Trial Outcomes & Findings for Comparing Efficacy and Safety of 2 Dose Regimens of Subcutaneous Administration of TEV-48125 Versus Placebo for the Preventive Treatment of Chronic Migraine (NCT NCT02621931)

NCT ID: NCT02621931

Last Updated: 2021-11-09

Results Overview

Headaches were subjectively rated by participants as mild, moderate or severe. A headache day of at least moderate severity was defined as a calendar day (00:00 to 23:59) where the patient (using the electronic headache diary device) reports: - a day with headache pain that lasts ≥4 hours with a peak severity of at least moderate severity or - a day when the patient used acute migraine-specific medication (triptans or ergots) to treat a headache of any severity or duration. Monthly averages are derived and normalized to 28 days equivalent by the following formula: (# days of efficacy variable over relevant period / # days with assessments recorded in the e-diary over the relevant period) \* 28. The change is calculated as post-baseline value - baseline value.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1130 participants

Primary outcome timeframe

Baseline (Days -28 to Day -1), Treatment (Days 1 - Week 12)

Results posted on

2021-11-09

Participant Flow

A total of 3148 patients with migraine provided written informed consent and were screened for entry into either Study TV48125-CNS-30049 or Study TV48125-CNS-30050. Of the 3148 screened, 1130 met entry criteria, including criteria for chronic migraine and diary compliance during the run-in period, and were randomized into this study.

Participant milestones

Participant milestones
Measure	Placebo Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56 .	Fremanezumab 675 mg/Placebo/Placebo Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 675/225/225 mg Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
Overall Study STARTED	375	376	379
Overall Study Safety and ITT Populations	375	376	379
Overall Study Full Analysis Set	371	375	375
Overall Study COMPLETED	342	349	343
Overall Study NOT COMPLETED	33	27	36

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56 .	Fremanezumab 675 mg/Placebo/Placebo Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 675/225/225 mg Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
Overall Study Death	0	1	0
Overall Study Adverse Event	8	5	7
Overall Study Withdrawal by Subject	12	10	11
Overall Study Protocol Violation	2	2	2
Overall Study Pregnancy	2	0	0
Overall Study Noncompliance to study procedures	0	1	2
Overall Study Lost to Follow-up	8	7	10
Overall Study Lack of Efficacy	0	0	1
Overall Study Other	1	1	3

Baseline Characteristics

Two participants were missing baseline weight data

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=375 Participants Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56 .	Fremanezumab 675 mg/Placebo/Placebo n=376 Participants Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 675/225/225 mg n=379 Participants Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.	Total n=1130 Participants Total of all reporting groups
Age, Continuous	41.4 years STANDARD_DEVIATION 12.03 • n=375 Participants	42.0 years STANDARD_DEVIATION 12.37 • n=376 Participants	40.6 years STANDARD_DEVIATION 11.95 • n=379 Participants	41.3 years STANDARD_DEVIATION 12.12 • n=1130 Participants
Age, Customized 18-45 years	229 Participants n=375 Participants	218 Participants n=376 Participants	248 Participants n=379 Participants	695 Participants n=1130 Participants
Age, Customized 46-65 years	143 Participants n=375 Participants	149 Participants n=376 Participants	123 Participants n=379 Participants	415 Participants n=1130 Participants
Age, Customized >65 years	3 Participants n=375 Participants	9 Participants n=376 Participants	8 Participants n=379 Participants	20 Participants n=1130 Participants
Sex: Female, Male Female	330 Participants n=375 Participants	331 Participants n=376 Participants	330 Participants n=379 Participants	991 Participants n=1130 Participants
Sex: Female, Male Male	45 Participants n=375 Participants	45 Participants n=376 Participants	49 Participants n=379 Participants	139 Participants n=1130 Participants
Race/Ethnicity, Customized White	303 Participants n=375 Participants	293 Participants n=376 Participants	297 Participants n=379 Participants	893 Participants n=1130 Participants
Race/Ethnicity, Customized Black	29 Participants n=375 Participants	33 Participants n=376 Participants	37 Participants n=379 Participants	99 Participants n=1130 Participants
Race/Ethnicity, Customized Asian	40 Participants n=375 Participants	40 Participants n=376 Participants	41 Participants n=379 Participants	121 Participants n=1130 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants n=375 Participants	4 Participants n=376 Participants	2 Participants n=379 Participants	6 Participants n=1130 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	1 Participants n=375 Participants	2 Participants n=376 Participants	0 Participants n=379 Participants	3 Participants n=1130 Participants
Race/Ethnicity, Customized Other	2 Participants n=375 Participants	4 Participants n=376 Participants	2 Participants n=379 Participants	8 Participants n=1130 Participants
Race/Ethnicity, Customized Not HIspanic or Latino	343 Participants n=375 Participants	352 Participants n=376 Participants	338 Participants n=379 Participants	1033 Participants n=1130 Participants
Race/Ethnicity, Customized Hispanic or Latino	32 Participants n=375 Participants	22 Participants n=376 Participants	41 Participants n=379 Participants	95 Participants n=1130 Participants
Race/Ethnicity, Customized Unknown	0 Participants n=375 Participants	1 Participants n=376 Participants	0 Participants n=379 Participants	1 Participants n=1130 Participants
Race/Ethnicity, Customized Not reported	0 Participants n=375 Participants	1 Participants n=376 Participants	0 Participants n=379 Participants	1 Participants n=1130 Participants
Weight	72.6 kg STANDARD_DEVIATION 15.58 • n=375 Participants • Two participants were missing baseline weight data	72.4 kg STANDARD_DEVIATION 15.79 • n=376 Participants • Two participants were missing baseline weight data	72.5 kg STANDARD_DEVIATION 16.36 • n=377 Participants • Two participants were missing baseline weight data	72.5 kg STANDARD_DEVIATION 15.90 • n=1128 Participants • Two participants were missing baseline weight data
Time Since Initial Migraine Diagnosis	19.9 years STANDARD_DEVIATION 12.86 • n=375 Participants	19.7 years STANDARD_DEVIATION 12.84 • n=376 Participants	20.1 years STANDARD_DEVIATION 11.98 • n=379 Participants	19.9 years STANDARD_DEVIATION 12.55 • n=1130 Participants
Preventative Medication Use During Baseline Period Yes	77 Participants n=375 Participants	77 Participants n=376 Participants	85 Participants n=379 Participants	239 Participants n=1130 Participants
Preventative Medication Use During Baseline Period No	298 Participants n=375 Participants	299 Participants n=376 Participants	294 Participants n=379 Participants	891 Participants n=1130 Participants
Total Number of Headache Days of Any Duration And Any Severity During the 28 Day Baseline Period	20.3 days STANDARD_DEVIATION 4.19 • n=375 Participants	20.4 days STANDARD_DEVIATION 3.93 • n=376 Participants	20.3 days STANDARD_DEVIATION 4.26 • n=379 Participants	20.3 days STANDARD_DEVIATION 4.13 • n=1130 Participants
Number of Headache Days of At Least Moderate Severity	13.3 days STANDARD_DEVIATION 5.82 • n=375 Participants	13.2 days STANDARD_DEVIATION 5.47 • n=376 Participants	12.8 days STANDARD_DEVIATION 5.80 • n=379 Participants	13.1 days STANDARD_DEVIATION 5.70 • n=1130 Participants
Number of Migraine Days	16.4 days STANDARD_DEVIATION 5.15 • n=375 Participants	16.2 days STANDARD_DEVIATION 4.88 • n=376 Participants	16.0 days STANDARD_DEVIATION 5.19 • n=379 Participants	16.2 days STANDARD_DEVIATION 5.97 • n=1130 Participants
Number of Days of Use of Any Acute Headache Medications	13.0 days STANDARD_DEVIATION 6.92 • n=375 Participants	13.1 days STANDARD_DEVIATION 6.79 • n=376 Participants	13.1 days STANDARD_DEVIATION 7.20 • n=379 Participants	13.1 days STANDARD_DEVIATION 6.96 • n=1130 Participants
Headache Impact Test (HIT-6) Disability Score	64.1 units on a scale STANDARD_DEVIATION 4.80 • n=373 Participants • HIT-6 was not assessed at baseline for some patients.	64.3 units on a scale STANDARD_DEVIATION 4.74 • n=370 Participants • HIT-6 was not assessed at baseline for some patients.	64.6 units on a scale STANDARD_DEVIATION 4.42 • n=377 Participants • HIT-6 was not assessed at baseline for some patients.	64.3 units on a scale STANDARD_DEVIATION 4.65 • n=1120 Participants • HIT-6 was not assessed at baseline for some patients.

PRIMARY outcome

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

Population: Full analysis set (FAS) included those in the intent to treat (ITT) population who received at least 1 dose of study drug and had at least 10 days of post-baseline efficacy assessments on the primary endpoint.

Outcome measures

Outcome measures
Measure	Placebo n=371 Participants Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56 .	Fremanezumab 675 mg/Placebo/Placebo n=375 Participants Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 675/225/225 mg n=375 Participants Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
Change From Baseline in the Monthly Average Number of Headache Days of At Least Moderate Severity During the 12-Week Period After the First Dose of Study Drug	-2.5 days Interval -5.6 to 0.0	-4.2 days Interval -7.7 to -1.7	-4.5 days Interval -7.8 to -1.7

PRIMARY outcome

Timeframe: Day 1 to Week 12

Population: Safety population

An adverse event (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. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents usual activities. 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 patient and required medical intervention to prevent the previously listed serious outcomes.

Outcome measures

Outcome measures
Measure	Placebo n=375 Participants Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56 .	Fremanezumab 675 mg/Placebo/Placebo n=376 Participants Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 675/225/225 mg n=379 Participants Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
Participants With Treatment-Emergent Adverse Events (TEAEs) Any TEAE	240 Participants	265 Participants	270 Participants
Participants With Treatment-Emergent Adverse Events (TEAEs) Severe TEAE	20 Participants	14 Participants	15 Participants
Participants With Treatment-Emergent Adverse Events (TEAEs) Treatment-related TEAE	159 Participants	186 Participants	194 Participants
Participants With Treatment-Emergent Adverse Events (TEAEs) Serious TEAE	6 Participants	3 Participants	5 Participants
Participants With Treatment-Emergent Adverse Events (TEAEs) Death	0 Participants	1 Participants	0 Participants
Participants With Treatment-Emergent Adverse Events (TEAEs) TEAE leading to discontinuation	8 Participants	5 Participants	7 Participants

SECONDARY outcome

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

Population: Full analysis set (FAS)

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 endorsing criteria for migraine with or without aura - a calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache endorsing criteria for probable migraine, a migraine subtype where only 1 migraine criterion is 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 are derived and normalized to 28 days equivalent by the following formula: (# days of efficacy variable over relevant period / # days with assessments recorded in the e-diary over the relevant period) \* 28. The change is calculated as post-baseline value - baseline value.

Outcome measures

Outcome measures
Measure	Placebo n=371 Participants Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56 .	Fremanezumab 675 mg/Placebo/Placebo n=375 Participants Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 675/225/225 mg n=375 Participants Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
Change From Baseline in the Monthly Average Number of Migraine Days During the 12-Week Period After the First Dose of Study Drug	-3.2 migraine days / month Standard Error 0.35	-4.9 migraine days / month Standard Error 0.35	-5.0 migraine days / month Standard Error 0.35

SECONDARY outcome

Timeframe: Baseline (Days -28 to Day -1), Treatment: Month 1, Month 2, Month 3, Month 1-3 (Days 1 - Week 12)

Population: FAS. One participant in the Placebo and Fremanezumab 675/225/225 mg treatment arms had 0 headache days of \>= moderate severity during baseline and treatment and therefore was not included.

Responder rates were defined as the percentage of total subjects who reached at least a 50% reduction in the monthly average of headache days (as subjectively reported by participants in the study diary) of at least moderate severity relative to the baseline period. For the overall analysis (Month 1-3), patients who discontinued early were considered non-responders. Monthly averages are derived and normalized to 28 days equivalent by the following formula: (# days of efficacy variable over relevant period / # days with assessments recorded in the e-diary over the relevant period) \* 28. The percentage reduction in monthly average is calculated as: ((baseline value - post-baseline value) / baseline value) \* 100.

Outcome measures

Outcome measures
Measure	Placebo n=370 Participants Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56 .	Fremanezumab 675 mg/Placebo/Placebo n=375 Participants Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 675/225/225 mg n=374 Participants Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
Percentage of Participants With At Least 50% Reduction In Monthly Average Number of Headache Days of At Least Moderate Severity Month 1	21.6 percentage of total participants	41.3 percentage of total participants	40.0 percentage of total participants
Percentage of Participants With At Least 50% Reduction In Monthly Average Number of Headache Days of At Least Moderate Severity Month 2	24.3 percentage of total participants	39.7 percentage of total participants	41.9 percentage of total participants
Percentage of Participants With At Least 50% Reduction In Monthly Average Number of Headache Days of At Least Moderate Severity Month 3	26.4 percentage of total participants	40.5 percentage of total participants	44.5 percentage of total participants
Percentage of Participants With At Least 50% Reduction In Monthly Average Number of Headache Days of At Least Moderate Severity Overall - Months 1-3	18.1 percentage of total participants	37.6 percentage of total participants	40.8 percentage of total participants

SECONDARY outcome

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

Population: Full analysis set

Participants recorded any migraine medications (name of drug, number of tablets/capsules, and the dose in milligrams per tablet/capsule) taken on each day in their electronic headache diary device. Acute migraine-specific medication included triptans or ergots. Monthly averages are derived and normalized to 28 days equivalent by the following formula: (# days of efficacy variable over relevant period / # days with assessments recorded in the e-diary over the relevant period) \* 28. The change is calculated as post-baseline value - baseline value.

Outcome measures

Outcome measures
Measure	Placebo n=371 Participants Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56 .	Fremanezumab 675 mg/Placebo/Placebo n=375 Participants Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 675/225/225 mg n=375 Participants Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
Change From Baseline in the Monthly Average Number of Days of Use of Any Acute Headache Medicine During the 12 Week Period After the First Dose of Study Drug	-2.0 days Interval -5.3 to 0.2	-3.6 days Interval -7.3 to -0.7	-4.2 days Interval -7.6 to -1.1

SECONDARY outcome

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

Population: Full analysis set (FAS) included those in the ITT population who received at least 1 dose of study drug and had at least 10 days of post-baseline efficacy assessments on the primary endpoint.

Headaches were subjectively rated by participants as mild, moderate or severe. A headache day of at least moderate severity was defined as a calendar day (00:00 to 23:59) where the patient (using the electronic headache diary device) reports: - a day with headache pain that lasts ≥4 hours with a peak severity of at least moderate severity or - a day when the patient used acute migraine-specific medication (triptans or ergots) to treat a headache of any severity or duration. The change is calculated as post-baseline value - baseline value.

Outcome measures

Outcome measures
Measure	Placebo n=371 Participants Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56 .	Fremanezumab 675 mg/Placebo/Placebo n=750 Participants Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 675/225/225 mg Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
Change From Baseline in the Number of Headache Days of At Least Moderate Severity During the 4 Week Period After the First Dose of Study Drug	-2.3 days Standard Error 0.33	-4.6 days Standard Error 0.27	—

SECONDARY outcome

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

Population: FAS of participants who did not receive concomitant preventive migraine medications.

A subset of patients (specified in the protocol not to exceed 30%) were allowed to use 1 concomitant migraine preventive medication. This outcome only includes those participants who did not take concomitant preventive migraine medication during this study. Headaches were subjectively rated by participants as mild, moderate or severe. A headache day of \>= moderate severity was defined as a calendar day where the patient (using the electronic headache diary device) reports: - a day with headache pain that lasts ≥4 hours with a peak severity of \>= moderate severity or - a day when the patient used acute migraine-specific medication (triptans or ergots) to treat a headache of any severity or duration. Monthly averages are derived and normalized to 28 days equivalent by the following formula: (# days of efficacy variable over relevant period / # days with assessments recorded in the e-diary over the relevant period) \* 28. Change is post-baseline value - baseline value.

Outcome measures

Outcome measures
Measure	Placebo n=294 Participants Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56 .	Fremanezumab 675 mg/Placebo/Placebo n=298 Participants Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 675/225/225 mg n=290 Participants Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
Change From Baseline in the Monthly Average Number of Headache Days of At Least Moderate Severity During the 12 Week Period After the First Dose of Study Medication in Patients Not Receiving Concomitant Preventive Migraine Medications	-2.4 days Interval -5.3 to 0.0	-4.4 days Interval -8.0 to -1.7	-4.6 days Interval -7.8 to -1.5

SECONDARY outcome

Timeframe: Baseline, 12 weeks

Population: Full analysis set

The HIT-6 was developed by Kosinski et al (2003) as a short form for reliably assessing the adverse headache impact in clinical practice and clinical research settings. The questionnaire measures the adverse impact of headache on social functioning, role functioning, vitality, cognitive functioning, and psychological distress. It also assesses headache severity. Scores range from 36 to 78, where a higher score indicates a greater impact of headache on the daily life of the patient, i.e. scores ≤49 represent little or no impact, scores between 50 and 55 represent some impact, scores between 56 and 59 represent substantial impact; and scores ≥60 indicate severe impact. Negative change from baseline values indicate less adverse impact of headache.

Outcome measures

Outcome measures
Measure	Placebo n=371 Participants Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56 .	Fremanezumab 675 mg/Placebo/Placebo n=375 Participants Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 675/225/225 mg n=375 Participants Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
Change From Baseline in Migraine-Related Disability Score, As Measured by the 6-Item Headache Impact Test (HIT) At Week 12	-4.0 units on a scale Interval -7.0 to 0.0	-5.0 units on a scale Interval -10.0 to -2.0	-6.0 units on a scale Interval -11.0 to -2.0

SECONDARY outcome

Timeframe: Baseline (Day 0), Treatment Week 12 (or endpoint)

Population: Safety population of participants with both baseline and post-treatment ECGs.

12-lead ECGs were performed before other assessments (eg, blood draws and administration of questionnaires) and performed in triplicate. The worst post-baseline finding for the participant is summarized. Only participants with both baseline and post-baseline ECGs are included. The ECG was evaluated by the investigator at the time of recording (signed and dated), and the printout was kept in the source documentation file. When potentially clinically significant findings were detected by the investigator, a cardiologist at a central diagnostic center was consulted for a definitive interpretation. Any ECG finding that was judged by the investigator as a potentially clinically significant change (worsening) compared with a baseline value was considered an adverse event. - NCS = abnormal, not clinically significant. - CS= abnormal, clinically significant. Shift format is: baseline finding / worst post-baseline finding.

Outcome measures

Outcome measures
Measure	Placebo n=360 Participants Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56 .	Fremanezumab 675 mg/Placebo/Placebo n=361 Participants Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 675/225/225 mg n=362 Participants Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
Electrocardiogram (ECG) Findings Shifts From Baseline to Overall Normal / Normal	215 Participants	220 Participants	223 Participants
Electrocardiogram (ECG) Findings Shifts From Baseline to Overall Normal / NCS	54 Participants	48 Participants	43 Participants
Electrocardiogram (ECG) Findings Shifts From Baseline to Overall Normal / CS	1 Participants	0 Participants	0 Participants
Electrocardiogram (ECG) Findings Shifts From Baseline to Overall NCS / Normal	31 Participants	34 Participants	34 Participants
Electrocardiogram (ECG) Findings Shifts From Baseline to Overall NCS / NCS	59 Participants	59 Participants	62 Participants
Electrocardiogram (ECG) Findings Shifts From Baseline to Overall NCS / CS	0 Participants	0 Participants	0 Participants
Electrocardiogram (ECG) Findings Shifts From Baseline to Overall CS / Normal	0 Participants	0 Participants	0 Participants
Electrocardiogram (ECG) Findings Shifts From Baseline to Overall CS / NCS	0 Participants	0 Participants	0 Participants
Electrocardiogram (ECG) Findings Shifts From Baseline to Overall CS / CS	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Treatment Days 28, 56 and 84 (or endpoint). Changes from previous reading may reflect the baseline reading performed on Day 0.

Population: Safety population of participants with both baseline and post-treatment values for each vital sign.

Vital signs were performed before other assessments (eg, blood draws and administration of questionnaires). Vital signs with potentially clinically significant abnormal findings included: - Pulse Rate High: \>=120 and increase of \>=15 beats per minute - Pulse Rate Low: \<=50 and decrease of \>=15 beats per minute - Systolic Blood Pressure Low: \<=90 mmHg and decrease of \>=20 mmHg - Diastolic Blood Pressure High: \>=105 mmHg and increase of \>=15 mmHg - Diastolic Blood Pressure Low: \<=50 mmHg and decrease of \>=15 mmHg - Respiratory Rate Low: \<10 breaths / minute

Outcome measures

Outcome measures
Measure	Placebo n=366 Participants Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56 .	Fremanezumab 675 mg/Placebo/Placebo n=373 Participants Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 675/225/225 mg n=372 Participants Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
Participants With Vital Signs Potentially Clinically Significant Abnormal Values Participants with at least 1 abnormality	7 Participants	10 Participants	14 Participants
Participants With Vital Signs Potentially Clinically Significant Abnormal Values Pulse Rate High	0 Participants	0 Participants	1 Participants
Participants With Vital Signs Potentially Clinically Significant Abnormal Values Pulse Rate Low	1 Participants	1 Participants	0 Participants
Participants With Vital Signs Potentially Clinically Significant Abnormal Values Systolic Blood Pressure Low	2 Participants	4 Participants	6 Participants
Participants With Vital Signs Potentially Clinically Significant Abnormal Values Diastolic Blood Pressure High	1 Participants	2 Participants	3 Participants
Participants With Vital Signs Potentially Clinically Significant Abnormal Values Diastolic Blood Pressure Low	0 Participants	1 Participants	2 Participants
Participants With Vital Signs Potentially Clinically Significant Abnormal Values Respiratory Rate Low	3 Participants	2 Participants	3 Participants

SECONDARY outcome

Timeframe: Treatment Days 28, 56 and 84 (or endpoint)

Population: Safety population of participants with at least one post-baseline result for the tests

Serum chemistry and hematology laboratory tests with potentially clinically significant abnormal findings included: - Blood Urea Nitrogen (BUN) High: \>=10.71 mmol/L - Creatinine High: \>=177 umol/L - Bilirubin High: \>=34.2 umol/L - Alanine Aminotransferase (ALT): \>=3\*upper limit of normal (ULN) - Aspartate Aminotransferase (AST): \>=3\*upper limit of normal (ULN) - Gamma Glutamyl Transferase (GGT): \>=3\*upper limit of normal (ULN) - Hemoglobin: Male: \<115 g/L or Female: \<=95 g/L - Hematocrit: Male: \<0.37 L/L or Female: \<0.32 L/L - Leukocytes: \>=20\*10\^9/L or \<=3\*10\^9/L - Eosinophils/Leukocytes: \>=10% - Platelets: \>=700\*10\^9/L or \<=75\*10\^9/L

Outcome measures

Outcome measures
Measure	Placebo n=366 Participants Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56 .	Fremanezumab 675 mg/Placebo/Placebo n=373 Participants Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 675/225/225 mg n=371 Participants Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
Participants With Serum Chemistry and Hematology Potentially Clinically Significant Abnormal Results BUN	1 Participants	1 Participants	1 Participants
Participants With Serum Chemistry and Hematology Potentially Clinically Significant Abnormal Results Creatinine	2 Participants	0 Participants	0 Participants
Participants With Serum Chemistry and Hematology Potentially Clinically Significant Abnormal Results Bilirubin	0 Participants	2 Participants	0 Participants
Participants With Serum Chemistry and Hematology Potentially Clinically Significant Abnormal Results ALT	2 Participants	2 Participants	7 Participants
Participants With Serum Chemistry and Hematology Potentially Clinically Significant Abnormal Results AST	0 Participants	3 Participants	4 Participants
Participants With Serum Chemistry and Hematology Potentially Clinically Significant Abnormal Results GGT	7 Participants	7 Participants	8 Participants
Participants With Serum Chemistry and Hematology Potentially Clinically Significant Abnormal Results Hemoglobin	2 Participants	5 Participants	3 Participants
Participants With Serum Chemistry and Hematology Potentially Clinically Significant Abnormal Results Hematocrit	8 Participants	9 Participants	7 Participants
Participants With Serum Chemistry and Hematology Potentially Clinically Significant Abnormal Results Leukocytes	2 Participants	9 Participants	5 Participants
Participants With Serum Chemistry and Hematology Potentially Clinically Significant Abnormal Results Eosinophils/Leukocytes	4 Participants	5 Participants	4 Participants
Participants With Serum Chemistry and Hematology Potentially Clinically Significant Abnormal Results Platelets	1 Participants	2 Participants	0 Participants

SECONDARY outcome

Timeframe: Treatment Days 28, 56 and 84 (or endpoint). Changes from previous reading reflect the baseline reading performed on Day 0.

Population: Safety population of participants with at least one post-baseline result for the tests.

Urinalysis with potentially clinically significant abnormal findings included: - Blood: \>=2 unit increase from baseline - Urine Glucose (mg/dL): \>=2 unit increase from baseline - Ketones (mg/dL): \>=2 unit increase from baseline - Urine Protein (mg/dL): \>=2 unit increase from baseline

Outcome measures

Outcome measures
Measure	Placebo n=365 Participants Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56 .	Fremanezumab 675 mg/Placebo/Placebo n=373 Participants Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 675/225/225 mg n=372 Participants Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
Participants With Urinalysis Laboratory Tests Potentially Clinically Significant Abnormal Results Participants with at least 1 abnormality	78 Participants	57 Participants	68 Participants
Participants With Urinalysis Laboratory Tests Potentially Clinically Significant Abnormal Results Blood	33 Participants	32 Participants	35 Participants
Participants With Urinalysis Laboratory Tests Potentially Clinically Significant Abnormal Results Urine glucose	7 Participants	7 Participants	5 Participants
Participants With Urinalysis Laboratory Tests Potentially Clinically Significant Abnormal Results Ketones	7 Participants	7 Participants	7 Participants
Participants With Urinalysis Laboratory Tests Potentially Clinically Significant Abnormal Results Urine protein	40 Participants	19 Participants	34 Participants

SECONDARY outcome

Timeframe: Baseline (Day 0), Treatment Endpoint (Week 12)

Population: Safety population of participants with both baseline and post-treatment values

Shifts in prothrombin time from baseline to endpoint were summarized using patient 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) Shift format is: baseline finding / endpoint finding

Outcome measures

Outcome measures
Measure	Placebo n=366 Participants Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56 .	Fremanezumab 675 mg/Placebo/Placebo n=373 Participants Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 675/225/225 mg n=370 Participants Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
Prothrombin Time Shifts From Baseline to Endpoint Low / Low	0 Participants	0 Participants	0 Participants
Prothrombin Time Shifts From Baseline to Endpoint Low / Normal	2 Participants	0 Participants	1 Participants
Prothrombin Time Shifts From Baseline to Endpoint Low / High	0 Participants	0 Participants	0 Participants
Prothrombin Time Shifts From Baseline to Endpoint Normal / Low	0 Participants	1 Participants	2 Participants
Prothrombin Time Shifts From Baseline to Endpoint Normal / Normal	330 Participants	318 Participants	327 Participants
Prothrombin Time Shifts From Baseline to Endpoint Normal / High	13 Participants	17 Participants	19 Participants
Prothrombin Time Shifts From Baseline to Endpoint High / Low	0 Participants	0 Participants	0 Participants
Prothrombin Time Shifts From Baseline to Endpoint High / Normal	14 Participants	19 Participants	12 Participants
Prothrombin Time Shifts From Baseline to Endpoint High / High	7 Participants	18 Participants	9 Participants

SECONDARY outcome

Timeframe: Day 1 to Week 12

Population: Safety population

Counts of participants who reported treatment-emergent injection site reactions as AEs are summarized. Preferred terms from MedDRA version 18.1 are offered without a threshold applied.

Outcome measures

Outcome measures
Measure	Placebo n=375 Participants Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56 .	Fremanezumab 675 mg/Placebo/Placebo n=376 Participants Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 675/225/225 mg n=379 Participants Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
Injection Site Reaction Adverse Events Injection site inflammation	0 Participants	0 Participants	1 Participants
Injection Site Reaction Adverse Events Participants with >= 1 injection site reaction	151 Participants	176 Participants	183 Participants
Injection Site Reaction Adverse Events Injection site pain	104 Participants	114 Participants	99 Participants
Injection Site Reaction Adverse Events Injection site induration	68 Participants	74 Participants	90 Participants
Injection Site Reaction Adverse Events Injection site erythema	60 Participants	80 Participants	75 Participants
Injection Site Reaction Adverse Events Injection site haemorrhage	10 Participants	7 Participants	8 Participants
Injection Site Reaction Adverse Events Injection site pruritus	0 Participants	6 Participants	8 Participants
Injection Site Reaction Adverse Events Injection site rash	0 Participants	4 Participants	3 Participants
Injection Site Reaction Adverse Events Injection site bruising	2 Participants	1 Participants	2 Participants
Injection Site Reaction Adverse Events Injection site swelling	0 Participants	2 Participants	1 Participants
Injection Site Reaction Adverse Events Injection site dermatitis	0 Participants	1 Participants	0 Participants
Injection Site Reaction Adverse Events Injection site discomfort	0 Participants	1 Participants	0 Participants
Injection Site Reaction Adverse Events Injection site haematoma	0 Participants	0 Participants	1 Participants
Injection Site Reaction Adverse Events Injection site hypoaesthesia	0 Participants	0 Participants	1 Participants
Injection Site Reaction Adverse Events Injection site oedema	0 Participants	1 Participants	0 Participants
Injection Site Reaction Adverse Events Injection site paraesthesia	0 Participants	0 Participants	1 Participants
Injection Site Reaction Adverse Events Injection site urticaria	2 Participants	0 Participants	1 Participants
Injection Site Reaction Adverse Events Injection site warmth	2 Participants	0 Participants	1 Participants

SECONDARY outcome

Timeframe: Baseline (Day 0), Treatment Days 28, 56, 84

Population: Safety population

The electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) was used to assess the participant's suicidal ideation (severity and intensity) and behavior (Posner et al 2011). Suicidal behavior is 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 is defined as a "yes" answer to any one of 5 suicidal ideation questions: wish to be dead, and 4 different categories of active suicidal ideation. The eC-SSRS Baseline/Screening version was completed by the participant at baseline, and the eC-SSRS Since Last Visit version was completed by the participant at all other time points. Any positive findings on the eC-SSRS Since Last Visit version required evaluation by a physician or doctoral-level psychologist. Findings after the first dose of study drug using the eC-SSRS Since Last Visit version are summarized.

Outcome measures

Outcome measures
Measure	Placebo n=375 Participants Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56 .	Fremanezumab 675 mg/Placebo/Placebo n=376 Participants Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 675/225/225 mg n=379 Participants Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
Participants With Positive Electronic Columbia Suicide Severity Rating Scale (eC-SSRS) Results After the First Dose of Study Drug Participants with positive eC-SSRS responses	1 Participants	1 Participants	1 Participants
Participants With Positive Electronic Columbia Suicide Severity Rating Scale (eC-SSRS) Results After the First Dose of Study Drug Specific finding: interrupted suicide attempt	1 Participants	1 Participants	0 Participants
Participants With Positive Electronic Columbia Suicide Severity Rating Scale (eC-SSRS) Results After the First Dose of Study Drug Specific finding: suicidal ideation	0 Participants	0 Participants	1 Participants

Adverse Events

Placebo

Serious events: 6 serious events

Other events: 160 other events

Deaths: 0 deaths

Fremanezumab 675 mg/Placebo/Placebo

Serious events: 3 serious events

Other events: 185 other events

Deaths: 1 deaths

Fremanezumab 675/225/225 mg

Serious events: 5 serious events

Other events: 178 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=375 participants at risk Participants randomized to receive placebo received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56.	Fremanezumab 675 mg/Placebo/Placebo n=376 participants at risk Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 675/225/225 mg n=379 participants at risk Participants randomized to receive fremanezumab 675/225/225 mg received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
Eye disorders Diplopia	0.27% 1/375 • Number of events 1 • Day 1 to Week 12	0.00% 0/376 • Day 1 to Week 12	0.00% 0/379 • Day 1 to Week 12
General disorders Oedema peripheral	0.27% 1/375 • Number of events 1 • Day 1 to Week 12	0.00% 0/376 • Day 1 to Week 12	0.00% 0/379 • Day 1 to Week 12
Immune system disorders Drug hypersensitivity	0.27% 1/375 • Number of events 1 • Day 1 to Week 12	0.00% 0/376 • Day 1 to Week 12	0.00% 0/379 • Day 1 to Week 12
Infections and infestations Pneumonia	0.00% 0/375 • Day 1 to Week 12	0.27% 1/376 • Number of events 1 • Day 1 to Week 12	0.00% 0/379 • Day 1 to Week 12
Injury, poisoning and procedural complications Accident	0.27% 1/375 • Number of events 1 • Day 1 to Week 12	0.00% 0/376 • Day 1 to Week 12	0.00% 0/379 • Day 1 to Week 12
Injury, poisoning and procedural complications Clavicle fracture	0.27% 1/375 • Number of events 1 • Day 1 to Week 12	0.00% 0/376 • Day 1 to Week 12	0.00% 0/379 • Day 1 to Week 12
Injury, poisoning and procedural complications Fall	0.00% 0/375 • Day 1 to Week 12	0.00% 0/376 • Day 1 to Week 12	0.26% 1/379 • Number of events 1 • Day 1 to Week 12
Injury, poisoning and procedural complications Radius fracture	0.00% 0/375 • Day 1 to Week 12	0.00% 0/376 • Day 1 to Week 12	0.26% 1/379 • Number of events 1 • Day 1 to Week 12
Injury, poisoning and procedural complications Road traffic accident	0.00% 0/375 • Day 1 to Week 12	0.27% 1/376 • Number of events 1 • Day 1 to Week 12	0.00% 0/379 • Day 1 to Week 12
Injury, poisoning and procedural complications Ulna fracture	0.00% 0/375 • Day 1 to Week 12	0.00% 0/376 • Day 1 to Week 12	0.26% 1/379 • Number of events 1 • Day 1 to Week 12
Injury, poisoning and procedural complications Wrist fracture	0.00% 0/375 • Day 1 to Week 12	0.27% 1/376 • Number of events 1 • Day 1 to Week 12	0.00% 0/379 • Day 1 to Week 12
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/375 • Day 1 to Week 12	0.00% 0/376 • Day 1 to Week 12	0.26% 1/379 • Number of events 1 • Day 1 to Week 12
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uterine leiomyoma	0.27% 1/375 • Number of events 1 • Day 1 to Week 12	0.00% 0/376 • Day 1 to Week 12	0.00% 0/379 • Day 1 to Week 12
Nervous system disorders Migraine	0.27% 1/375 • Number of events 1 • Day 1 to Week 12	0.00% 0/376 • Day 1 to Week 12	0.00% 0/379 • Day 1 to Week 12
Psychiatric disorders Suicidal ideation	0.00% 0/375 • Day 1 to Week 12	0.00% 0/376 • Day 1 to Week 12	0.26% 1/379 • Number of events 1 • Day 1 to Week 12
Renal and urinary disorders Calculus urinary	0.00% 0/375 • Day 1 to Week 12	0.00% 0/376 • Day 1 to Week 12	0.26% 1/379 • Number of events 1 • Day 1 to Week 12
Renal and urinary disorders Nephrolithiasis	0.27% 1/375 • Number of events 1 • Day 1 to Week 12	0.00% 0/376 • Day 1 to Week 12	0.00% 0/379 • Day 1 to Week 12
Respiratory, thoracic and mediastinal disorders Asthma	0.27% 1/375 • Number of events 1 • Day 1 to Week 12	0.00% 0/376 • Day 1 to Week 12	0.00% 0/379 • Day 1 to Week 12
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.00% 0/375 • Day 1 to Week 12	0.27% 1/376 • Number of events 1 • Day 1 to Week 12	0.00% 0/379 • Day 1 to Week 12
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.27% 1/375 • Number of events 1 • Day 1 to Week 12	0.00% 0/376 • Day 1 to Week 12	0.00% 0/379 • Day 1 to Week 12
Vascular disorders Hypertensive crisis	0.00% 0/375 • Day 1 to Week 12	0.00% 0/376 • Day 1 to Week 12	0.26% 1/379 • Number of events 1 • Day 1 to Week 12

Other adverse events

Other adverse events
Measure	Placebo n=375 participants at risk Participants randomized to receive placebo received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56.	Fremanezumab 675 mg/Placebo/Placebo n=376 participants at risk Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 675/225/225 mg n=379 participants at risk Participants randomized to receive fremanezumab 675/225/225 mg received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
General disorders Injection site erythema	16.0% 60/375 • Number of events 129 • Day 1 to Week 12	21.3% 80/376 • Number of events 172 • Day 1 to Week 12	19.8% 75/379 • Number of events 166 • Day 1 to Week 12
General disorders Injection site induration	18.1% 68/375 • Number of events 130 • Day 1 to Week 12	19.7% 74/376 • Number of events 159 • Day 1 to Week 12	23.7% 90/379 • Number of events 196 • Day 1 to Week 12
General disorders Injection site pain	27.7% 104/375 • Number of events 288 • Day 1 to Week 12	30.3% 114/376 • Number of events 296 • Day 1 to Week 12	26.1% 99/379 • Number of events 271 • Day 1 to Week 12
Infections and infestations Nasopharyngitis	5.3% 20/375 • Number of events 24 • Day 1 to Week 12	5.1% 19/376 • Number of events 20 • Day 1 to Week 12	4.0% 15/379 • Number of events 16 • Day 1 to Week 12

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.
Publication restrictions are in place

Restriction type: OTHER