Trial Outcomes & Findings for An Efficacy and Safety Study of Fremanezumab in Adults With Migraine (NCT NCT03308968)

Last Updated: 2021-11-09

Results Overview

A migraine day was defined as when at least 1 of the following situations occurred: A calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache meeting criteria for migraine with or without aura; a calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache meeting criteria for probable migraine, a migraine subtype where only 1 migraine criterion was missing; a calendar day (0:00 to 23:59) demonstrating a headache of any duration that was treated with migraine-specific medications (triptans and ergot compounds). Monthly averages were derived and normalized to 28 days equivalent by formula: (number of days of efficacy variable over relevant period/number of days with assessments recorded in e-diary over relevant period)\*28. Change was calculated as post-baseline value - baseline value.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

838 participants

Primary outcome timeframe

Baseline (Day -28 to Day -1), up to Week 12

Results posted on

2021-11-09

Participant Flow

A total of 838 participants were randomized in a 1:1:1 ratio to placebo, fremanezumab quarterly, or fremanezumab monthly treatment groups.

Participant milestones

Participant milestones
Measure	Placebo Double-blind (DB) period: Participants with chronic migraine (CM) or episodic migraine (EM) received 3 injections of placebo 1.5 milliliters (mL) subcutaneously (SC) on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56. Open-label (OL) period: Participants with CM or EM received fremanezumab (TEV-48125) 225 milligrams (mg) SC (1 injection of fremanezumab 225 mg/1.5 mL) at Days 84, 112, and 140.	Fremanezumab Quarterly DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56). OL period: Participants with CM or EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL) at Days 84, 112, and 140.	Fremanezumab Monthly DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56).OL period: Participants with CM or EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL) at Days 84, 112, and 140.
Double-Blind Period (12 Weeks) STARTED	279	276	283
Double-Blind Period (12 Weeks) DB Safety Analysis Set	277	276	285
Double-Blind Period (12 Weeks) DB Modified ITT (mITT) Analysis Set	278	276	283
Double-Blind Period (12 Weeks) COMPLETED	264	271	272
Double-Blind Period (12 Weeks) NOT COMPLETED	15	5	11
Open-Label Period (12 Weeks) STARTED	264	271	272
Open-Label Period (12 Weeks) OL mITT Analysis Set	263	271	272
Open-Label Period (12 Weeks) COMPLETED	253	259	260
Open-Label Period (12 Weeks) NOT COMPLETED	11	12	12

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Double-blind (DB) period: Participants with chronic migraine (CM) or episodic migraine (EM) received 3 injections of placebo 1.5 milliliters (mL) subcutaneously (SC) on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56. Open-label (OL) period: Participants with CM or EM received fremanezumab (TEV-48125) 225 milligrams (mg) SC (1 injection of fremanezumab 225 mg/1.5 mL) at Days 84, 112, and 140.	Fremanezumab Quarterly DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56). OL period: Participants with CM or EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL) at Days 84, 112, and 140.	Fremanezumab Monthly DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56).OL period: Participants with CM or EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL) at Days 84, 112, and 140.
Double-Blind Period (12 Weeks) Adverse Event	3	1	4
Double-Blind Period (12 Weeks) Withdrawal by Subject	2	2	3
Double-Blind Period (12 Weeks) Protocol Violation	6	0	2
Double-Blind Period (12 Weeks) Non-compliance to study procedures	1	1	0
Double-Blind Period (12 Weeks) Lost to Follow-up	1	0	0
Double-Blind Period (12 Weeks) Lack of Efficacy	1	1	0
Double-Blind Period (12 Weeks) Other than specified	1	0	2
Open-Label Period (12 Weeks) Other than specified	1	2	1
Open-Label Period (12 Weeks) Adverse Event	4	1	1
Open-Label Period (12 Weeks) Withdrawal by Subject	5	5	7
Open-Label Period (12 Weeks) Protocol Violation	0	1	1
Open-Label Period (12 Weeks) Non-compliance to study procedures	0	0	1
Open-Label Period (12 Weeks) Lost to Follow-up	0	1	1
Open-Label Period (12 Weeks) Lack of Efficacy	1	2	0

Baseline Characteristics

Here, 'Number analyzed' signifies participants evaluable for this measure.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=279 Participants DB period: Participants with CM or EM received 3 injections of placebo 1.5 mL SC on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56. OL period: Participants with CM or EM received fremanezumab (TEV-48125) 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL) at Days 84, 112, and 140.	Fremanezumab Quarterly n=276 Participants DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56). OL period: Participants with CM or EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL) at Days 84, 112, and 140.	Fremanezumab Monthly n=283 Participants DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). OL period: Participants with CM or EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL) at Days 84, 112, and 140.	Total n=838 Participants Total of all reporting groups
Age, Continuous	46.8 years STANDARD_DEVIATION 11.10 • n=279 Participants	45.8 years STANDARD_DEVIATION 10.97 • n=276 Participants	45.9 years STANDARD_DEVIATION 11.05 • n=283 Participants	46.2 years STANDARD_DEVIATION 11.04 • n=838 Participants
Sex: Female, Male Female	233 Participants n=279 Participants	229 Participants n=276 Participants	238 Participants n=283 Participants	700 Participants n=838 Participants
Sex: Female, Male Male	46 Participants n=279 Participants	47 Participants n=276 Participants	45 Participants n=283 Participants	138 Participants n=838 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	11 Participants n=279 Participants	6 Participants n=276 Participants	7 Participants n=283 Participants	24 Participants n=838 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	255 Participants n=279 Participants	260 Participants n=276 Participants	264 Participants n=283 Participants	779 Participants n=838 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	13 Participants n=279 Participants	10 Participants n=276 Participants	12 Participants n=283 Participants	35 Participants n=838 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants n=279 Participants	0 Participants n=276 Participants	1 Participants n=283 Participants	1 Participants n=838 Participants
Race/Ethnicity, Customized Asian	1 Participants n=279 Participants	0 Participants n=276 Participants	3 Participants n=283 Participants	4 Participants n=838 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants n=279 Participants	0 Participants n=276 Participants	0 Participants n=283 Participants	0 Participants n=838 Participants
Race/Ethnicity, Customized Black or African American	2 Participants n=279 Participants	2 Participants n=276 Participants	4 Participants n=283 Participants	8 Participants n=838 Participants
Race/Ethnicity, Customized White	262 Participants n=279 Participants	262 Participants n=276 Participants	262 Participants n=283 Participants	786 Participants n=838 Participants
Race/Ethnicity, Customized Other	1 Participants n=279 Participants	2 Participants n=276 Participants	1 Participants n=283 Participants	4 Participants n=838 Participants
Race/Ethnicity, Customized Unknown or Not Reported	13 Participants n=279 Participants	10 Participants n=276 Participants	12 Participants n=283 Participants	35 Participants n=838 Participants
Number of Migraine Days During the 28 Day Baseline Period	14.3 days STANDARD_DEVIATION 6.12 • n=279 Participants • Here, 'Number analyzed' signifies participants evaluable for this measure.	14.1 days STANDARD_DEVIATION 5.61 • n=275 Participants • Here, 'Number analyzed' signifies participants evaluable for this measure.	14.1 days STANDARD_DEVIATION 5.58 • n=283 Participants • Here, 'Number analyzed' signifies participants evaluable for this measure.	14.2 days STANDARD_DEVIATION 5.77 • n=837 Participants • Here, 'Number analyzed' signifies participants evaluable for this measure.
Number of Headache Days of at Least Moderate Severity During the 28 Day Baseline Period	12.8 days STANDARD_DEVIATION 5.92 • n=279 Participants • Here, 'Number analyzed' signifies participants evaluable for this measure.	12.4 days STANDARD_DEVIATION 5.84 • n=275 Participants • Here, 'Number analyzed' signifies participants evaluable for this measure.	12.7 days STANDARD_DEVIATION 5.82 • n=283 Participants • Here, 'Number analyzed' signifies participants evaluable for this measure.	12.6 days STANDARD_DEVIATION 5.85 • n=837 Participants • Here, 'Number analyzed' signifies participants evaluable for this measure.

PRIMARY outcome

Timeframe: Baseline (Day -28 to Day -1), up to Week 12

Population: DB mITT analysis set included participants who received at least 1 dose of study drug and had at least 10 days of postbaseline efficacy assessment on the primary endpoint.

Outcome measures

Outcome measures
Measure	Placebo n=278 Participants DB period: Participants with CM or EM received 3 injections of placebo 1.5 mL SC on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56.	Fremanezumab Quarterly n=276 Participants DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56).	Fremanezumab Monthly n=283 Participants DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56).
DB Period: Change From Baseline in Monthly Average Number of Migraine Days During the 12-Week Period After the First Dose of Fremanezumab	-0.6 days/month Standard Error 0.34	-3.7 days/month Standard Error 0.34	-4.1 days/month Standard Error 0.34

SECONDARY outcome

Timeframe: Baseline (Day -28 to Day-1), up to Week 12

Population: DB mITT analysis set included participants who received at least 1 dose of study drug and had at least 10 days of postbaseline efficacy assessment on the primary endpoint.

Outcome measures

Outcome measures
Measure	Placebo n=278 Participants DB period: Participants with CM or EM received 3 injections of placebo 1.5 mL SC on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56.	Fremanezumab Quarterly n=276 Participants DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56).	Fremanezumab Monthly n=283 Participants DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56).
DB Period: Percentage of Participants Reaching at Least 50 Percent (%) Reduction From Baseline in Monthly Average Number of Migraine Days During the 12-Week Period After the First Dose of Fremanezumab	9 percentage of participants	34 percentage of participants	34 percentage of participants

SECONDARY outcome

Timeframe: Baseline (Day -28 to Day -1), up to Week 12

Population: DB mITT analysis set included participants who received at least 1 dose of study drug and had at least 10 days of postbaseline efficacy assessment on the primary endpoint.

A headache day of at least moderate severity was defined as a calendar day (00:00 to 23:59) demonstrating at least 4 consecutive hours of headache of at least moderate severity or; a calendar day (0:00 to 23:59) demonstrating a headache of any duration that was treated with migraine-specific acute medications (triptans and ergot compounds). Monthly averages were derived and normalized to 28 days equivalent by the following formula: (number of days of efficacy variable over relevant period/number of days with assessments recorded in the e-diary over the relevant period) \* 28. The change was calculated as post-baseline value - baseline value. LS mean calculated using ANCOVA model with treatment, gender, region, special group of treatment failure (yes/no), migraine classification (EM/CM), and treatment\*migraine classification as fixed effects and baseline number of headache days of at least moderate severity and years since onset of migraine as covariates.

Outcome measures

Outcome measures
Measure	Placebo n=278 Participants DB period: Participants with CM or EM received 3 injections of placebo 1.5 mL SC on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56.	Fremanezumab Quarterly n=276 Participants DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56).	Fremanezumab Monthly n=283 Participants DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56).
DB Period: Change From Baseline in Monthly Average Number of Headache Days of at Least Moderate Severity During the 12-Week Period After the First Dose of Fremanezumab	-0.6 days/month Standard Error 0.33	-3.9 days/month Standard Error 0.34	-4.2 days/month Standard Error 0.34

SECONDARY outcome

Timeframe: Baseline (Day -28 to Day -1), up to Week 4

Population: DB mITT analysis set included participants who received at least 1 dose of study drug and had at least 10 days of postbaseline efficacy assessment on the primary endpoint.

A migraine day was defined as when at least 1 of following occurred: A calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache meeting criteria for migraine with or without aura; a calendar day demonstrating at least 4 consecutive hours of a headache meeting criteria for probable migraine, a migraine subtype where only 1 migraine criterion was missing; a calendar day demonstrating a headache of any duration that was treated with migraine-specific medications. Monthly averages were derived and normalized to 28 days equivalent by formula: (number of days of efficacy variable over relevant period/number of days with assessments recorded in e-diary over relevant period)\*28. LS mean calculated using ANCOVA model with treatment, gender, region, special group of treatment failure (yes/no), migraine classification (EM/CM), and treatment\*migraine classification as fixed effects, and baseline number of migraine days and years since onset of migraines as covariates.

Outcome measures

Outcome measures
Measure	Placebo n=278 Participants DB period: Participants with CM or EM received 3 injections of placebo 1.5 mL SC on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56.	Fremanezumab Quarterly n=276 Participants DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56).	Fremanezumab Monthly n=283 Participants DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56).
DB Period: Change From Baseline in Monthly Average Number of Migraine Days During the 4-Week Period After the First Dose of Fremanezumab	-0.6 days/month Standard Error 0.35	-4.1 days/month Standard Error 0.35	-4.1 days/month Standard Error 0.35

SECONDARY outcome

Timeframe: Baseline (Day -28 to Day-1), up to Week 4

Population: DB mITT analysis set included participants who received at least 1 dose of study drug and had at least 10 days of postbaseline efficacy assessment on the primary endpoint.

Outcome measures

Outcome measures
Measure	Placebo n=278 Participants DB period: Participants with CM or EM received 3 injections of placebo 1.5 mL SC on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56.	Fremanezumab Quarterly n=276 Participants DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56).	Fremanezumab Monthly n=283 Participants DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56).
DB Period: Percentage of Participants Reaching at Least 50% Reduction From Baseline in Monthly Average Number of Migraine Days During the 4-Week Period After the First Dose of Fremanezumab	10 percentage of participants	38 percentage of participants	36 percentage of participants

SECONDARY outcome

Timeframe: Baseline (Day -28 to Day -1), up to Week 12

Population: DB mITT analysis set included participants who received at least 1 dose of study drug and had at least 10 days of postbaseline efficacy assessment on the primary endpoint.

Baseline data and the mean change from baseline in the monthly average number of days of use of any acute headache medications during the 12-week period after administration of the first dose of study drug (based on Week 0 to 12 data) is reported. Least Squares (LS) mean calculated using analysis of covariance (ANCOVA) model with treatment, gender, region, special group of treatment failure (yes/no), migraine classification (EM/CM), and treatment\*migraine classification as fixed effects, and baseline number of migraine days and years since onset of migraines as covariates.

Outcome measures

Outcome measures
Measure	Placebo n=278 Participants DB period: Participants with CM or EM received 3 injections of placebo 1.5 mL SC on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56.	Fremanezumab Quarterly n=276 Participants DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56).	Fremanezumab Monthly n=283 Participants DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56).
DB Period: Change From Baseline in Monthly Average Number of Days of Use of Any Acute Headache Medications During the 12-Week Period After the First Dose of Fremanezumab	-0.6 days/month Standard Error 0.32	-3.7 days/month Standard Error 0.32	-3.9 days/month Standard Error 0.32

SECONDARY outcome

Timeframe: Baseline (Day -28 to Day -1), up to Week 4

Population: DB mITT analysis set included participants who received at least 1 dose of study drug and had at least 10 days of postbaseline efficacy assessment on the primary endpoint.

A headache day of at least moderate severity was defined as a calendar day (00:00 to 23:59) demonstrating at least 4 consecutive hours of headache of at least moderate severity or; a calendar day (0:00 to 23:59) demonstrating a headache of any duration that was treated with migraine-specific acute medications (triptans and ergot compounds). Monthly averages were derived and normalized to 28 days equivalent by the following formula: (number of days of efficacy variable over relevant period/number of days with assessments recorded in the e-diary over the relevant period) \* 28. The change was calculated as post-baseline value - baseline value. LS mean calculated using ANCOVA model with treatment, gender, region, special group of treatment failure (yes/no), migraine classification (EM/CM), and treatment\*migraine classification as fixed effects, and baseline number of headache days of at least moderate severity and years since onset of migraines as covariates.

Outcome measures

Outcome measures
Measure	Placebo n=278 Participants DB period: Participants with CM or EM received 3 injections of placebo 1.5 mL SC on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56.	Fremanezumab Quarterly n=276 Participants DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56).	Fremanezumab Monthly n=283 Participants DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56).
DB Period: Change From Baseline in Monthly Average Number of Headache Days of at Least Moderate Severity During the 4-Week Period After the First Dose of Fremanezumab	-0.5 days/month Standard Error 0.34	-4.2 days/month Standard Error 0.35	-4.5 days/month Standard Error 0.34

SECONDARY outcome

Timeframe: Baseline (Day 0) up to Week 12

Population: DB safety analysis set included all randomized participants who received at least 1 dose of study drug during the DB treatment period.

An AE was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Severe AE was defined as inability to carry out usual activities. Treatment-related AEs were defined as AEs with possible, probable, definite, or missing relationship to study drug. Serious AEs were defined as death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.

Outcome measures

Outcome measures
Measure	Placebo n=277 Participants DB period: Participants with CM or EM received 3 injections of placebo 1.5 mL SC on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56.	Fremanezumab Quarterly n=276 Participants DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56).	Fremanezumab Monthly n=285 Participants DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56).
DB Period: Number of Participants With Adverse Events (AEs) and Who Did Not Complete the Study Due to AEs Any AEs	134 Participants	151 Participants	129 Participants
DB Period: Number of Participants With Adverse Events (AEs) and Who Did Not Complete the Study Due to AEs AEs leading to withdrawal from study	3 Participants	1 Participants	4 Participants

SECONDARY outcome

Timeframe: Week 12 up to Week 24

Population: OL safety analysis set included all participants who received at least 1 dose of study drug during the OL treatment period.

Outcome measures

Outcome measures
Measure	Placebo n=262 Participants DB period: Participants with CM or EM received 3 injections of placebo 1.5 mL SC on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56.	Fremanezumab Quarterly n=271 Participants DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56).	Fremanezumab Monthly n=274 Participants DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56).
OL Period: Number of Participants With AEs and Who Did Not Complete the Study Due to AEs Any AEs	137 Participants	149 Participants	155 Participants
OL Period: Number of Participants With AEs and Who Did Not Complete the Study Due to AEs AEs leading to withdrawal from study	4 Participants	1 Participants	2 Participants

SECONDARY outcome

Timeframe: Baseline up to Week 12

Population: DB safety analysis set included all randomized participants who received at least 1 dose of study drug during the DB treatment period. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.

Criteria for potentially clinically significant abnormal serum chemistry values included: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), and lactate dehydrogenase (LDH) (units/liter \[U/L\]): greater than or equal to (≥) 3\*upper limit of normal (ULN); Blood Urea Nitrogen (BUN): ≥10.71 millimoles/liter (mmol/L); creatinine: ≥177 micromoles/liter (µmol/L); bilirubin (total): ≥34.2 µmol/L; and uric acid: ≥625 µmol/L (men), and ≥506 µmol/L (women). A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.

Outcome measures

Outcome measures
Measure	Placebo n=272 Participants DB period: Participants with CM or EM received 3 injections of placebo 1.5 mL SC on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56.	Fremanezumab Quarterly n=268 Participants DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56).	Fremanezumab Monthly n=280 Participants DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56).
DB Period: Number of Participants With Potentially Clinically Significant Abnormal Serum Chemistry Results	1 Participants	3 Participants	4 Participants

SECONDARY outcome

Timeframe: Week 12 up to Week 24

Population: OL safety analysis set included all participants who received at least 1 dose of study drug during the OL treatment period. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.

Criteria for potentially clinically significant abnormal serum chemistry values included: ALT, AST, ALP, GGT, and LDH (U/L): ≥3\*ULN; BUN: ≥10.71 mmol/L; creatinine: ≥177 µmol/L; bilirubin (total): ≥34.2 µmol/L; and uric acid: ≥625 µmol/L (men), and ≥506 µmol/L (women). A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.

Outcome measures

Outcome measures
Measure	Placebo n=259 Participants DB period: Participants with CM or EM received 3 injections of placebo 1.5 mL SC on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56.	Fremanezumab Quarterly n=270 Participants DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56).	Fremanezumab Monthly n=273 Participants DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56).
OL Period: Number of Participants With Potentially Clinically Significant Abnormal Serum Chemistry Results	2 Participants	3 Participants	2 Participants

SECONDARY outcome

Timeframe: Baseline up to Week 12

Criteria for potentially clinically significant abnormal hematology values included: hemoglobin: less than (\<) 115 grams/liter (g/L) (in men) or less than or equal to (≤) 95 g/L (in women), hematocrit: \<0.37 L/L (in men) or \<0.32 L/L (in women), leukocytes: ≥20\*10\^9/L or ≤3\*10\^9/L, eosinophils: \>=10%, platelets: ≥700\*10\^9/L or ≤75\*10\^9/L, and absolute neutrophil count (ANC): ≤1\*10\^9/L. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.

Outcome measures

Outcome measures
Measure	Placebo n=271 Participants DB period: Participants with CM or EM received 3 injections of placebo 1.5 mL SC on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56.	Fremanezumab Quarterly n=268 Participants DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56).	Fremanezumab Monthly n=278 Participants DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56).
DB Period: Number of Participants With Potentially Clinically Significant Abnormal Hematology Results	11 Participants	12 Participants	3 Participants

SECONDARY outcome

Timeframe: Week 12 up to Week 24

Criteria for potentially clinically significant abnormal hematology values included: hemoglobin: \<115 g/L (in men) or ≤95 g/L (in women), hematocrit: \<0.37 L/L (in men) or \<0.32 L/L (in women), leukocytes: ≥20\*10\^9/L or ≤3\*10\^9/L, eosinophils: \>=10%, platelets: ≥700\*10\^9/L or ≤75\*10\^9/L, and ANC: ≤1\*10\^9/L. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.

Outcome measures

Outcome measures
Measure	Placebo n=259 Participants DB period: Participants with CM or EM received 3 injections of placebo 1.5 mL SC on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56.	Fremanezumab Quarterly n=270 Participants DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56).	Fremanezumab Monthly n=273 Participants DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56).
OL Period: Number of Participants With Potentially Clinically Significant Abnormal Hematology Results	9 Participants	11 Participants	5 Participants

SECONDARY outcome

Timeframe: Baseline up to Week 12

Criteria for potentially clinically significant abnormal coagulation values included: prothrombin international normalized ratio (INR): greater than (\>) 1.5. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.

Outcome measures

Outcome measures
Measure	Placebo n=269 Participants DB period: Participants with CM or EM received 3 injections of placebo 1.5 mL SC on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56.	Fremanezumab Quarterly n=267 Participants DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56).	Fremanezumab Monthly n=277 Participants DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56).
DB Period: Number of Participants With Potentially Clinically Significant Abnormal Coagulation Laboratory Test Results	2 Participants	4 Participants	4 Participants

SECONDARY outcome

Timeframe: Week 12 up to Week 24

Criteria for potentially clinically significant abnormal coagulation values included: prothrombin INR: \>1.5. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.

Outcome measures

Outcome measures
Measure	Placebo n=257 Participants DB period: Participants with CM or EM received 3 injections of placebo 1.5 mL SC on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56.	Fremanezumab Quarterly n=270 Participants DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56).	Fremanezumab Monthly n=272 Participants DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56).
OL Period: Number of Participants With Potentially Clinically Significant Abnormal Coagulation Laboratory Test Results	3 Participants	1 Participants	3 Participants

SECONDARY outcome

Timeframe: Baseline up to Week 12

Population: DB safety analysis set included all randomized participants who received at least 1 dose of study drug during the DB treatment period.

Criteria for potentially clinically significant abnormal urinalysis values included: urine glucose (milligrams/deciliter \[mg/dL\]): ≥2 unit increase from baseline, ketones (mg/dL): ≥2 unit increase from baseline, urine total protein (mg/dL): ≥2 unit increase from baseline, and haemoglobin ≥2 unit increase from baseline. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.

Outcome measures

Outcome measures
Measure	Placebo n=277 Participants DB period: Participants with CM or EM received 3 injections of placebo 1.5 mL SC on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56.	Fremanezumab Quarterly n=276 Participants DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56).	Fremanezumab Monthly n=285 Participants DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56).
DB Period: Number of Participants With Potentially Clinically Significant Abnormal Urinalysis Laboratory Tests Results	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Week 12 up to Week 24

Population: OL safety analysis set included all participants who received at least 1 dose of study drug during the OL treatment period.

Criteria for potentially clinically significant abnormal urinalysis values included: urine glucose (mg/dL): ≥2 unit increase from baseline, ketones (mg/dL): ≥2 unit increase from baseline, urine total protein (mg/dL): ≥2 unit increase from baseline, and haemoglobin ≥2 unit increase from baseline. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.

Outcome measures

Outcome measures
Measure	Placebo n=262 Participants DB period: Participants with CM or EM received 3 injections of placebo 1.5 mL SC on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56.	Fremanezumab Quarterly n=271 Participants DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56).	Fremanezumab Monthly n=274 Participants DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56).
OL Period: Number of Participants With Potentially Clinically Significant Abnormal Urinalysis Laboratory Tests Results	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline up to Week 12

Criteria for potentially clinically significant abnormal vital signs values included: pulse rate: ≤50 beats/minute (bpm) and decrease of ≥15 bpm, or ≥120 bpm and increase of ≥15 bpm; systolic blood pressure: ≤90 millimeters of mercury (mmHg) and decrease of ≥20 mmHg, or ≥180 mmHg and increase of ≥20 mmHg; diastolic blood pressure: ≤50 mmHg and decrease of ≥15 mmHg or ≥105 mmHg and increase of ≥15 mmHg; respiratory rate: \<10 breaths/minute; and body temperature ≥38.3 degrees celsius and change of ≥1.1 degrees celsius. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.

Outcome measures

Outcome measures
Measure	Placebo n=277 Participants DB period: Participants with CM or EM received 3 injections of placebo 1.5 mL SC on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56.	Fremanezumab Quarterly n=276 Participants DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56).	Fremanezumab Monthly n=283 Participants DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56).
DB Period: Number of Participants With Potentially Clinically Significant Abnormal Vital Signs Values	9 Participants	8 Participants	8 Participants

SECONDARY outcome

Timeframe: Week 12 up to Week 24

Criteria for potentially clinically significant abnormal vital signs values included: pulse rate: ≤50 bpm and decrease of ≥15 bpm, or ≥120 bpm and increase of ≥15 bpm; systolic blood pressure: ≤90 mmHg and decrease of ≥20 mmHg, or ≥180 mmHg and increase of ≥20 mmHg; diastolic blood pressure: ≤50 mmHg and decrease of ≥15 mmHg or ≥105 mmHg and increase of ≥15 mmHg; respiratory rate: \<10 breaths/minute; and body temperature ≥38.3 degrees celsius and change of ≥1.1 degrees celsius. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.

Outcome measures

Outcome measures
Measure	Placebo n=261 Participants DB period: Participants with CM or EM received 3 injections of placebo 1.5 mL SC on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56.	Fremanezumab Quarterly n=270 Participants DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56).	Fremanezumab Monthly n=273 Participants DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56).
OL Period: Number of Participants With Potentially Clinically Significant Abnormal Vital Signs Values	10 Participants	14 Participants	8 Participants

SECONDARY outcome

Timeframe: Baseline, Week 12

Population: DB safety analysis set included all randomized participants who received at least 1 dose of study drug during the DB treatment period. Here, 'Overall number of participants analyzed' = participants with both baseline and Week 12 ECG findings.

ECG parameters included: heart rate, PR interval, QRS interval, QT interval corrected using the Fridericia formula (QTcF), QT interval corrected using the Bazett's formula (QTcB) and RR interval. Shifts represented as Baseline - Week 12 value. Abnormal NCS indicated an abnormal but not clinically significant finding. Abnormal CS indicated an abnormal and clinically significant finding. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.

Outcome measures

Outcome measures
Measure	Placebo n=258 Participants DB period: Participants with CM or EM received 3 injections of placebo 1.5 mL SC on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56.	Fremanezumab Quarterly n=271 Participants DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56).	Fremanezumab Monthly n=270 Participants DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56).
DB Period: Number of Participants With Shift From Baseline to Week 12 in Electrocardiogram (ECG) Parameters Normal - Normal	199 Participants	218 Participants	212 Participants
DB Period: Number of Participants With Shift From Baseline to Week 12 in Electrocardiogram (ECG) Parameters Normal - Abnormal NCS	21 Participants	14 Participants	15 Participants
DB Period: Number of Participants With Shift From Baseline to Week 12 in Electrocardiogram (ECG) Parameters Abnormal NCS - Normal	10 Participants	19 Participants	12 Participants
DB Period: Number of Participants With Shift From Baseline to Week 12 in Electrocardiogram (ECG) Parameters Abnormal NCS - Abnormal NCS	28 Participants	20 Participants	31 Participants
DB Period: Number of Participants With Shift From Baseline to Week 12 in Electrocardiogram (ECG) Parameters Abnormal NCS - Abnormal CS	0 Participants	0 Participants	0 Participants
DB Period: Number of Participants With Shift From Baseline to Week 12 in Electrocardiogram (ECG) Parameters Abnormal CS - Abnormal NCS	0 Participants	0 Participants	0 Participants
DB Period: Number of Participants With Shift From Baseline to Week 12 in Electrocardiogram (ECG) Parameters Abnormal CS - Abnormal CS	0 Participants	0 Participants	0 Participants
DB Period: Number of Participants With Shift From Baseline to Week 12 in Electrocardiogram (ECG) Parameters Normal - Abnormal CS	0 Participants	0 Participants	0 Participants
DB Period: Number of Participants With Shift From Baseline to Week 12 in Electrocardiogram (ECG) Parameters Abnormal CS - Normal	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline, Week 24

Population: OL safety analysis set included all participants who received at least 1 dose of study drug during the OL treatment period. Here, 'Overall number of participants analyzed' = participants with both baseline and Week 24 ECG findings.

ECG parameters included: heart rate, PR interval, QRS interval, QT interval corrected using the Fridericia formula (QTcF), QT interval corrected using the Bazett's formula (QTcB) and RR interval. Shifts represented as Baseline - Week 24 value. Abnormal NCS indicated an abnormal but not clinically significant finding. Abnormal CS indicated an abnormal and clinically significant finding. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.

Outcome measures

Outcome measures
Measure	Placebo n=247 Participants DB period: Participants with CM or EM received 3 injections of placebo 1.5 mL SC on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56.	Fremanezumab Quarterly n=257 Participants DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56).	Fremanezumab Monthly n=261 Participants DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56).
OL Period: Number of Participants With Shift From Baseline to Week 24 in ECG Parameters Normal - Normal	194 Participants	215 Participants	204 Participants
OL Period: Number of Participants With Shift From Baseline to Week 24 in ECG Parameters Normal - Abnormal NCS	15 Participants	5 Participants	15 Participants
OL Period: Number of Participants With Shift From Baseline to Week 24 in ECG Parameters Abnormal NCS - Normal	14 Participants	20 Participants	16 Participants
OL Period: Number of Participants With Shift From Baseline to Week 24 in ECG Parameters Abnormal CS - Abnormal CS	0 Participants	0 Participants	0 Participants
OL Period: Number of Participants With Shift From Baseline to Week 24 in ECG Parameters Normal - Abnormal CS	0 Participants	0 Participants	1 Participants
OL Period: Number of Participants With Shift From Baseline to Week 24 in ECG Parameters Abnormal NCS - Abnormal NCS	24 Participants	17 Participants	25 Participants
OL Period: Number of Participants With Shift From Baseline to Week 24 in ECG Parameters Abnormal NCS - Abnormal CS	0 Participants	0 Participants	0 Participants
OL Period: Number of Participants With Shift From Baseline to Week 24 in ECG Parameters Abnormal CS - Normal	0 Participants	0 Participants	0 Participants
OL Period: Number of Participants With Shift From Baseline to Week 24 in ECG Parameters Abnormal CS - Abnormal NCS	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline up to Week 12

Population: DB safety analysis set included all randomized participants who received at least 1 dose of study drug during the DB treatment period.

Concomitant medications included: agents acting on the renin-angiotensin system, all other therapeutic products (for example: homeopathic preparation), allergens, analgesics, anesthetics, anti-parkinson drugs, antianemic preparations, antibacterials for systemic use, antibiotics and chemotherapeutics for dermatological use, antidiarrheals, intestinal antiinflammatory/antiinfective agents, antiemetic, antiepileptics, antifungals for dermatologiocal use, antigout preparations, antihemorrhagics, antihistamines for systemic use, antihypertensives, antiinflammatory and antirheumatic products, antimycotics for systemic use, antipruritics, antipsoriatics, antivirals for systemic use, beta blocking agents, blood substitutes and perfusion solutions, cardiac therapy, corticosteroids, cough and cold preparations, diagnostic radiopharmaceuticals, diuretics, thyroid therapy, urologicals, vaccines, psycoleptics, psycoanaleptics, ophthalmologicals, muscle relaxants, drugs used in diabetes etc.

Outcome measures

Outcome measures
Measure	Placebo n=277 Participants DB period: Participants with CM or EM received 3 injections of placebo 1.5 mL SC on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56.	Fremanezumab Quarterly n=276 Participants DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56).	Fremanezumab Monthly n=285 Participants DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56).
DB Period: Number of Participants Who Received Concomitant Medications for Adverse Events	274 Participants	269 Participants	280 Participants

SECONDARY outcome

Timeframe: Week 12 up to Week 24

Population: OL safety analysis set included all participants who received at least 1 dose of study drug during the OL treatment period.

Outcome measures

Outcome measures
Measure	Placebo n=262 Participants DB period: Participants with CM or EM received 3 injections of placebo 1.5 mL SC on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56.	Fremanezumab Quarterly n=271 Participants DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56).	Fremanezumab Monthly n=274 Participants DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56).
OL Period: Number of Participants Who Received Concomitant Medications for Adverse Events	262 Participants	266 Participants	270 Participants

Adverse Events

Placebo

Serious events: 13 serious events

Other events: 88 other events

Deaths: 0 deaths

Fremanezumab Quarterly

Serious events: 10 serious events

Other events: 90 other events

Deaths: 0 deaths

Fremanezumab Monthly

Serious events: 11 serious events

Other events: 81 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Placebo n=277 participants at risk DB period: Participants with CM or EM received 3 injections of placebo 1.5 mL SC on Day 0 and single injection of placebo 1.5 mL SC on Days 28 and 56. OL period: Participants with CM or EM received fremanezumab (TEV-48125) 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL) at Days 84, 112, and 140.	Fremanezumab Quarterly n=276 participants at risk DB period: Participants with CM or EM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of placebo 1.5 mL for 2 months (on Days 28 and 56). OL period: Participants with CM or EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL) at Days 84, 112, and 140.	Fremanezumab Monthly n=285 participants at risk DB period: Participants with CM received fremanezumab 675 mg SC (3 injections of fremanezumab 225 mg/1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56). Participants with EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL and 2 injections of placebo 1.5 mL) on Day 0 followed by monthly SC administration of fremanezumab 225 mg (1 injection of fremanezumab 225 mg/1.5 mL) for 2 months (on Days 28 and 56).OL period: Participants with CM or EM received fremanezumab 225 mg SC (1 injection of fremanezumab 225 mg/1.5 mL) at Days 84, 112, and 140.
General disorders Injection site erythema	8.7% 24/277 • Number of events 53 • Baseline (Day 0) up to follow-up visit (Week 46) Safety analysis set included all participants who received at least 1 dose of study drug. AE data per system organ class (SOC) and preferred term (PT) were summarized collectively for both periods. 2 participants (1 with CM and 1 with EM) randomized to placebo but received Fremanezumab monthly dosing during double-blind treatment period. They were analyzed in the treatment arm per actual treatment received.	11.2% 31/276 • Number of events 66 • Baseline (Day 0) up to follow-up visit (Week 46) Safety analysis set included all participants who received at least 1 dose of study drug. AE data per system organ class (SOC) and preferred term (PT) were summarized collectively for both periods. 2 participants (1 with CM and 1 with EM) randomized to placebo but received Fremanezumab monthly dosing during double-blind treatment period. They were analyzed in the treatment arm per actual treatment received.	11.2% 32/285 • Number of events 80 • Baseline (Day 0) up to follow-up visit (Week 46) Safety analysis set included all participants who received at least 1 dose of study drug. AE data per system organ class (SOC) and preferred term (PT) were summarized collectively for both periods. 2 participants (1 with CM and 1 with EM) randomized to placebo but received Fremanezumab monthly dosing during double-blind treatment period. They were analyzed in the treatment arm per actual treatment received.
General disorders Injection site induration	5.8% 16/277 • Number of events 52 • Baseline (Day 0) up to follow-up visit (Week 46) Safety analysis set included all participants who received at least 1 dose of study drug. AE data per system organ class (SOC) and preferred term (PT) were summarized collectively for both periods. 2 participants (1 with CM and 1 with EM) randomized to placebo but received Fremanezumab monthly dosing during double-blind treatment period. They were analyzed in the treatment arm per actual treatment received.	6.9% 19/276 • Number of events 41 • Baseline (Day 0) up to follow-up visit (Week 46) Safety analysis set included all participants who received at least 1 dose of study drug. AE data per system organ class (SOC) and preferred term (PT) were summarized collectively for both periods. 2 participants (1 with CM and 1 with EM) randomized to placebo but received Fremanezumab monthly dosing during double-blind treatment period. They were analyzed in the treatment arm per actual treatment received.	6.3% 18/285 • Number of events 65 • Baseline (Day 0) up to follow-up visit (Week 46) Safety analysis set included all participants who received at least 1 dose of study drug. AE data per system organ class (SOC) and preferred term (PT) were summarized collectively for both periods. 2 participants (1 with CM and 1 with EM) randomized to placebo but received Fremanezumab monthly dosing during double-blind treatment period. They were analyzed in the treatment arm per actual treatment received.
General disorders Injection site pain	3.6% 10/277 • Number of events 20 • Baseline (Day 0) up to follow-up visit (Week 46) Safety analysis set included all participants who received at least 1 dose of study drug. AE data per system organ class (SOC) and preferred term (PT) were summarized collectively for both periods. 2 participants (1 with CM and 1 with EM) randomized to placebo but received Fremanezumab monthly dosing during double-blind treatment period. They were analyzed in the treatment arm per actual treatment received.	5.4% 15/276 • Number of events 42 • Baseline (Day 0) up to follow-up visit (Week 46) Safety analysis set included all participants who received at least 1 dose of study drug. AE data per system organ class (SOC) and preferred term (PT) were summarized collectively for both periods. 2 participants (1 with CM and 1 with EM) randomized to placebo but received Fremanezumab monthly dosing during double-blind treatment period. They were analyzed in the treatment arm per actual treatment received.	4.9% 14/285 • Number of events 42 • Baseline (Day 0) up to follow-up visit (Week 46) Safety analysis set included all participants who received at least 1 dose of study drug. AE data per system organ class (SOC) and preferred term (PT) were summarized collectively for both periods. 2 participants (1 with CM and 1 with EM) randomized to placebo but received Fremanezumab monthly dosing during double-blind treatment period. They were analyzed in the treatment arm per actual treatment received.
Infections and infestations Nasopharyngitis	11.6% 32/277 • Number of events 37 • Baseline (Day 0) up to follow-up visit (Week 46) Safety analysis set included all participants who received at least 1 dose of study drug. AE data per system organ class (SOC) and preferred term (PT) were summarized collectively for both periods. 2 participants (1 with CM and 1 with EM) randomized to placebo but received Fremanezumab monthly dosing during double-blind treatment period. They were analyzed in the treatment arm per actual treatment received.	10.9% 30/276 • Number of events 41 • Baseline (Day 0) up to follow-up visit (Week 46) Safety analysis set included all participants who received at least 1 dose of study drug. AE data per system organ class (SOC) and preferred term (PT) were summarized collectively for both periods. 2 participants (1 with CM and 1 with EM) randomized to placebo but received Fremanezumab monthly dosing during double-blind treatment period. They were analyzed in the treatment arm per actual treatment received.	8.8% 25/285 • Number of events 30 • Baseline (Day 0) up to follow-up visit (Week 46) Safety analysis set included all participants who received at least 1 dose of study drug. AE data per system organ class (SOC) and preferred term (PT) were summarized collectively for both periods. 2 participants (1 with CM and 1 with EM) randomized to placebo but received Fremanezumab monthly dosing during double-blind treatment period. They were analyzed in the treatment arm per actual treatment received.
Infections and infestations Upper respiratory tract infection	3.6% 10/277 • Number of events 10 • Baseline (Day 0) up to follow-up visit (Week 46) Safety analysis set included all participants who received at least 1 dose of study drug. AE data per system organ class (SOC) and preferred term (PT) were summarized collectively for both periods. 2 participants (1 with CM and 1 with EM) randomized to placebo but received Fremanezumab monthly dosing during double-blind treatment period. They were analyzed in the treatment arm per actual treatment received.	2.9% 8/276 • Number of events 11 • Baseline (Day 0) up to follow-up visit (Week 46) Safety analysis set included all participants who received at least 1 dose of study drug. AE data per system organ class (SOC) and preferred term (PT) were summarized collectively for both periods. 2 participants (1 with CM and 1 with EM) randomized to placebo but received Fremanezumab monthly dosing during double-blind treatment period. They were analyzed in the treatment arm per actual treatment received.	5.6% 16/285 • Number of events 17 • Baseline (Day 0) up to follow-up visit (Week 46) Safety analysis set included all participants who received at least 1 dose of study drug. AE data per system organ class (SOC) and preferred term (PT) were summarized collectively for both periods. 2 participants (1 with CM and 1 with EM) randomized to placebo but received Fremanezumab monthly dosing during double-blind treatment period. They were analyzed in the treatment arm per actual treatment received.
Nervous system disorders Migraine	7.6% 21/277 • Number of events 26 • Baseline (Day 0) up to follow-up visit (Week 46) Safety analysis set included all participants who received at least 1 dose of study drug. AE data per system organ class (SOC) and preferred term (PT) were summarized collectively for both periods. 2 participants (1 with CM and 1 with EM) randomized to placebo but received Fremanezumab monthly dosing during double-blind treatment period. They were analyzed in the treatment arm per actual treatment received.	5.1% 14/276 • Number of events 15 • Baseline (Day 0) up to follow-up visit (Week 46) Safety analysis set included all participants who received at least 1 dose of study drug. AE data per system organ class (SOC) and preferred term (PT) were summarized collectively for both periods. 2 participants (1 with CM and 1 with EM) randomized to placebo but received Fremanezumab monthly dosing during double-blind treatment period. They were analyzed in the treatment arm per actual treatment received.	4.2% 12/285 • Number of events 14 • Baseline (Day 0) up to follow-up visit (Week 46) Safety analysis set included all participants who received at least 1 dose of study drug. AE data per system organ class (SOC) and preferred term (PT) were summarized collectively for both periods. 2 participants (1 with CM and 1 with EM) randomized to placebo but received Fremanezumab monthly dosing during double-blind treatment period. They were analyzed in the treatment arm per actual treatment received.

Additional Information

Director, Clinical Research

Teva Branded Pharmaceutical Products, R&D Inc.

Phone: 1-888-483-8279

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Sponsor has the right 60 days before submission for publication to review/provide comments. If the Sponsor's review shows that potentially patentable subject matter would be disclosed, publication or public disclosure shall be delayed for up to 90 additional days in order for the Sponsor, or Sponsor's designees, to file the necessary patent applications. In multicenter trials, each PI will postpone single center publications until after disclosure or publication of multicenter data.
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