A Study Comparing the Efficacy and Safety of Fremanezumab (TEV-48125) for the Prevention of Chronic Cluster Headache (CCH)

• ClinicalTrials.gov Identifier: NCT02964338
• Recruitment Status: Terminated
• First Posted: November 16, 2016
• Results First Posted: September 18, 2019
• Last Update Posted: November 9, 2021
• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
• Information provided by (Responsible Party): Teva Branded Pharmaceutical Products R&D, Inc.

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Chronic Cluster Headache
• Interventions: Drug: Fremanezumab; Drug: Placebo
• Enrollment: 259

Participant Flow

Recruitment Details	Participants with a history of chronic cluster headache (CCH) were enrolled. Eligible participants entered baseline cluster headache (CH) attack information into an electronic diary device daily for greater than or equal to (≥)4 weeks during the Baseline Period.
Pre-assignment Details	A total of 259 participants were randomly assigned with stratification based on sex, country, and baseline concomitant preventive medication use (yes/no) to either placebo, fremanezumab 675/225/225 milligrams (mg), or fremanezumab 900/225/225 mg treatment groups in a 1:1:1 ratio.

Arm/Group Title	Placebo	Fremanezumab 675/225/225 mg	Fremanezumab 900/225/225 mg
Arm/Group Description	Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8.	Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 milliliters [mL]) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.	Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.
Period Title: Overall Study
Started [1]	84	88	87
Safety Analysis Set [2]	83	88	87
Full Analysis Set [3]	81	86	87
Completed	67	64	68
Not Completed	17	24	19
Reason Not Completed
Sponsor terminated study for futility	12	15	14
Lack of Efficacy	0	3	0
Lost to Follow-up	1	0	3
Protocol Violation	0	1	0
Withdrawal by Subject	1	3	1
Adverse Event	2	1	1
Non-compliant with e-diary	0	1	0
Did not meet criteria	1	0	0
[1] Intent-to-Treat (ITT) Analysis Set: All randomized participants; [2] All randomized participants who received at least 1 dose of study drug.; [3] ITT analysis set, received ≥1 dose of study drug, ≥10 days of postbaseline efficacy assessments

Baseline Characteristics

Arm/Group Title		Placebo	Fremanezumab 675/225/225 mg	Fremanezumab 900/225/225 mg	Total
Arm/Group Description		Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8.	Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.	Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.	Total of all reporting groups
Overall Number of Baseline Participants		84	88	87	259
Baseline Analysis Population Description		Intent-to-treat analysis set included all randomized participants.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	84 participants	88 participants	87 participants	259 participants
		46.3 (11.29)	45.3 (11.40)	43.8 (12.92)	45.1 (11.90)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	84 participants	88 participants	87 participants	259 participants
	Female	35 41.7%	36 40.9%	36 41.4%	107 41.3%
	Male	49 58.3%	52 59.1%	51 58.6%	152 58.7%
Race/Ethnicity, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	84 participants	88 participants	87 participants	259 participants
White		79	83	79	241
Black or African American		4	4	8	16
Asian		0	1	0	1
American Indian or Alaska native		0	0	0	0
Native Hawaiian or other Pacific Islander		0	0	0	0
Middle Eastern		1	0	0	1
Not Hispanic or Latino		77	78	83	238
Hispanic or Latino		5	9	4	18
Missing Ethnicity		2	1	0	3
Number of CH Attacks During the Baseline Period [1]; Mean (Standard Deviation); Unit of measure: CH attacks
	Number Analyzed	84 participants	88 participants	87 participants	259 participants
		38.0 (33.88)	33.9 (27.37)	44.0 (43.78)	38.6 (35.75)
		[1] Measure Description: CH attack defined as a severe/very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15-180 minutes with either or both of following 2 categories: 1) ≥1 of following symptoms/signs, ipsilateral to headache: -conjunctival injection and/or lacrimation; -nasal congestion and/or rhinorrhea; -eyelid edema; -forehead and facial sweating; -forehead and facial flushing; -sensation of fullness in ear; -miosis and/or ptosis. 2) sense of restlessness or agitation. Baseline period (≥4 weeks) defined as date informed consent was signed up to day before first dose of study drug.

Outcome Measures

1. Primary Outcome

Title	Mean Change From Baseline in the Overall Monthly Average Number of CH Attacks Up to Week 12
Description	A CH attack was defined as a severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15 to 180 minutes with either or both of the following 2 categories: 1) at least 1 of the following symptoms or signs, ipsilateral to the headache: -conjunctival injection and/or lacrimation; -nasal congestion and/or rhinorrhea; -eyelid edema; -forehead and facial sweating; -forehead and facial flushing; -sensation of fullness in the ear; -miosis and/or ptosis. 2) a sense of restlessness or agitation. Least Squares (LS) mean calculated using analysis of covariance (ANCOVA) model with baseline preventive medication use (yes or no), sex, region (United States [US]/Canada or other), and treatment as fixed effects and the baseline number of CH attacks as a covariate. Change from baseline in the overall monthly average number of CH attacks during the 12-week period after administration of the first dose of study drug (based on Week 0 to 12 data) is reported.
Time Frame	Baseline Period (from at least Week -4 to Week 0), Up to Week 12

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants who received at least 1 dose of study drug and had at least 10 days of postbaseline efficacy assessments by the Week 12 assessment.

Arm/Group Title	Placebo	Fremanezumab 675/225/225 mg	Fremanezumab 900/225/225 mg
Arm/Group Description:	Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8.	Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.	Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.
Overall Number of Participants Analyzed	81	86	87
Least Squares Mean (Standard Error); Unit of Measure: CH attacks/month
	-12.2 (2.32)	-8.7 (2.26)	-15.5 (2.24)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Fremanezumab 675/225/225 mg
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2741
	Comments	Threshold for significance at 0.05 level.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Least square (LS) mean difference
	Estimated Value	3.5
	Confidence Interval	(2-Sided) 95%; -2.80 to 9.82
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Fremanezumab 900/225/225 mg
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3047
	Comments	Threshold for significance at 0.05 level.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-3.3
	Confidence Interval	(2-Sided) 95%; -9.59 to 3.01
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Percentage of Participants With a ≥50% Reduction From Baseline in the Monthly Average Number of CH Attacks Up to Week 12
Description	A CH attack was defined as a severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15 to 180 minutes with either or both of the following 2 categories: 1) at least 1 of the following symptoms or signs, ipsilateral to the headache: -conjunctival injection and/or lacrimation; -nasal congestion and/or rhinorrhea; -eyelid edema; -forehead and facial sweating; -forehead and facial flushing; -sensation of fullness in the ear; -miosis and/or ptosis. 2) a sense of restlessness or agitation.
Time Frame	Baseline Period (from at least Week -4 to Week 0) up to Week 12

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants who received at least 1 dose of study drug and had at least 10 days of postbaseline efficacy assessments by the Week 12 assessment.

Arm/Group Title	Placebo	Fremanezumab 675/225/225 mg	Fremanezumab 900/225/225 mg
Arm/Group Description:	Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8.	Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.	Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.
Overall Number of Participants Analyzed	81	86	87
Measure Type: Number; Unit of Measure: percentage of participants
	40	40	45

3. Secondary Outcome

Title	Mean Change From Baseline in the Monthly Average Number of CH Attacks at Week 4 and Week 12
Description	A CH attack was defined as a severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15 to 180 minutes with either or both of the following 2 categories: 1) ≥1 of the following symptoms or signs, ipsilateral to the headache: -conjunctival injection and/or lacrimation; -nasal congestion and/or rhinorrhea; -eyelid edema; -forehead and facial sweating; -forehead and facial flushing; -sensation of fullness in the ear; -miosis and/or ptosis. 2) a sense of restlessness or agitation. Mean change from baseline in monthly average number of CH attacks during 4-week period after administration of first dose of study drug (based on Week 0 to 4 data) and during 4-week period after administration of third dose of study drug (based on Week 8 to 12 data) is reported.
Time Frame	Baseline Period (from at least Week -4 to Week 0), Week 4 and Week 12

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants who received at least 1 dose of study drug and had at least 10 days of postbaseline efficacy assessments by the Week 12 assessment. Here, 'Number analyzed' signifies participants evaluable at specified timepoint.

Arm/Group Title		Placebo	Fremanezumab 675/225/225 mg	Fremanezumab 900/225/225 mg
Arm/Group Description:		Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8.	Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.	Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.
Overall Number of Participants Analyzed		81	86	87
Mean (Standard Deviation); Unit of Measure: CH attacks/month
Change at Week 4	Number Analyzed	81 participants	86 participants	87 participants
		-10.4 (17.22)	-7.7 (19.53)	-15.0 (24.17)
Change at Week 12	Number Analyzed	67 participants	62 participants	72 participants
		-12.6 (25.72)	-3.1 (34.42)	-17.9 (25.98)

4. Secondary Outcome

Title	Mean Change From Baseline in the Overall Weekly Average Number of Days With Use of Cluster-Specific Acute Headache Medications (Triptans and Ergot Compounds) Up to Week 12
Description	A maximum of 2 concomitant preventive medications for CH were allowed during the study. Participants must have been on a stable dose and regimen of the concomitant medication for at least 2 weeks before screening and throughout the study. Baseline data and the mean change from baseline in the overall weekly average number of days with the use of cluster-specific acute headache medications (triptans and ergot compounds) during the 12-week period after administration of the first dose of study drug (based on Week 0 to 12 data) is reported.
Time Frame	Baseline Period (from at least Week -4 to Week 0), Up to Week 12

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants who received at least 1 dose of study drug and had at least 10 days of postbaseline efficacy assessments by the Week 12 assessment.

Arm/Group Title	Placebo	Fremanezumab 675/225/225 mg	Fremanezumab 900/225/225 mg
Arm/Group Description:	Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8.	Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.	Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.
Overall Number of Participants Analyzed	81	86	87
Mean (Standard Deviation); Unit of Measure: days of use/week
Baseline	2.4 (2.42)	2.4 (2.18)	2.2 (2.27)
Change at Week 12	-0.7 (1.34)	-0.8 (1.57)	-0.8 (1.20)

5. Secondary Outcome

Title	Mean Change From Baseline in the Weekly Average Number of Days Oxygen Was Used to Treat CCH Up to Week 12
Description	Baseline data and the mean change from baseline in the overall weekly average number of days oxygen was used to treat CCH during the 12-week period after administration of the first dose of study drug (based on Week 0 to 12 data) is reported.
Time Frame	Baseline Period (from at least Week -4 to Week 0), Up to Week 12

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants who received at least 1 dose of study drug and had at least 10 days of postbaseline efficacy assessments by the Week 12 assessment.

Arm/Group Title	Placebo	Fremanezumab 675/225/225 mg	Fremanezumab 900/225/225 mg
Arm/Group Description:	Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8.	Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.	Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.
Overall Number of Participants Analyzed	81	86	87
Mean (Standard Deviation); Unit of Measure: days of use/week
Baseline	2.2 (2.59)	1.9 (2.53)	1.9 (2.59)
Change at Week 12	-0.5 (1.35)	-0.5 (1.35)	-0.5 (1.09)

6. Secondary Outcome

Title	Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12
Description	The PPSI assessment was developed to measure pain intensity and was adjusted for CH symptoms improvement. Participants marked the level of CH-associated pain and indicated if pain is "1=much worse," "2=moderately worse," "3=slightly worse," "4=unchanged," "5=slightly improved," "6=moderately improved," or "7=much improved" compared with 4 weeks prior. PPSI was defined as the change in pain that corresponds with a minimal rating of "5=slightly improved." Data at Week 1 was recorded on Day 7 in the electronic diary device at home. Week 12 data also included assessment at the early withdrawal visit for participants who discontinued the study early.
Time Frame	Baseline and Weeks 1, 4, 8, and 12

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants who received at least 1 dose of study drug and had at least 10 days of postbaseline efficacy assessments by the Week 12 assessment.

Arm/Group Title	Placebo	Fremanezumab 675/225/225 mg	Fremanezumab 900/225/225 mg
Arm/Group Description:	Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8.	Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.	Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.
Overall Number of Participants Analyzed	81	86	87
Measure Type: Count of Participants; Unit of Measure: Participants
Much worse, Baseline	3 3.7%	1 1.2%	1 1.1%
Moderately worse, Baseline	1 1.2%	4 4.7%	4 4.6%
Slightly worse, Baseline	1 1.2%	5 5.8%	4 4.6%
Unchanged, Baseline	69 85.2%	72 83.7%	75 86.2%
Slightly improved, Baseline	5 6.2%	3 3.5%	3 3.4%
Moderately improved, Baseline	1 1.2%	1 1.2%	0 0.0%
Much improved, Baseline	1 1.2%	0 0.0%	0 0.0%
Missing, Baseline	0 0.0%	0 0.0%	0 0.0%
Much worse, Week 1	0 0.0%	3 3.5%	3 3.4%
Moderately worse, Week 1	0 0.0%	2 2.3%	1 1.1%
Slightly worse, Week 1	0 0.0%	2 2.3%	5 5.7%
Unchanged, Week 1	35 43.2%	31 36.0%	26 29.9%
Slightly improved, Week 1	23 28.4%	20 23.3%	32 36.8%
Moderately improved, Week 1	5 6.2%	4 4.7%	8 9.2%
Much improved, Week 1	6 7.4%	13 15.1%	8 9.2%
Missing, Week 1	12 14.8%	11 12.8%	4 4.6%
Much worse, Week 4	0 0.0%	1 1.2%	0 0.0%
Moderately worse, Week 4	1 1.2%	2 2.3%	3 3.4%
Slightly worse, Week 4	1 1.2%	2 2.3%	2 2.3%
Unchanged, Week 4	24 29.6%	24 27.9%	25 28.7%
Slightly improved, Week 4	30 37.0%	17 19.8%	25 28.7%
Moderately improved, Week 4	5 6.2%	9 10.5%	12 13.8%
Much improved, Week 4	12 14.8%	18 20.9%	11 12.6%
Missing, Week 4	8 9.9%	13 15.1%	9 10.3%
Much worse, Week 8	3 3.7%	2 2.3%	0 0.0%
Moderately worse, Week 8	1 1.2%	3 3.5%	3 3.4%
Slightly worse, Week 8	3 3.7%	4 4.7%	5 5.7%
Unchanged, Week 8	27 33.3%	18 20.9%	24 27.6%
Slightly improved, Week 8	18 22.2%	12 14.0%	13 14.9%
Moderately improved, Week 8	10 12.3%	13 15.1%	14 16.1%
Much improved, Week 8	4 4.9%	12 14.0%	15 17.2%
Missing, Week 8	15 18.5%	22 25.6%	13 14.9%
Much worse, Week 12	0 0.0%	2 2.3%	1 1.1%
Moderately worse, Week 12	3 3.7%	5 5.8%	3 3.4%
Slightly worse, Week 12	4 4.9%	6 7.0%	6 6.9%
Unchanged, Week 12	29 35.8%	27 31.4%	31 35.6%
Slightly improved, Week 12	21 25.9%	18 20.9%	15 17.2%
Moderately improved, Week 12	8 9.9%	11 12.8%	11 12.6%
Much improved, Week 12	13 16.0%	14 16.3%	12 13.8%
Missing, Week 12	3 3.7%	3 3.5%	8 9.2%

7. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs)
Description	An AE was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the Investigator on a scale of mild, moderate and severe, with severe as an AE that 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 participant and required medical intervention to prevent the previously listed serious outcomes. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
Time Frame	Baseline up to Week 12

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Placebo	Fremanezumab 675/225/225 mg	Fremanezumab 900/225/225 mg
Arm/Group Description:	Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8.	Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.	Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.
Overall Number of Participants Analyzed	83	88	87
Measure Type: Count of Participants; Unit of Measure: Participants
Any AE	43 51.8%	51 58.0%	49 56.3%
Severe AE	3 3.6%	1 1.1%	3 3.4%
Treatment-related AE	17 20.5%	23 26.1%	28 32.2%
Serious AE	2 2.4%	2 2.3%	3 3.4%
AE leading to discontinuation	2 2.4%	1 1.1%	2 2.3%

8. Secondary Outcome

Title	Number of Participants With Potentially Clinically Significant Laboratory (Serum Chemistry, Hematology, and Urinalysis) Abnormal Results
Description	Serum chemistry, hematology, urinalysis laboratory tests with potentially clinically significant abnormal findings included: Alanine Aminotransferase (units/liter [U/L]) ≥3*upper limit of normal (ULN); Aspartate Aminotransferase (U/L) ≥3*ULN; Bilirubin (Total) ≥34.2 micromole/liter (umol/L); Blood Urea Nitrogen ≥10.71 millimole (mmol)/L; Creatinine ≥177 umol/L; Gamma Glutamyl Transferase (U/L) ≥3*ULN; hemoglobin less than (<)115 grams (g)/L (males) or less than or equal to (≤)95 g/L (females); leukocytes ≥20*10^9/L or ≤3*10^9/L; Eosinophils/Leukocytes ≥10%; Hematocrit <0.37 L/L (males) and <0.32 L/L (females); platelets ≥700*10^9/L or ≤75*10^9/L; blood ≥2 unit increase from baseline; urine glucose (milligrams/decilitre [mg/dL]) ≥2 U increase from baseline; ketones (mg/dL) ≥2 U increase from baseline; urine protein (mg/dL) ≥2 U increase from baseline. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
Time Frame	Baseline up to Week 12

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Placebo	Fremanezumab 675/225/225 mg	Fremanezumab 900/225/225 mg
Arm/Group Description:	Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8.	Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.	Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.
Overall Number of Participants Analyzed	83	88	87
Measure Type: Count of Participants; Unit of Measure: Participants
With at least 1 serum chemistry abnormality	1 1.2%	2 2.3%	0 0.0%
With at least 1 hematology abnormality	2 2.4%	1 1.1%	3 3.4%
With at least 1 urinalysis abnormality	0 0.0%	0 0.0%	0 0.0%

9. Secondary Outcome

Title	Number of Participants With Shift From Baseline to Endpoint in Coagulation Laboratory Test Results
Description	Coagulation parameters included: prothrombin time (PT) (seconds) and prothrombin international normalized ratio (INR). Shifts represented as Baseline - endpoint value (last observed post-baseline value). Shifts from baseline to endpoint were summarized using participant counts grouped into three categories: - Low (below normal range) - Normal (within the normal range of 9.4 to 12.5 seconds) - High (above normal range). Missing PT and prothrombin INR shift data are also presented. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
Time Frame	Baseline up to Week 12

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least 1 dose of study drug. Here, 'Number analyzed' signifies participants evaluable at the timepoint.

Arm/Group Title	Placebo	Fremanezumab 675/225/225 mg	Fremanezumab 900/225/225 mg
Arm/Group Description:	Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8.	Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.	Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.
Overall Number of Participants Analyzed	83	88	87
Measure Type: Count of Participants; Unit of Measure: Participants
PT: Low-Low	0 0.0%	0 0.0%	0 0.0%
PT: Low-Normal	0 0.0%	0 0.0%	0 0.0%
PT: Low-High	0 0.0%	0 0.0%	0 0.0%
PT: Normal-Low	0 0.0%	0 0.0%	0 0.0%
PT: Normal-Normal	68 81.9%	69 78.4%	62 71.3%
PT: Normal-High	3 3.6%	2 2.3%	5 5.7%
PT: High-Low	0 0.0%	0 0.0%	0 0.0%
PT: High-Normal	5 6.0%	8 9.1%	11 12.6%
PT: High-High	5 6.0%	4 4.5%	3 3.4%
PT: Missing	2 2.4%	5 5.7%	6 6.9%
Prothrombin INR: Low-Low	0 0.0%	0 0.0%	0 0.0%
Prothrombin INR: Low-Normal	0 0.0%	0 0.0%	0 0.0%
Prothrombin INR: Low-High	0 0.0%	0 0.0%	0 0.0%
Prothrombin INR: Normal-Low	0 0.0%	0 0.0%	0 0.0%
Prothrombin INR: Normal-Normal	70 84.3%	71 80.7%	69 79.3%
Prothrombin INR: Normal-High	4 4.8%	2 2.3%	5 5.7%
Prothrombin INR: High-Low	0 0.0%	0 0.0%	0 0.0%
Prothrombin INR: High-Normal	5 6.0%	7 8.0%	6 6.9%
Prothrombin INR: High-High	2 2.4%	3 3.4%	1 1.1%
Prothrombin INR: Missing	2 2.4%	5 5.7%	6 6.9%

10. Secondary Outcome

Title	Number of Participants With Potentially Clinically Significant Abnormal Vital Signs Values
Description	Potentially clinically significant abnormal vital signs findings included: pulse rate ≤50 beats/minute (bpm) and decrease of ≥15 bpm, or ≥120 bpm and increase of ≥15 bpm; systolic blood pressure ≤90 millimeters of mercury (mmHg) and decrease of ≥20 mmHg, or ≥180 mmHg and increase of ≥20 mmHg; diastolic blood pressure ≤50 mmHg and decrease of ≥15 mmHg, or ≥105 mmHg and increase of ≥15 mmHg; respiratory rate <10 breaths/minute; and body temperature ≥38.3 degrees centigrade and change of ≥1.1 degrees centigrade. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
Time Frame	Baseline up to Week 12

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Placebo	Fremanezumab 675/225/225 mg	Fremanezumab 900/225/225 mg
Arm/Group Description:	Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8.	Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.	Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.
Overall Number of Participants Analyzed	83	88	87
Measure Type: Count of Participants; Unit of Measure: Participants
	3 3.6%	0 0.0%	0 0.0%

11. Secondary Outcome

Title	Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Electrocardiogram (ECG) Parameters
Description	ECG parameters included: heart rate, PR interval, QRS interval, QT interval corrected using the Fridericia formula (QTcF), QT interval corrected using the Bazett's formula (QTcB) and RR interval. Shifts represented as Baseline - endpoint value (last observed post-baseline value). Abnormal NCS indicated an abnormal but not clinically significant finding. Abnormal CS indicated an abnormal and clinically significant finding. Missing ECG shift data are also presented. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least 1 dose of study drug. Here, 'Number analyzed' signifies participants evaluable at the timepoint.

Arm/Group Title	Placebo	Fremanezumab 675/225/225 mg	Fremanezumab 900/225/225 mg
Arm/Group Description:	Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8.	Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.	Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.
Overall Number of Participants Analyzed	83	88	87
Measure Type: Count of Participants; Unit of Measure: Participants
Normal / Normal	47 56.6%	46 52.3%	45 51.7%
Normal / NCS	8 9.6%	11 12.5%	14 16.1%
Normal / CS	0 0.0%	0 0.0%	0 0.0%
NCS / Normal	10 12.0%	7 8.0%	8 9.2%
NCS / NCS	15 18.1%	20 22.7%	12 13.8%
NCS / CS	0 0.0%	0 0.0%	0 0.0%
CS / Normal	0 0.0%	0 0.0%	0 0.0%
CS / NCS	0 0.0%	0 0.0%	0 0.0%
CS / CS	0 0.0%	0 0.0%	0 0.0%
Missing	3 3.6%	4 4.5%	8 9.2%

12. Secondary Outcome

Title	Number of Participants With Injection Site Reactions
Description	Number of participants who reported treatment-emergent injection site reactions are summarized. Preferred terms from Medical Dictionary for Regulatory Activities (MedDRA) version 18.1 were offered without a threshold applied. Injection site reactions included injection site erythema, induration, pain, haemorrhage, bruising, hypersensitivity, swelling, rash, and flushing. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
Time Frame	Baseline up to Week 12

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Placebo	Fremanezumab 675/225/225 mg	Fremanezumab 900/225/225 mg
Arm/Group Description:	Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8.	Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.	Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.
Overall Number of Participants Analyzed	83	88	87
Measure Type: Count of Participants; Unit of Measure: Participants
Injection site erythema	3 3.6%	7 8.0%	5 5.7%
Injection site induration	3 3.6%	6 6.8%	6 6.9%
Injection site pain	6 7.2%	5 5.7%	2 2.3%
Injection site haemorrhage	0 0.0%	0 0.0%	2 2.3%
Injection site bruising	0 0.0%	0 0.0%	1 1.1%
Injection site hypersensitivity	0 0.0%	1 1.1%	0 0.0%
Injection site swelling	2 2.4%	0 0.0%	0 0.0%
Injection site rash	1 1.2%	0 0.0%	0 0.0%
Injection site flushing	0 0.0%	1 1.1%	0 0.0%

13. Secondary Outcome

Title	Number of Participants With Suicidal Ideation and Suicidal Behavior as Assessed by the Electronic Columbia Suicide Severity Rating Scale (eC-SSRS)
Description	eC-SSRS is a questionnaire to assess suicidal ideation and suicidal behavior. Suicidal behavior was defined as a "yes" answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation was defined as a "yes" answer to any one of 5 suicidal ideation questions: wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent, any self-injurious behavior with no suicidal intent.
Time Frame	Baseline up to Week 12

Outcome Measure Data

Analysis Population Description

Safety population included all randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Placebo	Fremanezumab 675/225/225 mg	Fremanezumab 900/225/225 mg
Arm/Group Description:	Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8.	Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.	Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.
Overall Number of Participants Analyzed	83	88	87
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%	0 0.0%	0 0.0%

Adverse Events

Time Frame	Baseline up to Week 12
Adverse Event Reporting Description	Safety population included all randomized participants who received at least 1 dose of study drug.
Arm/Group Title	Placebo		Fremanezumab 675/225/225 mg		Fremanezumab 900/225/225 mg
Arm/Group Description	Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8.		Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.		Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.
All-Cause Mortality
	Placebo		Fremanezumab 675/225/225 mg		Fremanezumab 900/225/225 mg
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	0/83 (0.00%)		0/88 (0.00%)		0/87 (0.00%)
Serious Adverse Events
	Placebo		Fremanezumab 675/225/225 mg		Fremanezumab 900/225/225 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/83 (2.41%)		2/88 (2.27%)		3/87 (3.45%)
Gastrointestinal disorders
Gastric haemorrhage † 1	0/83 (0.00%)	0	1/88 (1.14%)	1	0/87 (0.00%)	0
Pancreatitis acute † 1	1/83 (1.20%)	1	0/88 (0.00%)	0	0/87 (0.00%)	0
General disorders
Infusion site necrosis † 1	0/83 (0.00%)	0	0/88 (0.00%)	0	1/87 (1.15%)	1
Hepatobiliary disorders
Cholecystitis † 1	0/83 (0.00%)	0	0/88 (0.00%)	0	1/87 (1.15%)	1
Immune system disorders
Anaphylactic reaction † 1	0/83 (0.00%)	0	1/88 (1.14%)	1	0/87 (0.00%)	0
Infections and infestations
Cellulitis † 1	0/83 (0.00%)	0	0/88 (0.00%)	0	1/87 (1.15%)	1
Pelvic abscess † 1	0/83 (0.00%)	0	0/88 (0.00%)	0	1/87 (1.15%)	1
Psychiatric disorders
Conversion disorder † 1	1/83 (1.20%)	1	0/88 (0.00%)	0	0/87 (0.00%)	0
Surgical and medical procedures
Hospitalisation † 1	0/83 (0.00%)	0	0/88 (0.00%)	0	1/87 (1.15%)	1
1 Term from vocabulary, MedDRA 18.1; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo		Fremanezumab 675/225/225 mg		Fremanezumab 900/225/225 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/83 (21.69%)		22/88 (25.00%)		19/87 (21.84%)
Gastrointestinal disorders
Nausea † 1	4/83 (4.82%)	4	5/88 (5.68%)	5	3/87 (3.45%)	4
General disorders
Injection site erythema † 1	3/83 (3.61%)	4	7/88 (7.95%)	15	5/87 (5.75%)	6
Injection site induration † 1	3/83 (3.61%)	8	6/88 (6.82%)	12	6/87 (6.90%)	12
Injection site pain † 1	6/83 (7.23%)	11	5/88 (5.68%)	9	2/87 (2.30%)	2
Infections and infestations
Nasopharyngitis † 1	6/83 (7.23%)	7	6/88 (6.82%)	7	8/87 (9.20%)	9
1 Term from vocabulary, MedDRA 18.1; † Indicates events were collected by systematic assessment

Limitations and Caveats

Futility analysis revealed that the primary endpoint is unlikely to be met. There were no safety concerns observed with fremanezumab treatment in the trial.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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.

Results Point of Contact

• Name/Title: Director, Clinical Research
• Organization: Teva Branded Pharmaceutical Products, R&D Inc.
• Phone: 1-888-483-8279
• EMail: USMedInfo@tevapharm.com

• Responsible Party: Teva Branded Pharmaceutical Products R&D, Inc.
• ClinicalTrials.gov Identifier: NCT02964338
• Other Study ID Numbers: TV48125-CNS-30057; 2016-003171-21 ( EudraCT Number )
• First Submitted: November 11, 2016
• First Posted: November 16, 2016
• Results First Submitted: July 16, 2019
• Results First Posted: September 18, 2019
• Last Update Posted: November 9, 2021