Trial Outcomes & Findings for A Study to Evaluate the Efficacy and Safety of TEV-48125 (Fremanezumab) for the Prevention of Episodic Cluster Headache (ECH) (NCT NCT02945046)

NCT ID: NCT02945046

Last Updated: 2021-11-09

Results Overview

A CH attack was defined as a severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15 to 180 minutes with either or both of the following 2 categories: 1) at least 1 of the following symptoms or signs, ipsilateral to the headache: -conjunctival injection and/or lacrimation; -nasal congestion and/or rhinorrhea; -eyelid edema; -forehead and facial sweating; -forehead and facial flushing; -sensation of fullness in the ear; -miosis and/or ptosis. 2) a sense of restlessness or agitation. Least Squares (LS) mean calculated using analysis of covariance (ANCOVA) model with baseline preventive medication use (yes or no), sex, region (United States \[US\]/Canada or other), and treatment as fixed effects and the baseline number of CH attacks as a covariate. Change from baseline in the overall weekly average number of CH attacks during the 4-week period after administration of the first dose of study drug (based on Week 0 to 4 data) is reported.

• Recruitment status: TERMINATED
• Study phase: PHASE3
• Target enrollment: 169 participants
• Primary outcome timeframe: Baseline (Week 0), up to Week 4
• Results posted on: 2021-11-09

Participant Flow

A total of 169 participants were randomized in a 1:1:1 ratio to placebo, fremanezumab 675 milligrams (mg)/placebo/placebo, or fremanezumab 900/225/225 mg groups.

Participant milestones

Measure	Placebo Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Fremanezumab 675 mg/Placebo/Placebo Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 milligrams (mg) administered as 3 subcutaneous injections (225 mg/1.5 milliliters \[mL\]) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Fremanezumab 900/225/225 mg Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Overall Study STARTED	59	55	55
Overall Study Safety Analysis Set	59	55	55
Overall Study Full Analysis Set	57	53	55
Overall Study COMPLETED	46	42	40
Overall Study NOT COMPLETED	13	13	15

Reasons for withdrawal

Measure	Placebo Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Fremanezumab 675 mg/Placebo/Placebo Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 milligrams (mg) administered as 3 subcutaneous injections (225 mg/1.5 milliliters \[mL\]) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Fremanezumab 900/225/225 mg Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Overall Study Adverse Event	1	0	2
Overall Study Withdrawal by Subject	3	3	3
Overall Study Protocol Violation	2	3	2
Overall Study Lost to Follow-up	1	1	0
Overall Study Lack of Efficacy	1	2	1
Overall Study Other than specified	5	4	7

Baseline Characteristics

A Study to Evaluate the Efficacy and Safety of TEV-48125 (Fremanezumab) for the Prevention of Episodic Cluster Headache (ECH)

Baseline characteristics by cohort

Measure	Placebo n=59 Participants Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Fremanezumab 675 mg/Placebo/Placebo n=55 Participants Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Fremanezumab 900/225/225 mg n=55 Participants Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Total n=169 Participants Total of all reporting groups
Age, Continuous	43.1 years STANDARD_DEVIATION 10.39 • n=5 Participants	45.4 years STANDARD_DEVIATION 11.23 • n=7 Participants	43.5 years STANDARD_DEVIATION 11.48 • n=5 Participants	43.9 years STANDARD_DEVIATION 11.01 • n=4 Participants
Sex: Female, Male Female	16 Participants n=5 Participants	17 Participants n=7 Participants	17 Participants n=5 Participants	50 Participants n=4 Participants
Sex: Female, Male Male	43 Participants n=5 Participants	38 Participants n=7 Participants	38 Participants n=5 Participants	119 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=5 Participants	3 Participants n=7 Participants	5 Participants n=5 Participants	10 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	56 Participants n=5 Participants	52 Participants n=7 Participants	49 Participants n=5 Participants	157 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	3 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants	5 Participants n=4 Participants
Race (NIH/OMB) White	54 Participants n=5 Participants	55 Participants n=7 Participants	51 Participants n=5 Participants	160 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants
Number of CH Attacks	14.8 CH attacks STANDARD_DEVIATION 10.50 • n=5 Participants	15.9 CH attacks STANDARD_DEVIATION 9.18 • n=7 Participants	14.5 CH attacks STANDARD_DEVIATION 7.55 • n=5 Participants	15.1 CH attacks STANDARD_DEVIATION 9.15 • n=4 Participants

PRIMARY outcome

Timeframe: Baseline (Week 0), up to Week 4

Population: Full analysis set included all randomized participants who received at least 1 dose of IMP and had at least 10 days of postbaseline efficacy assessment in the first 4 weeks on the primary endpoint.

A CH attack was defined as a severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15 to 180 minutes with either or both of the following 2 categories: 1) at least 1 of the following symptoms or signs, ipsilateral to the headache: -conjunctival injection and/or lacrimation; -nasal congestion and/or rhinorrhea; -eyelid edema; -forehead and facial sweating; -forehead and facial flushing; -sensation of fullness in the ear; -miosis and/or ptosis. 2) a sense of restlessness or agitation. Least Squares (LS) mean calculated using analysis of covariance (ANCOVA) model with baseline preventive medication use (yes or no), sex, region (United States [US]/Canada or other), and treatment as fixed effects and the baseline number of CH attacks as a covariate. Change from baseline in the overall weekly average number of CH attacks during the 4-week period after administration of the first dose of study drug (based on Week 0 to 4 data) is reported.

Outcome measures

Measure	Placebo n=57 Participants Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Fremanezumab 675 mg/Placebo/Placebo n=53 Participants Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Fremanezumab 900/225/225 mg n=55 Participants Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Mean Change From Baseline in the Weekly Average Number of Cluster Headache (CH) Attacks During the 4-Week Period After Administration of the First Dose of the IMP	-5.7 CH attacks/week Standard Error 1.00	-5.8 CH attacks/week Standard Error 1.02	-7.6 CH attacks/week Standard Error 1.01

SECONDARY outcome

Timeframe: Baseline (Week 0), up to Week 4

Population: Full analysis set included all randomized participants who received at least 1 dose of IMP and had at least 10 days of postbaseline efficacy assessment in the first 4 weeks on the primary endpoint.

A CH attack was defined as a severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15 to 180 minutes with either or both of the following 2 categories: 1) at least 1 of the following symptoms or signs, ipsilateral to the headache: -conjunctival injection and/or lacrimation; -nasal congestion and/or rhinorrhea; -eyelid edema; -forehead and facial sweating; -forehead and facial flushing; -sensation of fullness in the ear; -miosis and/or ptosis. 2) a sense of restlessness or agitation.

Outcome measures

Measure	Placebo n=57 Participants Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Fremanezumab 675 mg/Placebo/Placebo n=53 Participants Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Fremanezumab 900/225/225 mg n=55 Participants Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Percentage of Participants With a ≥50% Reduction From Baseline in the Weekly Average Number of CH Attacks During the 4-Week Period After the First Dose of the IMP	60 percentage of participants	55 percentage of participants	75 percentage of participants

SECONDARY outcome

Timeframe: Baseline (Week 0), up to Week 12

Population: Full analysis set included all randomized participants who received at least 1 dose of IMP and had at least 10 days of postbaseline efficacy assessment in the first 4 weeks on the primary endpoint.

A CH attack was defined as a severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15 to 180 minutes with either or both of the following 2 categories: 1) at least 1 of the following symptoms or signs, ipsilateral to the headache: -conjunctival injection and/or lacrimation; -nasal congestion and/or rhinorrhea; -eyelid edema; -forehead and facial sweating; -forehead and facial flushing; -sensation of fullness in the ear; -miosis and/or ptosis. 2) a sense of restlessness or agitation. LS mean calculated using mixed model for repeated measures (MMRM) with baseline preventive medication use (yes or no), gender, region (US/Canada or other), treatment, month, and month-by-treatment interaction as fixed effects and baseline number of CH attacks as a covariate. Change from baseline in the overall weekly average number of CH attacks during the 12-week period after administration of the first dose of study drug (based on Week 0 to 12 data) is reported.

Outcome measures

Measure	Placebo n=57 Participants Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Fremanezumab 675 mg/Placebo/Placebo n=53 Participants Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Fremanezumab 900/225/225 mg n=55 Participants Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Mean Change From Baseline in Weekly Average Number of CH Attacks During the 12-Week Period After Administration of the First Dose of the IMP	-8.4 CH attacks/week Standard Error 0.66	-8.9 CH attacks/week Standard Error 0.68	-9.6 CH attacks/week Standard Error 0.67

SECONDARY outcome

Timeframe: Baseline (Week 0), Week 8 up to Week 12

Population: Full analysis set included all randomized participants who received at least 1 dose of IMP and had at least 10 days of postbaseline efficacy assessment in the first 4 weeks on the primary endpoint. Here, 'overall number of participants analyzed'=participants evaluable for this outcome measure.

A CH attack was defined as a severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15 to 180 minutes with either or both of the following 2 categories: 1) at least 1 of the following symptoms or signs, ipsilateral to the headache: -conjunctival injection and/or lacrimation; -nasal congestion and/or rhinorrhea; -eyelid edema; -forehead and facial sweating; -forehead and facial flushing; -sensation of fullness in the ear; -miosis and/or ptosis. 2) a sense of restlessness or agitation. LS mean calculated using MMRM with baseline preventive medication use (yes or no), gender, region (US/Canada or other), treatment, month, and month-by-treatment interaction as fixed effects and baseline number of CH attacks as a covariate. Change from baseline in the overall weekly average number of CH attacks during the 4-week period after administration of the first dose of study drug (based on Week 8 to 12 data) is reported.

Outcome measures

Measure	Placebo n=46 Participants Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Fremanezumab 675 mg/Placebo/Placebo n=42 Participants Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Fremanezumab 900/225/225 mg n=40 Participants Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Mean Change From Baseline in Weekly Average Number of CH Attacks During the 4-Week Period After Administration of the Third Dose of the IMP	-10.8 CH attacks/week Standard Error 0.75	-10.8 CH attacks/week Standard Error 0.78	-10.9 CH attacks/week Standard Error 0.78

SECONDARY outcome

Timeframe: Baseline (Week 0), up to Week 12

Population: Full analysis set included all randomized participants who received at least 1 dose of IMP and had at least 10 days of postbaseline efficacy assessment in the first 4 weeks on the primary endpoint.

A maximum of 2 concomitant preventive medications for CH were allowed during the study. Participants must have been on a stable dose and regimen of the concomitant medication for at least 2 weeks before screening and throughout the study. LS mean calculated using ANCOVA model with baseline preventive medication use (yes or no), gender, region (US/Canada or other), and treatment as fixed effects and the baseline number of cluster headache attacks as a covariate. Baseline data and the mean change from baseline in the overall weekly average number of days with the use of cluster-specific acute headache medications (triptans and ergot compounds) during the 12-week period after administration of the first dose of study drug (based on Week 0 to 12 data) is reported.

Outcome measures

Measure	Placebo n=57 Participants Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Fremanezumab 675 mg/Placebo/Placebo n=53 Participants Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Fremanezumab 900/225/225 mg n=55 Participants Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Mean Change From Baseline in the Weekly Average Number of Days With Use of Cluster-Specific Acute Headache Medications (Triptans and Ergot Compounds) During the 12-Week Period After the First Dose of the IMP	-1.6 days of use/week Standard Error 0.36	-2.4 days of use/week Standard Error 0.36	-2.8 days of use/week Standard Error 0.36

SECONDARY outcome

Timeframe: Baseline (Week 0), up to Week 12

Population: Full analysis set included all randomized participants who received at least 1 dose of IMP and had at least 10 days of postbaseline efficacy assessment in the first 4 weeks on the primary endpoint.

LS mean calculated using ANCOVA model with baseline preventive medication use (yes or no), gender, region (US/Canada or other), and treatment as fixed effects and the baseline number of cluster headache attacks as a covariate. Baseline data and the mean change from baseline in the overall weekly average number of days oxygen was used to treat ECH during the 12-week period after administration of the first dose of IMP (based on Week 0 to 12 data) is reported.

Outcome measures

Measure	Placebo n=57 Participants Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Fremanezumab 675 mg/Placebo/Placebo n=53 Participants Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Fremanezumab 900/225/225 mg n=55 Participants Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Mean Change From Baseline in the Weekly Average Number of Days Oxygen Was Used to Treat Episodic Cluster Headache (ECH) During the 12-Week Period After the First Dose of the IMP	-1.1 days of use/week Standard Error 0.30	-1.5 days of use/week Standard Error 0.31	-1.0 days of use/week Standard Error 0.30

SECONDARY outcome

Timeframe: Baseline, Weeks 1, 4, 8, and 12

Population: Full analysis set included all randomized participants who received at least 1 dose of IMP and had at least 10 days of postbaseline efficacy assessment in the first 4 weeks on the primary endpoint.

The PPSI assessment was developed to measure pain intensity and was adjusted for CH symptoms improvement. Participants marked the level of CH-associated pain and indicated if pain is "1=much worse," "2=moderately worse," "3=slightly worse," "4=unchanged," "5=slightly improved," "6=moderately improved," or "7=much improved" compared with 4 weeks prior. PPSI was defined as the change in pain that corresponds with a minimal rating of "5=slightly improved." Data at Week 1 was recorded on Day 7 in the electronic diary device at home. Week 12 data also included assessment at the early withdrawal visit for participants who discontinued the study early.

Outcome measures

Measure	Placebo n=57 Participants Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Fremanezumab 675 mg/Placebo/Placebo n=53 Participants Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Fremanezumab 900/225/225 mg n=55 Participants Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Week 12 · Slightly improved	5 Participants	5 Participants	4 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Week 12 · Moderately improved	8 Participants	7 Participants	5 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Week 12 · Much improved	17 Participants	19 Participants	24 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Week 12 · Missing	6 Participants	3 Participants	3 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Baseline · Much worse	10 Participants	14 Participants	7 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Baseline · Moderately worse	3 Participants	5 Participants	8 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Baseline · Slightly worse	3 Participants	3 Participants	3 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Baseline · Unchanged	37 Participants	31 Participants	28 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Baseline · Slightly improved	3 Participants	0 Participants	6 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Baseline · Moderately improved	1 Participants	0 Participants	1 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Baseline · Much improved	0 Participants	0 Participants	2 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Baseline · Missing	0 Participants	0 Participants	0 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Week 1 · Much worse	2 Participants	4 Participants	1 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Week 1 · Moderately worse	2 Participants	2 Participants	1 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Week 1 · Slightly worse	5 Participants	3 Participants	2 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Week 1 · Unchanged	19 Participants	11 Participants	9 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Week 1 · Slightly improved	11 Participants	8 Participants	14 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Week 1 · Moderately improved	5 Participants	3 Participants	6 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Week 1 · Much improved	6 Participants	12 Participants	12 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Week 1 · Missing	7 Participants	10 Participants	10 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Week 4 · Much worse	1 Participants	1 Participants	2 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Week 4 · Moderately worse	3 Participants	0 Participants	1 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Week 4 · Slightly worse	4 Participants	2 Participants	0 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Week 4 · Unchanged	8 Participants	11 Participants	5 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Week 4 · Slightly improved	9 Participants	9 Participants	8 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Week 4 · Moderately improved	5 Participants	7 Participants	8 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Week 4 · Much improved	23 Participants	19 Participants	27 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Week 4 · Missing	4 Participants	4 Participants	4 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Week 8 · Much worse	1 Participants	1 Participants	0 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Week 8 · Moderately worse	3 Participants	0 Participants	1 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Week 8 · Slightly worse	0 Participants	1 Participants	1 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Week 8 · Unchanged	13 Participants	8 Participants	12 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Week 8 · Slightly improved	1 Participants	6 Participants	5 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Week 8 · Moderately improved	7 Participants	6 Participants	7 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Week 8 · Much improved	20 Participants	20 Participants	17 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Week 8 · Missing	12 Participants	11 Participants	12 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Week 12 · Much worse	3 Participants	2 Participants	2 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Week 12 · Moderately worse	0 Participants	0 Participants	1 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Week 12 · Slightly worse	2 Participants	1 Participants	0 Participants
Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 Week 12 · Unchanged	16 Participants	16 Participants	16 Participants

SECONDARY outcome

Timeframe: Baseline up to Week 12

Population: Safety analysis set included all randomized participants who received at least 1 dose of the IMP.

An AE was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Relationship of AE to treatment was determined by the Investigator. Serious AEs include death, a life-threatening adverse event, 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 the participant and required medical intervention to prevent the previously listed serious outcomes. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.

Outcome measures

Measure	Placebo n=59 Participants Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Fremanezumab 675 mg/Placebo/Placebo n=55 Participants Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Fremanezumab 900/225/225 mg n=55 Participants Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Number of Participants With Adverse Events (AEs) AEs leading to discontinuation	1 Participants	0 Participants	2 Participants
Number of Participants With Adverse Events (AEs) Any AEs	28 Participants	26 Participants	28 Participants
Number of Participants With Adverse Events (AEs) Treatment-related AEs	8 Participants	11 Participants	13 Participants
Number of Participants With Adverse Events (AEs) Serious AEs	5 Participants	0 Participants	1 Participants

SECONDARY outcome

Timeframe: Baseline up to Week 12

Population: Safety analysis set included all randomized participants who received at least 1 dose of the IMP. Here, 'overall number of participants analyzed'=participants evaluable for this outcome measure.

Serum chemistry, hematology, urinalysis laboratory tests with potentially clinically significant abnormal findings included: alanine aminotransferase (ALP), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), lactate dehydrogenase (LDH) each ≥3*upper limit of normal (ULN); blood urea nitrogen (BUN) ≥10.71 millimole (mmol)/L; Bilirubin (Total) ≥34.2 micromole/liter (umol/L); Blood Urea Nitrogen ≥10.71 millimoles (mmol)/L; creatinine ≥177 umol/L; hemoglobin less than or equal to (≤)115 grams (g)/L (males) or ≤95 g/L (females); leukocytes ≥20*10^9/L or ≤3*10^9/L; eosinophils ≥10%; hematocrit <0.37 L/L (males) and <0.32 L/L (females); platelets ≥700*10^9/L or ≤75*10^9/L; haemoglobin, urine glucose, ketones, urine total protein each ≥2 unit (U) 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

Measure	Placebo n=56 Participants Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Fremanezumab 675 mg/Placebo/Placebo n=54 Participants Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Fremanezumab 900/225/225 mg n=54 Participants Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Number of Participants With Potentially Clinically Significant Laboratory (Serum Chemistry, Hematology, and Urinalysis) Abnormal Results With at least 1 serum chemistry abnormality	1 Participants	1 Participants	0 Participants
Number of Participants With Potentially Clinically Significant Laboratory (Serum Chemistry, Hematology, and Urinalysis) Abnormal Results With at least 1 hematology abnormality	4 Participants	1 Participants	4 Participants
Number of Participants With Potentially Clinically Significant Laboratory (Serum Chemistry, Hematology, and Urinalysis) Abnormal Results With at least 1 urinalysis abnormality	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline up to Week 12

Population: Safety analysis set included all randomized participants who received at least 1 dose of the IMP.

Coagulation parameters included: prothrombin time (PT) (seconds) and prothrombin international normalized ratio (INR). Shifts represented as Baseline - endpoint value (last observed post-baseline value). Shifts from baseline to endpoint were summarized using participant counts grouped into three categories: - Low (below normal range) - Normal (within the normal range of 9.4 to 12.5 seconds) - High (above normal range). Missing PT and prothrombin INR shift data are also presented. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.

Outcome measures

Measure	Placebo n=59 Participants Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Fremanezumab 675 mg/Placebo/Placebo n=55 Participants Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Fremanezumab 900/225/225 mg n=55 Participants Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Number of Participants With Shift From Baseline to Endpoint in Coagulation Laboratory Test Results PT · Low-Low	0 Participants	0 Participants	0 Participants
Number of Participants With Shift From Baseline to Endpoint in Coagulation Laboratory Test Results PT · Low-Normal	0 Participants	0 Participants	0 Participants
Number of Participants With Shift From Baseline to Endpoint in Coagulation Laboratory Test Results PT · Low-High	0 Participants	0 Participants	0 Participants
Number of Participants With Shift From Baseline to Endpoint in Coagulation Laboratory Test Results PT · Normal-Low	0 Participants	0 Participants	0 Participants
Number of Participants With Shift From Baseline to Endpoint in Coagulation Laboratory Test Results PT · Normal-Normal	47 Participants	46 Participants	44 Participants
Number of Participants With Shift From Baseline to Endpoint in Coagulation Laboratory Test Results PT · Normal-High	2 Participants	2 Participants	3 Participants
Number of Participants With Shift From Baseline to Endpoint in Coagulation Laboratory Test Results PT · High-Low	0 Participants	0 Participants	0 Participants
Number of Participants With Shift From Baseline to Endpoint in Coagulation Laboratory Test Results PT · High-Normal	4 Participants	4 Participants	4 Participants
Number of Participants With Shift From Baseline to Endpoint in Coagulation Laboratory Test Results PT · High-High	1 Participants	1 Participants	2 Participants
Number of Participants With Shift From Baseline to Endpoint in Coagulation Laboratory Test Results PT · Missing	5 Participants	2 Participants	2 Participants
Number of Participants With Shift From Baseline to Endpoint in Coagulation Laboratory Test Results Prothrombin INR · Low-Low	0 Participants	0 Participants	0 Participants
Number of Participants With Shift From Baseline to Endpoint in Coagulation Laboratory Test Results Prothrombin INR · Low-Normal	0 Participants	0 Participants	0 Participants
Number of Participants With Shift From Baseline to Endpoint in Coagulation Laboratory Test Results Prothrombin INR · Low-High	0 Participants	0 Participants	0 Participants
Number of Participants With Shift From Baseline to Endpoint in Coagulation Laboratory Test Results Prothrombin INR · Normal-Low	0 Participants	0 Participants	0 Participants
Number of Participants With Shift From Baseline to Endpoint in Coagulation Laboratory Test Results Prothrombin INR · Normal-Normal	48 Participants	48 Participants	47 Participants
Number of Participants With Shift From Baseline to Endpoint in Coagulation Laboratory Test Results Prothrombin INR · Normal-High	2 Participants	2 Participants	1 Participants
Number of Participants With Shift From Baseline to Endpoint in Coagulation Laboratory Test Results Prothrombin INR · High-Low	0 Participants	0 Participants	0 Participants
Number of Participants With Shift From Baseline to Endpoint in Coagulation Laboratory Test Results Prothrombin INR · High-Normal	3 Participants	3 Participants	3 Participants
Number of Participants With Shift From Baseline to Endpoint in Coagulation Laboratory Test Results Prothrombin INR · High-High	1 Participants	0 Participants	2 Participants
Number of Participants With Shift From Baseline to Endpoint in Coagulation Laboratory Test Results Prothrombin INR · Missing	5 Participants	2 Participants	2 Participants

SECONDARY outcome

Timeframe: Baseline up to Week 12

Population: Safety analysis set included all randomized participants who received at least 1 dose of the IMP. Here, 'overall number of participants analyzed'=participants evaluable for this outcome measure.

Potentially clinically significant abnormal vital signs findings included: pulse rate ≥120 beats per minute (bpm) and increase of 15 bpm; systolic blood pressure ≤90 millimeters of mercury (mmHg) and decrease of 20 mmHg; diastolic blood pressure ≤50 mmHg and decrease of 15 mmHg, or ≥105 mmHg and increase of 15 mmHg. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.

Outcome measures

Measure	Placebo n=56 Participants Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Fremanezumab 675 mg/Placebo/Placebo n=54 Participants Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Fremanezumab 900/225/225 mg n=54 Participants Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Number of Participants With Potentially Clinically Significant Abnormal Vital Signs Values	3 Participants	0 Participants	1 Participants

SECONDARY outcome

Timeframe: Baseline up to Week 12

Population: Safety analysis set included all randomized participants who received at least 1 dose of the IMP.

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 - endpoint value (last observed post-baseline value). Abnormal NCS indicated an abnormal but not clinically significant finding. Abnormal CS indicated an abnormal and clinically significant finding. Missing ECG shift data are also presented. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.

Outcome measures

Measure	Placebo n=59 Participants Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Fremanezumab 675 mg/Placebo/Placebo n=55 Participants Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Fremanezumab 900/225/225 mg n=55 Participants Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Electrocardiogram (ECG) Parameters Normal / Normal	35 Participants	33 Participants	23 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Electrocardiogram (ECG) Parameters Normal / Abnormal NCS	6 Participants	1 Participants	5 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Electrocardiogram (ECG) Parameters Normal / Abnormal CS	0 Participants	0 Participants	0 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Electrocardiogram (ECG) Parameters Abnormal NCS / Normal	4 Participants	9 Participants	4 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Electrocardiogram (ECG) Parameters Abnormal NCS / Abnormal NCS	7 Participants	9 Participants	18 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Electrocardiogram (ECG) Parameters Abnormal NCS / Abnormal CS	0 Participants	0 Participants	0 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Electrocardiogram (ECG) Parameters Abnormal CS / Normal	0 Participants	0 Participants	0 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Electrocardiogram (ECG) Parameters Abnormal CS / Abnormal NCS	0 Participants	0 Participants	0 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Electrocardiogram (ECG) Parameters Abnormal CS / Abnormal CS	0 Participants	0 Participants	0 Participants
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Electrocardiogram (ECG) Parameters Missing	7 Participants	3 Participants	5 Participants

SECONDARY outcome

Timeframe: Baseline up to Week 12

Population: Safety analysis set included all randomized participants who received at least 1 dose of the IMP.

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

Measure	Placebo n=59 Participants Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Fremanezumab 675 mg/Placebo/Placebo n=55 Participants Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Fremanezumab 900/225/225 mg n=55 Participants Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Number of Participants Who Received Concomitant Medications	57 Participants	52 Participants	52 Participants

SECONDARY outcome

Timeframe: Baseline up to Week 12

Population: Safety analysis set included all randomized participants who received at least 1 dose of the IMP.

Number of participants who reported treatment-emergent injection site reactions are summarized. Preferred terms from Medical Dictionary for Regulatory Activities (MedDRA) version 18.1 were offered without a threshold applied. Injection site reactions included injection site erythema, induration, pain, haemorrhage, swelling, and pruritus. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.

Outcome measures

Measure	Placebo n=59 Participants Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Fremanezumab 675 mg/Placebo/Placebo n=55 Participants Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Fremanezumab 900/225/225 mg n=55 Participants Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Number of Participants With Injection Site Reactions Injection site induration	1 Participants	3 Participants	6 Participants
Number of Participants With Injection Site Reactions Injection site pain	4 Participants	2 Participants	6 Participants
Number of Participants With Injection Site Reactions Injection site erythema	2 Participants	0 Participants	2 Participants
Number of Participants With Injection Site Reactions Injection site haemorrhage	0 Participants	0 Participants	1 Participants
Number of Participants With Injection Site Reactions Injection site pruritus	1 Participants	0 Participants	1 Participants
Number of Participants With Injection Site Reactions Injection site swelling	0 Participants	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline up to Week 12

Population: Safety analysis set included all randomized participants who received at least 1 dose of the IMP.

A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.

Outcome measures

Measure	Placebo n=59 Participants Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Fremanezumab 675 mg/Placebo/Placebo n=55 Participants Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Fremanezumab 900/225/225 mg n=55 Participants Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Number of Participants With Hypersensitivity/Anaphylaxis Reactions	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline up to Week 12

Population: Safety analysis set included all randomized participants who received at least 1 dose of the IMP.

eC-SSRS is a questionnaire to assess suicidal ideation and suicidal behavior. Suicidal behavior was defined as a "yes" answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation was defined as a "yes" answer to any one of 5 suicidal ideation questions: wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent, any self-injurious behavior with no suicidal intent.

Outcome measures

Measure	Placebo n=59 Participants Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Fremanezumab 675 mg/Placebo/Placebo n=55 Participants Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Fremanezumab 900/225/225 mg n=55 Participants Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Number of Participants With Suicidal Ideation and Suicidal Behavior as Assessed by the Electronic Columbia Suicide Severity Rating Scale (eC-SSRS)	0 Participants	1 Participants	4 Participants

Adverse Events

Placebo

Serious events: 5 serious events

Other events: 7 other events

Deaths: 0 deaths

Fremanezumab 675 mg/Placebo/Placebo

Serious events: 0 serious events

Other events: 9 other events

Deaths: 0 deaths

Fremanezumab 900/225/225 mg

Serious events: 1 serious events

Other events: 16 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo n=59 participants at risk Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Fremanezumab 675 mg/Placebo/Placebo n=55 participants at risk Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Fremanezumab 900/225/225 mg n=55 participants at risk Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Ear and labyrinth disorders Vertigo	1.7% 1/59 • Number of events 1 • Baseline up to Week 12 Safety analysis set included all randomized participants who received at least 1 dose of the IMP.	0.00% 0/55 • Baseline up to Week 12 Safety analysis set included all randomized participants who received at least 1 dose of the IMP.	0.00% 0/55 • Baseline up to Week 12 Safety analysis set included all randomized participants who received at least 1 dose of the IMP.
Gastrointestinal disorders Duodenitis	1.7% 1/59 • Number of events 1 • Baseline up to Week 12 Safety analysis set included all randomized participants who received at least 1 dose of the IMP.	0.00% 0/55 • Baseline up to Week 12 Safety analysis set included all randomized participants who received at least 1 dose of the IMP.	0.00% 0/55 • Baseline up to Week 12 Safety analysis set included all randomized participants who received at least 1 dose of the IMP.
General disorders Chest pain	1.7% 1/59 • Number of events 2 • Baseline up to Week 12 Safety analysis set included all randomized participants who received at least 1 dose of the IMP.	0.00% 0/55 • Baseline up to Week 12 Safety analysis set included all randomized participants who received at least 1 dose of the IMP.	0.00% 0/55 • Baseline up to Week 12 Safety analysis set included all randomized participants who received at least 1 dose of the IMP.
Injury, poisoning and procedural complications Lumbar vertebral fracture	1.7% 1/59 • Number of events 1 • Baseline up to Week 12 Safety analysis set included all randomized participants who received at least 1 dose of the IMP.	0.00% 0/55 • Baseline up to Week 12 Safety analysis set included all randomized participants who received at least 1 dose of the IMP.	0.00% 0/55 • Baseline up to Week 12 Safety analysis set included all randomized participants who received at least 1 dose of the IMP.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.00% 0/59 • Baseline up to Week 12 Safety analysis set included all randomized participants who received at least 1 dose of the IMP.	0.00% 0/55 • Baseline up to Week 12 Safety analysis set included all randomized participants who received at least 1 dose of the IMP.	1.8% 1/55 • Number of events 1 • Baseline up to Week 12 Safety analysis set included all randomized participants who received at least 1 dose of the IMP.
Nervous system disorders Cluster headache	3.4% 2/59 • Number of events 3 • Baseline up to Week 12 Safety analysis set included all randomized participants who received at least 1 dose of the IMP.	0.00% 0/55 • Baseline up to Week 12 Safety analysis set included all randomized participants who received at least 1 dose of the IMP.	0.00% 0/55 • Baseline up to Week 12 Safety analysis set included all randomized participants who received at least 1 dose of the IMP.

Other adverse events

Measure	Placebo n=59 participants at risk Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Fremanezumab 675 mg/Placebo/Placebo n=55 participants at risk Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Fremanezumab 900/225/225 mg n=55 participants at risk Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
General disorders Injection site induration	1.7% 1/59 • Number of events 1 • Baseline up to Week 12 Safety analysis set included all randomized participants who received at least 1 dose of the IMP.	5.5% 3/55 • Number of events 7 • Baseline up to Week 12 Safety analysis set included all randomized participants who received at least 1 dose of the IMP.	10.9% 6/55 • Number of events 10 • Baseline up to Week 12 Safety analysis set included all randomized participants who received at least 1 dose of the IMP.
General disorders Injection site pain	6.8% 4/59 • Number of events 6 • Baseline up to Week 12 Safety analysis set included all randomized participants who received at least 1 dose of the IMP.	3.6% 2/55 • Number of events 5 • Baseline up to Week 12 Safety analysis set included all randomized participants who received at least 1 dose of the IMP.	10.9% 6/55 • Number of events 17 • Baseline up to Week 12 Safety analysis set included all randomized participants who received at least 1 dose of the IMP.
Infections and infestations Influenza	3.4% 2/59 • Number of events 2 • Baseline up to Week 12 Safety analysis set included all randomized participants who received at least 1 dose of the IMP.	0.00% 0/55 • Baseline up to Week 12 Safety analysis set included all randomized participants who received at least 1 dose of the IMP.	5.5% 3/55 • Number of events 3 • Baseline up to Week 12 Safety analysis set included all randomized participants who received at least 1 dose of the IMP.
Infections and infestations Nasopharyngitis	1.7% 1/59 • Number of events 1 • Baseline up to Week 12 Safety analysis set included all randomized participants who received at least 1 dose of the IMP.	7.3% 4/55 • Number of events 5 • Baseline up to Week 12 Safety analysis set included all randomized participants who received at least 1 dose of the IMP.	7.3% 4/55 • Number of events 4 • Baseline up to Week 12 Safety analysis set included all randomized participants who received at least 1 dose of the IMP.

Additional Information

Director, Clinical Research

Teva Branded Pharmaceutical Products, R&D Inc.

Phone: 1-888-483-8279

Email: USMedInfo@tevapharm.com

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.
• Publication restrictions are in place

Restriction type: OTHER