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

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ClinicalTrials.gov Identifier: NCT02964338
Recruitment Status : Terminated (Futility analysis revealed that the primary endpoint is unlikely to be met. There were no safety concerns observed with fremanezumab treatment in the trial.)
First Posted : November 16, 2016
Results First Posted : September 18, 2019
Last Update Posted : February 16, 2021
Sponsor:
Information provided by (Responsible Party):
Teva Pharmaceutical Industries ( 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
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
Hide 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
Arm/Group Title Placebo Fremanezumab 675/225/225 mg Fremanezumab 900/225/225 mg Total
Hide 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
Hide 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.
1.Primary Outcome
Title Mean Change From Baseline in the Overall Monthly Average Number of CH Attacks Up to Week 12
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
Hide 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]
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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)
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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%
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
Hide 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%)    
Hide 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
Hide 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
Futility analysis revealed that the primary endpoint is unlikely to be met. There were no safety concerns observed with fremanezumab treatment in the trial.
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
Layout table for Results Point of Contact information
Name/Title: Director, Clinical Research
Organization: Teva Branded Pharmaceutical Products, R&D Inc.
Phone: 1-888-483-8279
EMail: USMedInfo@tevapharm.com
Layout table for additonal information
Responsible Party: Teva Pharmaceutical Industries ( 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: February 16, 2021