Trial Outcomes & Findings for Efficacy and Safety of 2 Dose Regimens of TEV-48125 Versus Placebo for the Preventive Treatment of Episodic Migraine (NCT NCT02629861)

Last Updated: 2021-11-09

Results Overview

An adverse event 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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

875 participants

Primary outcome timeframe

Day 1 to Week 12

Results posted on

2021-11-09

Participant Flow

A total of 2995 patients with migraine provided written informed consent. Of the 2995 patients screened, 875 met entry criteria, including diagnostic criteria for episodic migraine (EM) and diary compliance during the run-in period, and were randomized into this study from 123 study centers by 123 investigators.

Participant milestones

Participant milestones
Measure	Placebo Participants randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Fremanezumab 675 mg/Placebo/Placebo Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 225/225/225 mg Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.
Overall Study STARTED	294	291	290
Overall Study Intent to Treat (ITT)	294	291	290
Overall Study Safety Population	294	291	289
Overall Study Full Analysis Set	290	288	287
Overall Study COMPLETED	265	264	262
Overall Study NOT COMPLETED	29	27	28

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Participants randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Fremanezumab 675 mg/Placebo/Placebo Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 225/225/225 mg Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.
Overall Study Adverse Event	7	5	4
Overall Study Withdrawal by Subject	5	8	13
Overall Study Protocol Violation	2	3	7
Overall Study Lost to Follow-up	12	9	4
Overall Study Other	1	1	0
Overall Study Pregnancy	2	1	0

Baseline Characteristics

Three participants did not capture data in the e-diary.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=294 Participants Participants randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Fremanezumab 675 mg/Placebo/Placebo n=291 Participants Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 225/225/225 mg n=290 Participants Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.	Total n=875 Participants Total of all reporting groups
Age, Continuous	41.3 years STANDARD_DEVIATION 12.04 • n=294 Participants	41.1 years STANDARD_DEVIATION 11.41 • n=291 Participants	42.9 years STANDARD_DEVIATION 12.67 • n=290 Participants	41.8 years STANDARD_DEVIATION 12.06 • n=875 Participants
Age, Customized 18-45 years	184 Participants n=294 Participants	178 Participants n=291 Participants	163 Participants n=290 Participants	525 Participants n=875 Participants
Age, Customized 46-65 years	102 Participants n=294 Participants	110 Participants n=291 Participants	120 Participants n=290 Participants	332 Participants n=875 Participants
Age, Customized >65 years	8 Participants n=294 Participants	3 Participants n=291 Participants	7 Participants n=290 Participants	18 Participants n=875 Participants
Sex: Female, Male Female	247 Participants n=294 Participants	251 Participants n=291 Participants	244 Participants n=290 Participants	742 Participants n=875 Participants
Sex: Female, Male Male	47 Participants n=294 Participants	40 Participants n=291 Participants	46 Participants n=290 Participants	133 Participants n=875 Participants
Race/Ethnicity, Customized White	225 Participants n=294 Participants	232 Participants n=291 Participants	243 Participants n=290 Participants	700 Participants n=875 Participants
Race/Ethnicity, Customized Black	40 Participants n=294 Participants	28 Participants n=291 Participants	18 Participants n=290 Participants	86 Participants n=875 Participants
Race/Ethnicity, Customized Asian	25 Participants n=294 Participants	27 Participants n=291 Participants	25 Participants n=290 Participants	77 Participants n=875 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants n=294 Participants	1 Participants n=291 Participants	3 Participants n=290 Participants	4 Participants n=875 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants n=294 Participants	1 Participants n=291 Participants	0 Participants n=290 Participants	1 Participants n=875 Participants
Race/Ethnicity, Customized Other	4 Participants n=294 Participants	2 Participants n=291 Participants	1 Participants n=290 Participants	7 Participants n=875 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	267 Participants n=294 Participants	251 Participants n=291 Participants	252 Participants n=290 Participants	770 Participants n=875 Participants
Race/Ethnicity, Customized Hispanic or Latino	27 Participants n=294 Participants	39 Participants n=291 Participants	37 Participants n=290 Participants	103 Participants n=875 Participants
Race/Ethnicity, Customized Unknown	0 Participants n=294 Participants	1 Participants n=291 Participants	1 Participants n=290 Participants	2 Participants n=875 Participants
Preventive Medication Use During Baseline Period Yes	62 Participants n=294 Participants	58 Participants n=291 Participants	62 Participants n=290 Participants	182 Participants n=875 Participants
Preventive Medication Use During Baseline Period No	232 Participants n=294 Participants	233 Participants n=291 Participants	228 Participants n=290 Participants	693 Participants n=875 Participants
Weight	75.3 kg STANDARD_DEVIATION 16.01 • n=294 Participants	74.2 kg STANDARD_DEVIATION 15.42 • n=291 Participants	72.1 kg STANDARD_DEVIATION 15.77 • n=290 Participants	73.9 kg STANDARD_DEVIATION 15.77 • n=875 Participants
Time Since Initial Migraine Diagnosis	19.9 years STANDARD_DEVIATION 11.87 • n=294 Participants	20.0 years STANDARD_DEVIATION 12.14 • n=291 Participants	20.7 years STANDARD_DEVIATION 12.85 • n=290 Participants	20.2 years STANDARD_DEVIATION 12.28 • n=875 Participants
Total Number of Headache Days of Any Duration And Any Severity During the 28 Day Baseline Period	11.2 days STANDARD_DEVIATION 2.45 • n=293 Participants • Three participants did not capture data in the e-diary.	11.1 days STANDARD_DEVIATION 2.42 • n=291 Participants • Three participants did not capture data in the e-diary.	11.0 days STANDARD_DEVIATION 2.49 • n=288 Participants • Three participants did not capture data in the e-diary.	11.1 days STANDARD_DEVIATION 2.45 • n=872 Participants • Three participants did not capture data in the e-diary.
Number of Migraine Days	9.1 days STANDARD_DEVIATION 2.65 • n=293 Participants • Three participants did not capture data in the e-diary.	9.3 days STANDARD_DEVIATION 2.65 • n=291 Participants • Three participants did not capture data in the e-diary.	8.9 days STANDARD_DEVIATION 2.63 • n=288 Participants • Three participants did not capture data in the e-diary.	9.1 days STANDARD_DEVIATION 2.64 • n=872 Participants • Three participants did not capture data in the e-diary.
Number of Headache Days of At Least Moderate Severity	6.9 days STANDARD_DEVIATION 3.12 • n=293 Participants • Three participants did not capture data in the e-diary.	7.2 days STANDARD_DEVIATION 3.14 • n=291 Participants • Three participants did not capture data in the e-diary.	6.8 days STANDARD_DEVIATION 2.90 • n=288 Participants • Three participants did not capture data in the e-diary.	7.0 days STANDARD_DEVIATION 3.06 • n=872 Participants • Three participants did not capture data in the e-diary.
Number of Days of Use of Any Acute Headache Medications	7.7 days STANDARD_DEVIATION 3.60 • n=293 Participants • Three participants did not capture data in the e-diary.	7.8 days STANDARD_DEVIATION 3.74 • n=291 Participants • Three participants did not capture data in the e-diary.	7.7 days STANDARD_DEVIATION 3.37 • n=288 Participants • Three participants did not capture data in the e-diary.	7.8 days STANDARD_DEVIATION 3.57 • n=872 Participants • Three participants did not capture data in the e-diary.
Migraine Disability Assessment (MIDAS) Total Score	37.3 units on a scale STANDARD_DEVIATION 27.59 • n=290 Participants • Eleven participants did not capture data in the e-diary.	41.7 units on a scale STANDARD_DEVIATION 32.96 • n=287 Participants • Eleven participants did not capture data in the e-diary.	38.0 units on a scale STANDARD_DEVIATION 33.19 • n=287 Participants • Eleven participants did not capture data in the e-diary.	39.0 units on a scale STANDARD_DEVIATION 31.36 • n=864 Participants • Eleven participants did not capture data in the e-diary.

PRIMARY outcome

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

Population: Full analysis set

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 postbaseline value - baseline value.

Outcome measures

Outcome measures
Measure	Placebo n=290 Participants Participants randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Fremanezumab 675 mg/Placebo/Placebo n=288 Participants Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 225/225/225 mg n=287 Participants Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 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	-2.7 days Interval -4.7 to -0.5	-4.0 days Interval -6.4 to -1.9	-4.2 days Interval -6.2 to -2.0

PRIMARY outcome

Timeframe: Day 1 to Week 12

Population: Safety population

Outcome measures

Outcome measures
Measure	Placebo n=293 Participants Participants randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Fremanezumab 675 mg/Placebo/Placebo n=291 Participants Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 225/225/225 mg n=290 Participants Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.
Participants With Adverse Events Any AEs	171 Participants	193 Participants	192 Participants
Participants With Adverse Events Severe AEs	11 Participants	16 Participants	10 Participants
Participants With Adverse Events Treatment-related AEs	109 Participants	137 Participants	138 Participants
Participants With Adverse Events Serious adverse events	7 Participants	3 Participants	3 Participants
Participants With Adverse Events Deaths	0 Participants	1 Participants	0 Participants
Participants With Adverse Events Discontinued from study due to AE	5 Participants	5 Participants	5 Participants

SECONDARY outcome

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

Population: Full analysis set

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 nonresponders. 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 - postbaseline value) / baseline value) \* 100

Outcome measures

Outcome measures
Measure	Placebo n=290 Participants Participants randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Fremanezumab 675 mg/Placebo/Placebo n=288 Participants Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 225/225/225 mg n=287 Participants Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.
Percentage of Participants With At Least 50% Reduction In Monthly Average Number of Migraine Days During the 12-Week Period After the First Dose of Study Drug Month 1	25.2 percentage of participants	44.1 percentage of participants	47.0 percentage of participants
Percentage of Participants With At Least 50% Reduction In Monthly Average Number of Migraine Days During the 12-Week Period After the First Dose of Study Drug Month 2	34.8 percentage of participants	46.9 percentage of participants	48.4 percentage of participants
Percentage of Participants With At Least 50% Reduction In Monthly Average Number of Migraine Days During the 12-Week Period After the First Dose of Study Drug Month 3	37.2 percentage of participants	49.0 percentage of participants	51.2 percentage of participants
Percentage of Participants With At Least 50% Reduction In Monthly Average Number of Migraine Days During the 12-Week Period After the First Dose of Study Drug Overall - Months 1-3	27.9 percentage of participants	44.4 percentage of participants	47.7 percentage of participants

SECONDARY outcome

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

Population: Full analysis set

Patients 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 postbaseline value - baseline value.

Outcome measures

Outcome measures
Measure	Placebo n=290 Participants Participants randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Fremanezumab 675 mg/Placebo/Placebo n=288 Participants Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 225/225/225 mg n=287 Participants Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 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	-1.7 days Interval -4.0 to 0.0	-3.0 days Interval -5.6 to -0.8	-3.2 days Interval -5.2 to -1.2

SECONDARY outcome

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

Population: Full analysis set; includes participants with observations

Outcome measures

Outcome measures
Measure	Placebo n=290 Participants Participants randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Fremanezumab 675 mg/Placebo/Placebo n=285 Participants Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 225/225/225 mg n=286 Participants Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.
Change From Baseline in the Number of Migraine Days During the 4 Week Period After the First Dose of Study Drug	-2.0 days Interval -4.2 to 0.5	-4.0 days Interval -6.2 to -1.3	-4.0 days Interval -6.1 to -1.7

SECONDARY outcome

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

Population: Full analysis set of participants who did not receive concomitant migraine prevention medication

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. A migraine day has been previously defined. 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 postbaseline value - baseline value.

Outcome measures

Outcome measures
Measure	Placebo n=230 Participants Participants randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Fremanezumab 675 mg/Placebo/Placebo n=230 Participants Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 225/225/225 mg n=225 Participants Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 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 Medication in Patients Not Receiving Concomitant Preventive Migraine Medications	-2.9 days Interval -4.9 to -0.6	-4.0 days Interval -6.3 to -2.0	-4.2 days Interval -6.2 to -2.0

SECONDARY outcome

Timeframe: Baseline (Day 0), Treatment Week 12 (4 weeks after the 3rd dose)

Population: Full analysis set

The MIDAS questionnaire is a 5-item instrument developed to assess headache-related disability based on lost days of activity in 3 domains (work, household work, and nonwork) over the previous 3 months. The total score, ie, the sum of the # lost days answered for the first 5 questions, is used for grading of disability, with scores of 0-5 lost days = grade 1 (little or no disability), 6-10 lost days =grade 2 (mild disability), 11-20 lost days = grade 3 (moderate disability), and ≥21 lost days interpreted as grade 4 (severe disability). Negative change from baseline scores indicate a reduction (improvement) in headache-related disability.

Outcome measures

Outcome measures
Measure	Placebo n=290 Participants Participants randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Fremanezumab 675 mg/Placebo/Placebo n=288 Participants Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 225/225/225 mg n=287 Participants Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.
Change From Baseline in Migraine-Related Disability Score (MIDAS), As Measured by the Migraine Disability Assessment At 4 Weeks After the Last (3rd) Dose of Study Drug	-12.5 lost days Interval -29.5 to -2.0	-18.0 lost days Interval -39.0 to -6.0	-19.0 lost days Interval -36.0 to -7.0

SECONDARY outcome

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

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 patient is summarized. Only patients 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=278 Participants Participants randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Fremanezumab 675 mg/Placebo/Placebo n=276 Participants Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 225/225/225 mg n=281 Participants Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.
Electrocardiogram Finding Shifts From Baseline to Overall Normal / Normal	161 Participants	169 Participants	181 Participants
Electrocardiogram Finding Shifts From Baseline to Overall Normal / NCS	32 Participants	41 Participants	25 Participants
Electrocardiogram Finding Shifts From Baseline to Overall Normal / CS	0 Participants	0 Participants	0 Participants
Electrocardiogram Finding Shifts From Baseline to Overall NCS / Normal	27 Participants	23 Participants	29 Participants
Electrocardiogram Finding Shifts From Baseline to Overall NCS / NCS	58 Participants	43 Participants	46 Participants
Electrocardiogram Finding Shifts From Baseline to Overall NCS / CS	0 Participants	0 Participants	0 Participants
Electrocardiogram Finding Shifts From Baseline to Overall CS / Normal	0 Participants	0 Participants	0 Participants
Electrocardiogram Finding Shifts From Baseline to Overall CS / NCS	0 Participants	0 Participants	0 Participants
Electrocardiogram Finding Shifts From Baseline to Overall CS / CS	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Treatment Days 28, 56 and 84. 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 at least one participant showing potentially clinically significant abnormal findings included: - 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=285 Participants Participants randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Fremanezumab 675 mg/Placebo/Placebo n=285 Participants Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 225/225/225 mg n=285 Participants Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.
Participants With Vital Signs Potentially Clinically Significant Abnormal Values Participants with at least 1 abnormality	3 Participants	4 Participants	5 Participants
Participants With Vital Signs Potentially Clinically Significant Abnormal Values Pulse Rate Low	0 Participants	1 Participants	0 Participants
Participants With Vital Signs Potentially Clinically Significant Abnormal Values Systolic Blood Pressure Low	0 Participants	2 Participants	1 Participants
Participants With Vital Signs Potentially Clinically Significant Abnormal Values Diastolic Blood Pressure High	0 Participants	1 Participants	2 Participants
Participants With Vital Signs Potentially Clinically Significant Abnormal Values Diastolic Blood Pressure Low	2 Participants	1 Participants	0 Participants
Participants With Vital Signs Potentially Clinically Significant Abnormal Values Respiratory Rate Low	1 Participants	0 Participants	2 Participants

SECONDARY outcome

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

Population: Safety population of participants with at least one postbaseline 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 - 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=285 Participants Participants randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Fremanezumab 675 mg/Placebo/Placebo n=285 Participants Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 225/225/225 mg n=285 Participants Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.
Participants With Serum Chemistry and Hematology Potentially Clinically Significant Abnormal Results Blood Urea Nitrogen (BUN)	1 Participants	0 Participants	1 Participants
Participants With Serum Chemistry and Hematology Potentially Clinically Significant Abnormal Results Bilirubin	1 Participants	0 Participants	1 Participants
Participants With Serum Chemistry and Hematology Potentially Clinically Significant Abnormal Results Alanine Aminotransferase (ALT)	0 Participants	1 Participants	0 Participants
Participants With Serum Chemistry and Hematology Potentially Clinically Significant Abnormal Results Aspartate Aminotransferase (AST)	0 Participants	0 Participants	1 Participants
Participants With Serum Chemistry and Hematology Potentially Clinically Significant Abnormal Results Gamma Glutamyl Transferase (GGT)	4 Participants	4 Participants	8 Participants
Participants With Serum Chemistry and Hematology Potentially Clinically Significant Abnormal Results Hemoglobin	1 Participants	4 Participants	2 Participants
Participants With Serum Chemistry and Hematology Potentially Clinically Significant Abnormal Results Hematocrit	3 Participants	6 Participants	6 Participants
Participants With Serum Chemistry and Hematology Potentially Clinically Significant Abnormal Results Leukocytes	4 Participants	1 Participants	6 Participants
Participants With Serum Chemistry and Hematology Potentially Clinically Significant Abnormal Results Eosinophils/Leukocytes	7 Participants	3 Participants	5 Participants
Participants With Serum Chemistry and Hematology Potentially Clinically Significant Abnormal Results Platelets	1 Participants	0 Participants	0 Participants

SECONDARY outcome

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

Population: Safety population of participants with at least one postbaseline 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=285 Participants Participants randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Fremanezumab 675 mg/Placebo/Placebo n=285 Participants Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 225/225/225 mg n=285 Participants Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.
Participants With Urinalysis Laboratory Tests Potentially Clinically Significant Abnormal Results Participants with at least 1 abnormality	55 Participants	54 Participants	49 Participants
Participants With Urinalysis Laboratory Tests Potentially Clinically Significant Abnormal Results Blood	29 Participants	30 Participants	23 Participants
Participants With Urinalysis Laboratory Tests Potentially Clinically Significant Abnormal Results Urine glucose	5 Participants	8 Participants	2 Participants
Participants With Urinalysis Laboratory Tests Potentially Clinically Significant Abnormal Results Ketones	5 Participants	7 Participants	9 Participants
Participants With Urinalysis Laboratory Tests Potentially Clinically Significant Abnormal Results Urine protein	25 Participants	19 Participants	23 Participants

SECONDARY outcome

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

Population: Safety population of participants with both baseline and posttreatment 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=284 Participants Participants randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Fremanezumab 675 mg/Placebo/Placebo n=285 Participants Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 225/225/225 mg n=284 Participants Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.
Prothrombin Time Shifts From Baseline to Endpoint Normal / Normal	254 Participants	248 Participants	250 Participants
Prothrombin Time Shifts From Baseline to Endpoint Normal / High	14 Participants	10 Participants	13 Participants
Prothrombin Time Shifts From Baseline to Endpoint Low / Low	0 Participants	0 Participants	0 Participants
Prothrombin Time Shifts From Baseline to Endpoint Low / Normal	0 Participants	1 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	0 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	8 Participants	15 Participants	12 Participants
Prothrombin Time Shifts From Baseline to Endpoint High / High	8 Participants	10 Participants	8 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=293 Participants Participants randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Fremanezumab 675 mg/Placebo/Placebo n=291 Participants Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 225/225/225 mg n=290 Participants Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.
Injection Site Reaction Adverse Events Injection site hypersensitivity	0 Participants	0 Participants	1 Participants
Injection Site Reaction Adverse Events Participants with >=1 injection site reaction	106 Participants	131 Participants	130 Participants
Injection Site Reaction Adverse Events Injection site pain	76 Participants	86 Participants	87 Participants
Injection Site Reaction Adverse Events Injection site induration	45 Participants	57 Participants	71 Participants
Injection Site Reaction Adverse Events Injection site erythema	41 Participants	55 Participants	52 Participants
Injection Site Reaction Adverse Events Injection site haemorrhage	6 Participants	9 Participants	3 Participants
Injection Site Reaction Adverse Events Injection site pruritus	2 Participants	4 Participants	4 Participants
Injection Site Reaction Adverse Events Injection site swelling	0 Participants	2 Participants	3 Participants
Injection Site Reaction Adverse Events Injection site urticaria	2 Participants	2 Participants	1 Participants
Injection Site Reaction Adverse Events Injection site rash	0 Participants	1 Participants	3 Participants
Injection Site Reaction Adverse Events Fatigue	0 Participants	1 Participants	0 Participants
Injection Site Reaction Adverse Events Injection site bruising	1 Participants	0 Participants	0 Participants
Injection Site Reaction Adverse Events Injection site dermatitis	0 Participants	0 Participants	1 Participants
Injection Site Reaction Adverse Events Injection site nodule	0 Participants	0 Participants	1 Participants
Injection Site Reaction Adverse Events Injection site oedema	0 Participants	0 Participants	1 Participants
Injection Site Reaction Adverse Events Injection site warmth	0 Participants	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Day 1 to Week 12

Population: Safety population

The electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) was used to assess the patient's suicidal ideation (severity and intensity) and behavior (Posner et al 2011). The eC-SSRS Baseline/Screening version was completed by the patient at visit 2, and the eC-SSRS Since Last Visit version was completed by the patient 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=294 Participants Participants randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Fremanezumab 675 mg/Placebo/Placebo n=291 Participants Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Fremanezumab 225/225/225 mg n=289 Participants Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.
Participants With Positive Electronic Columbia Suicide Severity Rating Scale Results After the First Dose of Study Drug Suicidal Ideation	0 Participants	0 Participants	2 Participants
Participants With Positive Electronic Columbia Suicide Severity Rating Scale Results After the First Dose of Study Drug Suicidal Behaviour	0 Participants	0 Participants	0 Participants

Adverse Events

Placebo

Serious events: 7 serious events

Other events: 113 other events

Deaths: 0 deaths

Fremanezumab 225/225/225 mg

Serious events: 3 serious events

Other events: 132 other events

Deaths: 0 deaths

Fremanezumab 675 mg/Placebo/Placebo

Serious events: 3 serious events

Other events: 133 other events

Deaths: 1 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=294 participants at risk Participants randomized to receive placebo received three 1.5-mL placebo injections Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Fremanezumab 225/225/225 mg n=289 participants at risk Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.	Fremanezumab 675 mg/Placebo/Placebo n=291 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.
Gastrointestinal disorders Intestinal haemorrhage	0.00% 0/294 • Day 1 to Week 12	0.00% 0/289 • Day 1 to Week 12	0.34% 1/291 • Number of events 1 • Day 1 to Week 12
General disorders Death	0.00% 0/294 • Day 1 to Week 12	0.00% 0/289 • Day 1 to Week 12	0.34% 1/291 • Number of events 1 • Day 1 to Week 12
Immune system disorders Drug hypersensitivity	0.34% 1/294 • Number of events 1 • Day 1 to Week 12	0.00% 0/289 • Day 1 to Week 12	0.00% 0/291 • Day 1 to Week 12
Infections and infestations Appendicitis	0.00% 0/294 • Day 1 to Week 12	0.35% 1/289 • Number of events 1 • Day 1 to Week 12	0.00% 0/291 • Day 1 to Week 12
Injury, poisoning and procedural complications Fall	0.34% 1/294 • Number of events 1 • Day 1 to Week 12	0.00% 0/289 • Day 1 to Week 12	0.00% 0/291 • Day 1 to Week 12
Injury, poisoning and procedural complications Road traffic accident	0.34% 1/294 • Number of events 1 • Day 1 to Week 12	0.00% 0/289 • Day 1 to Week 12	0.00% 0/291 • Day 1 to Week 12
Injury, poisoning and procedural complications Tendon injury	0.00% 0/294 • Day 1 to Week 12	0.00% 0/289 • Day 1 to Week 12	0.34% 1/291 • Number of events 1 • Day 1 to Week 12
Injury, poisoning and procedural complications Wrist fracture	0.34% 1/294 • Number of events 1 • Day 1 to Week 12	0.00% 0/289 • Day 1 to Week 12	0.00% 0/291 • Day 1 to Week 12
Metabolism and nutrition disorders Hypoglycaemia	0.34% 1/294 • Number of events 1 • Day 1 to Week 12	0.00% 0/289 • Day 1 to Week 12	0.00% 0/291 • Day 1 to Week 12
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lentigo maligna	0.34% 1/294 • Number of events 1 • Day 1 to Week 12	0.00% 0/289 • Day 1 to Week 12	0.00% 0/291 • Day 1 to Week 12
Nervous system disorders Dizziness	0.34% 1/294 • Number of events 1 • Day 1 to Week 12	0.00% 0/289 • Day 1 to Week 12	0.00% 0/291 • Day 1 to Week 12
Nervous system disorders Generalised tonic-clonic seizure	0.00% 0/294 • Day 1 to Week 12	0.35% 1/289 • Number of events 1 • Day 1 to Week 12	0.00% 0/291 • Day 1 to Week 12
Nervous system disorders Status migrainosus	0.34% 1/294 • Number of events 2 • Day 1 to Week 12	0.00% 0/289 • Day 1 to Week 12	0.00% 0/291 • Day 1 to Week 12
Pregnancy, puerperium and perinatal conditions Abortion spontaneous	0.34% 1/294 • Number of events 1 • Day 1 to Week 12	0.00% 0/289 • Day 1 to Week 12	0.00% 0/291 • Day 1 to Week 12
Reproductive system and breast disorders Menorrhagia	0.00% 0/294 • Day 1 to Week 12	0.35% 1/289 • Number of events 1 • Day 1 to Week 12	0.00% 0/291 • Day 1 to Week 12

Other adverse events

Other adverse events
Measure	Placebo n=294 participants at risk Participants randomized to receive placebo received three 1.5-mL placebo injections Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Fremanezumab 225/225/225 mg n=289 participants at risk Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.	Fremanezumab 675 mg/Placebo/Placebo n=291 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.
General disorders Injection site erythema	13.9% 41/294 • Number of events 88 • Day 1 to Week 12	18.0% 52/289 • Number of events 102 • Day 1 to Week 12	18.9% 55/291 • Number of events 110 • Day 1 to Week 12
General disorders Injection site induration	15.3% 45/294 • Number of events 93 • Day 1 to Week 12	24.6% 71/289 • Number of events 134 • Day 1 to Week 12	19.6% 57/291 • Number of events 126 • Day 1 to Week 12
General disorders Injection site pain	25.9% 76/294 • Number of events 191 • Day 1 to Week 12	30.1% 87/289 • Number of events 245 • Day 1 to Week 12	29.6% 86/291 • Number of events 234 • Day 1 to Week 12
Infections and infestations Upper respiratory tract infection	5.1% 15/294 • Number of events 15 • Day 1 to Week 12	5.5% 16/289 • Number of events 17 • Day 1 to Week 12	3.8% 11/291 • Number of events 11 • 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