A Study to Test if Fremanezumab Reduces Headache in Participants With Posttraumatic Headache (PTH)

• ClinicalTrials.gov Identifier: NCT03347188
• Recruitment Status: Completed
• First Posted: November 20, 2017
• Results First Posted: March 26, 2021
• Last Update Posted: December 13, 2022
• 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: Prevention
• Condition: Post-Traumatic Headache
• Interventions: Drug: Fremanezumab; Drug: Placebo
• Enrollment: 87

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Fremanezumab	Placebo
Arm/Group Description	Participants received fremanezumab 675 milligrams (mg) administered as 3 subcutaneous (SC) injections (225 mg/1.5 milliliters [mL] each) at randomization (Week 0), Weeks 4, and 8 during the double-blind (DB) treatment period. Participants who completed the DB treatment period and continued into the open-label (OL) treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.	Participants received placebo matched to fremanezumab administered as 3 SC injections (1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.
Period Title: Double-blind (DB) Period (12 Weeks)
Started	44	43
Received at Least 1 Dose of Study Drug	43	43
Full Analysis Set (FAS) [1]	42	43
Completed	29	26
Not Completed	15	17
Reason Not Completed
Protocol Violation	2	2
Withdrawal by Subject	4	8
Lost to Follow-up	7	4
Adverse Event	1	1
Other than specified	1	2
[1] Received at least 1 dose of study drug and had at least 1 post-baseline efficacy assessment on primary endpoint.
Period Title: Open-label (OL) Period (12 Weeks)
Started	35	35
Entered in OL Period for Anti-drug Antibody (ADA) Only	26	28
Received at Least 1 Dose of Study Drug	9	7
Completed	8	6
Not Completed	27	29
Reason Not Completed
Entered for ADA assessment only, not treated	26	28
Withdrawal by Subject	1	0
Other than specified	0	1

Baseline Characteristics

Arm/Group Title		Fremanezumab	Placebo	Total
Arm/Group Description		Participants received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.	Participants received placebo matched to fremanezumab administered as 3 SC injections (1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.	Total of all reporting groups
Overall Number of Baseline Participants		44	43	87
Baseline Analysis Population Description		Intent-to-treat (ITT) analysis set included all randomized participants.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	44 participants	43 participants	87 participants
		42.6 (13.01)	43.8 (14.48)	43.2 (13.68)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	44 participants	43 participants	87 participants
	Female	25 56.8%	25 58.1%	50 57.5%
	Male	19 43.2%	18 41.9%	37 42.5%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	44 participants	43 participants	87 participants
	Hispanic or Latino	4 9.1%	4 9.3%	8 9.2%
	Not Hispanic or Latino	40 90.9%	38 88.4%	78 89.7%
	Unknown or Not Reported	0 0.0%	1 2.3%	1 1.1%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
Race	Number Analyzed	44 participants	43 participants	87 participants
	White	41 93.2%	39 90.7%	80 92.0%
	Black or African American	3 6.8%	1 2.3%	4 4.6%
	Native Hawaiian or other Pacific Islander	0 0.0%	1 2.3%	1 1.1%
	Other	0 0.0%	2 4.7%	2 2.3%
Number of Headache Days of at Least Moderate Severity [1]; Mean (Standard Deviation); Unit of measure: Days
	Number Analyzed	43 participants	43 participants	86 participants
		18.7 (7.03)	18.5 (6.12)	18.6 (6.56)
		[1] Measure Analysis Population Description: 'Number analyzed' signifies participants evaluable for this baseline measure.

Outcome Measures

1. Primary Outcome

Title	DB Period: Mean Change From Baseline in Monthly Average Number of Headache Days of at Least Moderate Severity During the 12-Week Treatment Period After the First Dose of Fremanezumab
Description	A headache day was defined as a day when a participant reported a headache of at least moderate severity. Monthly averages were derived and normalized to 28 days equivalent by the following formula: (number of days of efficacy variable over relevant period/number of days with assessments recorded in the e-diary over the relevant period) * 28. The change was calculated as post-baseline value - baseline value. Least square (LS) mean was calculated using analysis of covariance (ANCOVA) model with the duration of post traumatic headache history (less than 12 month since the brain injury or greater or equal to 12 month since the brain injury) and treatment as fixed effects and the baseline monthly average number of headache days of at least moderate severity as a covariate.
Time Frame	Baseline (Day -28 to Day -1), up to Week 12

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all randomized participants who received at least 1 dose of the study drug and had at least 1 post-baseline efficacy assessment on the primary endpoint.

Arm/Group Title	Fremanezumab	Placebo
Arm/Group Description:	Participants received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.	Participants received placebo matched to fremanezumab administered as 3 SC injections (1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.
Overall Number of Participants Analyzed	42	43
Least Squares Mean (Standard Error); Unit of Measure: days
	-3.6 (0.99)	-5.1 (1.01)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fremanezumab, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1876
	Comments	Threshold for significance at 0.05 level.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	1.5
	Confidence Interval	(2-Sided) 95%; -0.73 to 3.67
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.11
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	DB Period: Number of Participants Reaching at Least 50% Reduction From Baseline in Monthly Average Number of Headache Days of Any Severity During 12-Week Treatment With Fremanezumab
Description	Monthly averages were derived and normalized to 28 days equivalent by the following formula: (number of days of efficacy variable over relevant period/number of days with assessments recorded in the e-diary over the relevant period) * 28.
Time Frame	Baseline (Day -28 to Day-1) up to Week 12

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who received at least 1 dose of the study drug and had at least 1 post-baseline efficacy assessment on the primary endpoint.

Arm/Group Title	Fremanezumab	Placebo
Arm/Group Description:	Participants received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.	Participants received placebo matched to fremanezumab administered as 3 SC injections (1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.
Overall Number of Participants Analyzed	42	43
Measure Type: Count of Participants; Unit of Measure: Participants
	5 11.9%	4 9.3%

3. Secondary Outcome

Title	DB Period: Number of Participants Reaching at Least 50% Reduction From Baseline in the Monthly Average Number of Headache Days of at Least Moderate Severity During 12-Week Treatment With Fremanezumab
Description	A headache day was defined as a day when a participant reported a headache of at least moderate severity. Monthly averages were derived and normalized to 28 days equivalent by the following formula: (number of days of efficacy variable over relevant period/number of days with assessments recorded in the e-diary over the relevant period) * 28.
Time Frame	Baseline (Day -28 to Day-1) up to Week 12

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who received at least 1 dose of the study drug and had at least 1 post-baseline efficacy assessment on the primary endpoint.

Arm/Group Title	Fremanezumab	Placebo
Arm/Group Description:	Participants received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.	Participants received placebo matched to fremanezumab administered as 3 SC injections (1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.
Overall Number of Participants Analyzed	42	43
Measure Type: Count of Participants; Unit of Measure: Participants
	9 21.4%	11 25.6%

4. Secondary Outcome

Title	DB Period: Number of Participants Reaching at Least 50% Reduction From Baseline in the Monthly Average Number of Headache Days of at Least Moderate Severity During First 4-Week (Month 1), 5- to 8-Week (Month 2), and 9- to 12-Week (Month 3)
Description	A headache day was defined as a day when a participant reported a headache of at least moderate severity. Monthly averages were derived and normalized to 28 days equivalent by the following formula: (number of days of efficacy variable over relevant period/number of days with assessments recorded in the e-diary over the relevant period) * 28.
Time Frame	Baseline (Day -28 to Day-1) up to Months 1, 2, and 3

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who received at least 1 dose of the study drug and had at least 1 post-baseline efficacy assessment on the primary endpoint. Here, 'Number analyzed' signifies participants evaluable for this outcome measure at specified timepoints.

Arm/Group Title		Fremanezumab	Placebo
Arm/Group Description:		Participants received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.	Participants received placebo matched to fremanezumab administered as 3 SC injections (1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.
Overall Number of Participants Analyzed		42	43
Measure Type: Count of Participants; Unit of Measure: Participants
Month 1	Number Analyzed	42 participants	43 participants
		8 19.0%	11 25.6%
Month 2	Number Analyzed	38 participants	41 participants
		8 21.1%	14 34.1%
Month 3	Number Analyzed	37 participants	37 participants
		14 37.8%	12 32.4%

5. Secondary Outcome

Title	DB Period: Change From Baseline in the Number of Headache Days of At Least Moderate Severity During the First 4-Week (Month 1), 5- to 8-Week (Month 2), and 9- to 12-Week (Month 3)
Description	A headache day was defined as a day when a participant reported a headache of at least moderate severity. Monthly averages were derived and normalized to 28 days equivalent by the following formula: (number of days of efficacy variable over relevant period/number of days with assessments recorded in the e-diary over the relevant period) * 28. The change was calculated as post-baseline value - baseline value. LS mean was calculated using ANCOVA model with the duration of post traumatic headache history (less than 12 month since the brain injury or greater or equal to 12 month since the brain injury) and treatment as fixed effects and the baseline monthly average number of headache days of at least moderate severity as a covariate. This approach was used in generating the LS mean values only and was not considered to be an additional statistical analysis, no additional statistical analyses are reported for this outcome measure.
Time Frame	Baseline (Day -28 to Day -1), up to Months 1, 2, and 3

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who received at least 1 dose of the study drug and had at least 1 post-baseline efficacy assessment on the primary endpoint. Here, 'Number analyzed' signifies participants evaluable for this outcome measure at specified timepoints.

Arm/Group Title		Fremanezumab	Placebo
Arm/Group Description:		Participants received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.	Participants received placebo matched to fremanezumab administered as 3 SC injections (1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.
Overall Number of Participants Analyzed		42	43
Least Squares Mean (Standard Error); Unit of Measure: days
Change at Month 1	Number Analyzed	42 participants	43 participants
		-3.6 (0.97)	-4.0 (0.99)
Change at Month 2	Number Analyzed	38 participants	41 participants
		-3.7 (1.06)	-6.7 (1.06)
Change at Month 3	Number Analyzed	37 participants	37 participants
		-5.2 (1.20)	-7.2 (1.21)

6. Secondary Outcome

Title	DB Period: Change From Baseline in Disability Score, as Measured by the 6-Item Headache Impact Test (HIT-6) Total Score at Week 12 After the First Dose of Fremanezumab
Description	HIT-6 is a tool used to measure the impact headaches have on a participant's normal daily life and ability to function. The HIT-6 consists of 6 items, including pain, social functioning, role functioning, vitality, cognitive functioning, and psychological distress. Each item was answered on a 5-point Likert scale (6=never, 8=rarely, 10=sometimes, 11=very often, or 13=always), which were summed to produce a total score that ranged from 36 to 78, with larger scores reflecting greater impact of headache on the daily life of the participant.
Time Frame	Baseline (Day -28 to Day -1), Week 12

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who received at least 1 dose of the study drug and had at least 1 post-baseline efficacy assessment on the primary endpoint. Here, 'Overall number of participants analyzed' signifies participants evaluable for this outcome measure.

Arm/Group Title	Fremanezumab	Placebo
Arm/Group Description:	Participants received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.	Participants received placebo matched to fremanezumab administered as 3 SC injections (1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.
Overall Number of Participants Analyzed	35	37
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
	-6.9 (4.54)	-10.8 (4.65)

7. Secondary Outcome

Title	DB Period: Number of Participants (Responder and Non-Responder) With the Patient Global Impression of Change (PGIC) Scale at Weeks 4, 8, and 12 After the First Dose of Fremanezumab
Description	The PGIC scale is a validated generic tool for the assessment of overall change in the severity of illness following treatment. Participants rated how they felt during assigned time points compared with how they felt before receiving study drug on a 7-point scale, where 1 = No change (or it got worse); 2 = Almost the same, hardly any change at all; 3 = A little better, but no noticeable change; 4 = Somewhat better, but the change has not made any real difference; 5 = Moderately better, and a slight but noticeable change; 6 = Better, and a definite improvement that has made a real and worthwhile difference; and 7 = A great deal better, and a considerable improvement that has made all the difference. Responders were those with a scale of 5 to 7 and non-responders were those with a scale of 1 to 4.
Time Frame	Weeks 4, 8, and 12

Outcome Measure Data

Analysis Population Description

FAS included all randomized participants who received at least 1 dose of the study drug and had at least 1 post-baseline efficacy assessment on the primary endpoint.

Arm/Group Title		Fremanezumab	Placebo
Arm/Group Description:		Participants received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.	Participants received placebo matched to fremanezumab administered as 3 SC injections (1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.
Overall Number of Participants Analyzed		42	43
Measure Type: Count of Participants; Unit of Measure: Participants
Week 4	Responder	12 28.6%	11 25.6%
	Non-Responder	24 57.1%	26 60.5%
	Missing	6 14.3%	6 14.0%
Week 8	Responder	14 33.3%	17 39.5%
	Non-Responder	20 47.6%	21 48.8%
	Missing	8 19.0%	5 11.6%
Week 12	Responder	11 26.2%	16 37.2%
	Non-Responder	20 47.6%	16 37.2%
	Missing	11 26.2%	11 25.6%

8. Secondary Outcome

Title	DB Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
Description	An adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as AEs occurring at or after the first dose of the study drug. Serious AEs were defined as death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
Time Frame	Baseline (Day -28 to -1) up to Week 12

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Fremanezumab	Placebo
Arm/Group Description:	Participants received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.	Participants received placebo matched to fremanezumab administered as 3 SC injections (1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.
Overall Number of Participants Analyzed	43	43
Measure Type: Count of Participants; Unit of Measure: Participants
	31 72.1%	35 81.4%

9. Secondary Outcome

Title	OL Period: Number of Participants With TEAEs
Description	An AE was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as AEs occurring at or after the first dose of the study drug. Serious AEs were defined as death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
Time Frame	Week 12 up to Week 24

Outcome Measure Data

Analysis Population Description

OL-ITT analysis set included only participants who received at least 1 dose of study drug during the open-label treatment period.

Arm/Group Title	Fremanezumab	Placebo
Arm/Group Description:	Participants received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.	Participants received placebo matched to fremanezumab administered as 3 SC injections (1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.
Overall Number of Participants Analyzed	9	7
Measure Type: Count of Participants; Unit of Measure: Participants
	8 88.9%	6 85.7%

10. Secondary Outcome

Title	DB Period: Number of Participants Who Did Not Complete the Study
Description	Number of participants who did not complete the study due to any reason and due to AEs are reported.
Time Frame	Baseline (Day -28 to Day -1) up to Week 12

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Fremanezumab	Placebo
Arm/Group Description:	Participants received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.	Participants received placebo matched to fremanezumab administered as 3 SC injections (1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.
Overall Number of Participants Analyzed	43	43
Measure Type: Count of Participants; Unit of Measure: Participants
Discontinued study due to any reason	15 34.9%	17 39.5%
Discontinued study due to AEs	1 2.3%	1 2.3%

11. Secondary Outcome

Title	OL Period: Number of Participants Who Did Not Complete the Study
Description	Number of participants who did not complete the study due to any reason and due to AEs are reported.
Time Frame	Week 12 up to Week 24

Outcome Measure Data

Analysis Population Description

OL-ITT analysis set included only participants who received at least 1 dose of study drug during the open-label treatment period.

Arm/Group Title	Fremanezumab	Placebo
Arm/Group Description:	Participants received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.	Participants received placebo matched to fremanezumab administered as 3 SC injections (1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.
Overall Number of Participants Analyzed	9	7
Measure Type: Count of Participants; Unit of Measure: Participants
Discontinued study due to any reason	1 11.1%	1 14.3%
Discontinued study due to AEs	0 0.0%	0 0.0%

12. Secondary Outcome

Title	DB Period: Number of Participants Who Received Concomitant Medications
Description	Concomitant medications included: agents acting on renin-angiotensin system, analgesics, anesthetics, anti-parkinson drugs, antianemic preparations, antibacterials for systemic use, antidiarrheals, intestinal antiinflammatory/antiinfective agents, antiemetics and antinauseants, antiepileptics, antifungals for dermatologiocal use, antihistamines for systemic use, antihypertensives, antiinflammatory and antirheumatics, antineoplastic agents, antiobesity preparations, antipruritics, antithrombotics, antivirals for systemic use, beta blocking agents, calcium channel blockers, cardiac therapy, corticosteroids, cough and cold preparations, diuretics, lipid modifying agents, nasal preparations, thyroid therapy, urologicals, vaccines, psycholeptics, psycoanaleptics, ophthalmologicals, general nutrients, mineral supplements, muscle relaxants, vitamins, drugs used in diabetes, sex hormones and modulators of the genital system, immunosuppresants, drugs for acid related disorders etc.
Time Frame	Baseline (Day -28 to Day -1) up to Week 12

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Fremanezumab	Placebo
Arm/Group Description:	Participants received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.	Participants received placebo matched to fremanezumab administered as 3 SC injections (1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.
Overall Number of Participants Analyzed	43	43
Measure Type: Count of Participants; Unit of Measure: Participants
	43 100.0%	42 97.7%

13. Secondary Outcome

Title	OL Period: Number of Participants Who Received Concomitant Medications
Description	Concomitant medications included: agents acting on renin-angiotensin system, analgesics, anti-parkinson drugs, antianemic preparations, antibacterials for systemic use, antiemetics and antinauseants, antihistamines for systemic use, antihypertensives, antiinflammatory and antirheumatics, antineoplastic agents, antithrombotics, beta blocking agents, calcium channel blockers, corticosteroids for systemic use, cough and cold preparations, diuretics, lipid modifying agents, nasal preparations, other gynecologicals, other nervous system drugs, thyroid therapy, unspecified herbal and traditional medicine, urologicals, vaccines, psycholeptics, psycoanaleptics, general nutrients, mineral supplements, muscle relaxants, vitamins, sex hormones and modulators of the genital system, drugs for acid related disorders, drugs for constipation, drugs for obstructive airways disease etc.
Time Frame	Week 12 up to Week 24

Outcome Measure Data

Analysis Population Description

OL-ITT analysis set included only participants who received at least 1 dose of study drug during the open-label treatment period.

Arm/Group Title	Fremanezumab	Placebo
Arm/Group Description:	Participants received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.	Participants received placebo matched to fremanezumab administered as 3 SC injections (1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.
Overall Number of Participants Analyzed	9	7
Measure Type: Count of Participants; Unit of Measure: Participants
	9 100.0%	7 100.0%

14. Secondary Outcome

Title	Number of Participants With Positive Findings on Electronic Columbia Suicide Severity Rating Scale (eC-SSRS)
Description	eC-SSRS is a questionnaire to assess suicidal ideation (severity and intensity) and behavior. Suicidal ideation: A series of 1 -5 questions (with 'yes' or 'no' response) with 5 types of ideation of increasing severity: 1. wish to be dead, 2. non-specific active suicidal thoughts, 3. active suicidal ideation with any methods (not plan) without intent to act, 4. active suicidal ideation with some intent to act, without specific plan, 5. active suicidal ideation with specific plan and intent. A positive finding was defined as a 'yes' response to question 4 or 5.
Time Frame	Baseline (Day -28 to Day -1) up to Week 24

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Fremanezumab	Placebo
Arm/Group Description:	Participants received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.	Participants received placebo matched to fremanezumab administered as 3 SC injections (1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.
Overall Number of Participants Analyzed	43	43
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%	0 0.0%

15. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Antidrug Antibodies (ADA)
Description	Number of participants with treatment-emergent antidrug antibodies reported.
Time Frame	Baseline (Day -28 to Day -1) up to Week 24

Outcome Measure Data

Analysis Population Description

ITT analysis set included all randomized participants.

Arm/Group Title	Fremanezumab	Placebo
Arm/Group Description:	Participants received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.	Participants received placebo matched to fremanezumab administered as 3 SC injections (1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.
Overall Number of Participants Analyzed	44	43
Measure Type: Count of Participants; Unit of Measure: Participants
	0 0.0%	0 0.0%

Adverse Events

Time Frame	Baseline (Day -28 to Day -1) up to Week 24
Adverse Event Reporting Description	Safety analysis set included all randomized participants who received at least 1 dose of the study drug.
Arm/Group Title	Fremanezumab		Placebo
Arm/Group Description	Participants received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.		Participants received placebo matched to fremanezumab administered as 3 SC injections (1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who completed the DB treatment period and continued into the OL treatment period received fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.
All-Cause Mortality
	Fremanezumab		Placebo
	Affected / at Risk (%)		Affected / at Risk (%)
Total	0/43 (0.00%)		0/43 (0.00%)
Serious Adverse Events
	Fremanezumab		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/43 (4.65%)		1/43 (2.33%)
Gastrointestinal disorders
Gastrointestinal haemorrhage † 1	1/43 (2.33%)	1	0/43 (0.00%)	0
General disorders
Non-cardiac chest pain † 1	0/43 (0.00%)	0	1/43 (2.33%)	1
Hepatobiliary disorders
Cholelithiasis † 1	0/43 (0.00%)	0	1/43 (2.33%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung neoplasm malignant † 1	1/43 (2.33%)	1	0/43 (0.00%)	0
Vascular disorders
Hypotension † 1	1/43 (2.33%)	1	0/43 (0.00%)	0
1 Term from vocabulary, MedDRA 22.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Fremanezumab		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/43 (65.12%)		29/43 (67.44%)
Gastrointestinal disorders
Diarrhoea † 1	3/43 (6.98%)	4	2/43 (4.65%)	2
Nausea † 1	4/43 (9.30%)	6	2/43 (4.65%)	2
General disorders
Injection site erythema † 1	11/43 (25.58%)	30	14/43 (32.56%)	41
Injection site induration † 1	18/43 (41.86%)	60	14/43 (32.56%)	49
Injection site pain † 1	14/43 (32.56%)	48	15/43 (34.88%)	47
Injection site pruritus † 1	4/43 (9.30%)	8	2/43 (4.65%)	2
Infections and infestations
Influenza † 1	3/43 (6.98%)	3	1/43 (2.33%)	2
Nasopharyngitis † 1	2/43 (4.65%)	3	4/43 (9.30%)	4
Pneumonia † 1	3/43 (6.98%)	3	0/43 (0.00%)	0
Sinusitis † 1	4/43 (9.30%)	5	3/43 (6.98%)	4
Upper respiratory tract infection † 1	1/43 (2.33%)	1	5/43 (11.63%)	5
Investigations
International normalised ratio increased † 1	4/43 (9.30%)	4	1/43 (2.33%)	1
Nervous system disorders
Dizziness † 1	4/43 (9.30%)	4	2/43 (4.65%)	2
Headache † 1	6/43 (13.95%)	7	2/43 (4.65%)	3
1 Term from vocabulary, MedDRA 22.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

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: NCT03347188
• Other Study ID Numbers: TV48125-CNS-20024
• First Submitted: November 14, 2017
• First Posted: November 20, 2017
• Results First Submitted: February 22, 2021
• Results First Posted: March 26, 2021
• Last Update Posted: December 13, 2022