who continued MO. Among patients who reverted from MO at baseline, the reduction from baseline in the monthly average number of days of acute headache medication use was − 9.0 (0.4) with fremanezumab quarterly, − 8.9 (0.4) with fremanezumab monthly, and − 7.1 (0.5) with placebo (Fig. 4a). In comparison, patients with continued MO experienced numerically smaller reductions in the monthly average number of days of acute medication use in both the fremanezumab-treated groups (quarterly − 1.7 [0.4], monthly: − 2.2 [0.4]) and the placebo group (− 1.1 [0.4]; Fig. 4a).
Fig. 4 (a) Reduction in medication use and (b) ≥ 50% response in patients with CM by reversion to no MO. Values shown in part A are mean (SE) change from baseline over 12 weeks in the monthly average number of days of acute medication use in patients who reverted from MO to no MO (blue bars) and in those who did not revert from MO to no MO (green bars). Values shown in part B are the proportions of patients with a ≥ 50% response, defined as a ≥ 50% reduction in the monthly average number of headache days of at least moderate severity from baseline over 12 weeks, in patients who reverted from MO to no MO (blue bars) and in those who did not revert from MO to no MO (green bars). CM = chronic migraine; MO = medication overuse; SE = standard error
Furthermore, more than half of the patients who reverted from MO achieved a ≥ 50% reduction in the monthly average number of headache days of at least moderate severity after treatment with fremanezumab quarterly (66/111 [59.5%]) or monthly (67/120 [55.8%]); of those treated with placebo, 27.6% (24/87) achieved a ≥ 50% reduction (Fig. 4b). Among patients who continued to experience MO, the proportion of patients with a ≥ 50% reduction in the monthly average number of headache days of at least moderate severity was 4.4% (4/90) with fremanezumab quarterly, 14.1% (11/78) with fremanezumab monthly, and 2.0% (2/101) with placebo (Fig. 4b).