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Trial record 55 of 231 for:    CALCITONIN SALMON

Comparing Efficacy and Safety of 2 Dose Regimens of Subcutaneous Administration of TEV-48125 Versus Placebo for the Preventive Treatment of Chronic Migraine

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ClinicalTrials.gov Identifier: NCT02621931
Recruitment Status : Completed
First Posted : December 4, 2015
Results First Posted : December 6, 2018
Last Update Posted : December 6, 2018
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 Migraine
Interventions Drug: Fremanezumab
Drug: Placebo
Enrollment 1130
Recruitment Details  
Pre-assignment Details A total of 3148 patients with migraine provided written informed consent and were screened for entry into either Study TV48125-CNS-30049 or Study TV48125-CNS-30050. Of the 3148 screened, 1130 met entry criteria, including criteria for chronic migraine and diary compliance during the run-in period, and were randomized into this study.
Arm/Group Title Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 675/225/225 mg
Hide Arm/Group Description Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56 . Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56. Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
Period Title: Overall Study
Started 375 376 379
Safety and ITT Populations 375 376 379
Full Analysis Set 371 375 375
Completed 342 349 343
Not Completed 33 27 36
Reason Not Completed
Death             0             1             0
Adverse Event             8             5             7
Withdrawal by Subject             12             10             11
Protocol Violation             2             2             2
Pregnancy             2             0             0
Noncompliance to study procedures             0             1             2
Lost to Follow-up             8             7             10
Lack of Efficacy             0             0             1
Not specified             1             1             3
Arm/Group Title Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 675/225/225 mg Total
Hide Arm/Group Description Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56 . Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56. Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56. Total of all reporting groups
Overall Number of Baseline Participants 375 376 379 1130
Hide Baseline Analysis Population Description
Intent to treat (ITT) population
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 375 participants 376 participants 379 participants 1130 participants
41.4  (12.03) 42.0  (12.37) 40.6  (11.95) 41.3  (12.12)
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 375 participants 376 participants 379 participants 1130 participants
18-45 years
229
  61.1%
218
  58.0%
248
  65.4%
695
  61.5%
46-65 years
143
  38.1%
149
  39.6%
123
  32.5%
415
  36.7%
>65 years
3
   0.8%
9
   2.4%
8
   2.1%
20
   1.8%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 375 participants 376 participants 379 participants 1130 participants
Female
330
  88.0%
331
  88.0%
330
  87.1%
991
  87.7%
Male
45
  12.0%
45
  12.0%
49
  12.9%
139
  12.3%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 375 participants 376 participants 379 participants 1130 participants
White
303
  80.8%
293
  77.9%
297
  78.4%
893
  79.0%
Black
29
   7.7%
33
   8.8%
37
   9.8%
99
   8.8%
Asian
40
  10.7%
40
  10.6%
41
  10.8%
121
  10.7%
American Indian or Alaska Native
0
   0.0%
4
   1.1%
2
   0.5%
6
   0.5%
Native Hawaiian or Other Pacific Islander
1
   0.3%
2
   0.5%
0
   0.0%
3
   0.3%
Other
2
   0.5%
4
   1.1%
2
   0.5%
8
   0.7%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 375 participants 376 participants 379 participants 1130 participants
Not HIspanic or Latino
343
  91.5%
352
  93.6%
338
  89.2%
1033
  91.4%
Hispanic or Latino
32
   8.5%
22
   5.9%
41
  10.8%
95
   8.4%
Unknown
0
   0.0%
1
   0.3%
0
   0.0%
1
   0.1%
Not reported
0
   0.0%
1
   0.3%
0
   0.0%
1
   0.1%
Weight   [1] 
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 375 participants 376 participants 377 participants 1128 participants
72.6  (15.58) 72.4  (15.79) 72.5  (16.36) 72.5  (15.90)
[1]
Measure Analysis Population Description: Two participants were missing baseline weight data
Time Since Initial Migraine Diagnosis  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 375 participants 376 participants 379 participants 1130 participants
19.9  (12.86) 19.7  (12.84) 20.1  (11.98) 19.9  (12.55)
Preventative Medication Use During Baseline Period   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 375 participants 376 participants 379 participants 1130 participants
Yes
77
  20.5%
77
  20.5%
85
  22.4%
239
  21.2%
No
298
  79.5%
299
  79.5%
294
  77.6%
891
  78.8%
[1]
Measure Description: Eligible patients entered a 28-day run-in/baseline period during which headache information was captured daily throughout study participation using the electronic headache diary device. During randomization, patients were stratified based on sex, country, and baseline preventive migraine medication use (yes, no) to ensure balance for the covariates.
Total Number of Headache Days of Any Duration And Any Severity During the 28 Day Baseline Period   [1] 
Mean (Standard Deviation)
Unit of measure:  Days
Number Analyzed 375 participants 376 participants 379 participants 1130 participants
20.3  (4.19) 20.4  (3.93) 20.3  (4.26) 20.3  (4.13)
[1]
Measure Description: Eligible patients entered a 28-day run-in/baseline period during which headache information was captured daily throughout study participation using the electronic headache diary device.
Number of Headache Days of At Least Moderate Severity   [1] 
Mean (Standard Deviation)
Unit of measure:  Days
Number Analyzed 375 participants 376 participants 379 participants 1130 participants
13.3  (5.82) 13.2  (5.47) 12.8  (5.80) 13.1  (5.70)
[1]
Measure Description: Eligible patients entered a 28-day run-in/baseline period during which headache information was captured daily throughout study participation using the electronic headache diary device. Headache severity was subjectively rated by the patient as mild, moderate or severe.
Number of Migraine Days   [1] 
Mean (Standard Deviation)
Unit of measure:  Days
Number Analyzed 375 participants 376 participants 379 participants 1130 participants
16.4  (5.15) 16.2  (4.88) 16.0  (5.19) 16.2  (5.97)
[1]
Measure Description: Eligible patients entered a 28-day run-in/baseline period during which headache information was captured daily throughout study participation using the electronic headache diary device. Migraine headaches are as defined in The International Classification of Headache Disorders 3rd edition (ICHD-3).
Number of Days of Use of Any Acute Headache Medications   [1] 
Mean (Standard Deviation)
Unit of measure:  Days
Number Analyzed 375 participants 376 participants 379 participants 1130 participants
13.0  (6.92) 13.1  (6.79) 13.1  (7.20) 13.1  (6.96)
[1]
Measure Description: Eligible patients entered a 28-day run-in/baseline period during which headache information (including information about use of headache medications) was captured daily throughout study participation using the electronic headache diary device.
Headache Impact Test (HIT-6) Disability Score   [1] [2] 
Mean (Standard Deviation)
Unit of measure:  Units on a scale
Number Analyzed 373 participants 370 participants 377 participants 1120 participants
64.1  (4.80) 64.3  (4.74) 64.6  (4.42) 64.3  (4.65)
[1]
Measure Description: Eligible patients entered a 28-day run-in/baseline period during which headache information was captured daily throughout study participation using the electronic headache diary device. HIT-6 measures the adverse impact of headache on social functioning, role functioning, vitality, cognitive functioning, and psychological distress. It also assesses headache severity. Scores range from 36 to 78, where a higher score indicates a greater impact of headache on the daily life of the patient. Scores ≥60 indicate severe impact.
[2]
Measure Analysis Population Description: HIT-6 was not assessed at baseline for some patients.
1.Primary Outcome
Title Change From Baseline in the Monthly Average Number of Headache Days of At Least Moderate Severity During the 12-Week Period After the First Dose of Study Drug
Hide Description Headaches were subjectively rated by participants as mild, moderate or severe. A headache day of at least moderate severity was defined as a calendar day (00:00 to 23:59) where the patient (using the electronic headache diary device) reports: - a day with headache pain that lasts ≥4 hours with a peak severity of at least moderate severity or - a day when the patient used acute migraine-specific medication (triptans or ergots) to treat a headache of any severity or duration. Monthly averages are derived and normalized to 28 days equivalent by the following formula: (# days of efficacy variable over relevant period / # days with assessments recorded in the e-diary over the relevant period) * 28. The change is calculated as post-baseline value – baseline value.
Time Frame Baseline (Days -28 to Day -1), Treatment (Days 1 – Week 12)
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS) included those in the intent to treat (ITT) population who received at least 1 dose of study drug and had at least 10 days of post-baseline efficacy assessments on the primary endpoint.
Arm/Group Title Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 675/225/225 mg
Hide Arm/Group Description:
Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56 .
Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.
Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
Overall Number of Participants Analyzed 371 375 375
Median (Inter-Quartile Range)
Unit of Measure: days
-2.5
(-5.6 to 0.0)
-4.2
(-7.7 to -1.7)
-4.5
(-7.8 to -1.7)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Fremanezumab 675 mg/Placebo/Placebo
Comments Due to the deviation from the normal distribution assumption of the data, the primary analysis was conducted using the Wilcoxon rank-sum test as outlined in the statistical analysis plan (SAP).
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 0.05 level of significance
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Method of Estimation Estimation Parameter LSM difference from placebo
Estimated Value -1.8
Confidence Interval (2-Sided) 95%
-2.46 to -1.15
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.33
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Fremanezumab 675/225/225 mg
Comments Due to the deviation from the normal distribution assumption of the data, the primary analysis was conducted using the Wilcoxon rank-sum test as outlined in the SAP.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 0.05 level of significance
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Method of Estimation Estimation Parameter LSM difference from placebo
Estimated Value -2.1
Confidence Interval (2-Sided) 95%
-2.76 to -1.45
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.33
Estimation Comments [Not Specified]
2.Primary Outcome
Title Participants With Treatment-Emergent Adverse Events (TEAEs)
Hide Description An adverse event (AE) was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents usual activities. Relationship of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.
Time Frame Day 1 to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population
Arm/Group Title Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 675/225/225 mg
Hide Arm/Group Description:
Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56 .
Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.
Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
Overall Number of Participants Analyzed 375 376 379
Measure Type: Count of Participants
Unit of Measure: Participants
Any TEAE
240
  64.0%
265
  70.5%
270
  71.2%
Severe TEAE
20
   5.3%
14
   3.7%
15
   4.0%
Treatment-related TEAE
159
  42.4%
186
  49.5%
194
  51.2%
Serious TEAE
6
   1.6%
3
   0.8%
5
   1.3%
Death
0
   0.0%
1
   0.3%
0
   0.0%
TEAE leading to discontinuation
8
   2.1%
5
   1.3%
7
   1.8%
3.Secondary Outcome
Title Change From Baseline in the Monthly Average Number of Migraine Days During the 12-Week Period After the First Dose of Study Drug
Hide Description A migraine day was defined as when at least 1 of the following situations occurred: - a calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache endorsing criteria for migraine with or without aura - a calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache endorsing criteria for probable migraine, a migraine subtype where only 1 migraine criterion is missing - a calendar day (0:00 to 23:59) demonstrating a headache of any duration that was treated with migraine-specific medications (triptans and ergot compounds). Monthly averages are derived and normalized to 28 days equivalent by the following formula: (# days of efficacy variable over relevant period / # days with assessments recorded in the e-diary over the relevant period) * 28. The change is calculated as post-baseline value – baseline value.
Time Frame Baseline (Days -28 to Day -1), Treatment (Days 1 – Week 12)
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set (FAS)
Arm/Group Title Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 675/225/225 mg
Hide Arm/Group Description:
Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56 .
Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.
Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
Overall Number of Participants Analyzed 371 375 375
Least Squares Mean (Standard Error)
Unit of Measure: migraine days / month
-3.2  (0.35) -4.9  (0.35) -5.0  (0.35)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Fremanezumab 675 mg/Placebo/Placebo
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 0.05 level of significance
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LSM difference from placebo
Estimated Value -1.7
Confidence Interval (2-Sided) 95%
-2.48 to -0.97
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.39
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Fremanezumab 675/225/225 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 0.05 level of significance
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LSM difference from placebo
Estimated Value -1.8
Confidence Interval (2-Sided) 95%
-2.61 to -1.09
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.39
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Percentage of Participants With At Least 50% Reduction In Monthly Average Number of Headache Days of At Least Moderate Severity
Hide Description Responder rates were defined as the percentage of total subjects who reached at least a 50% reduction in the monthly average of headache days (as subjectively reported by participants in the study diary) of at least moderate severity relative to the baseline period. For the overall analysis (Month 1-3), patients who discontinued early were considered non-responders. Monthly averages are derived and normalized to 28 days equivalent by the following formula: (# days of efficacy variable over relevant period / # days with assessments recorded in the e-diary over the relevant period) * 28. The percentage reduction in monthly average is calculated as: ((baseline value - post-baseline value) / baseline value) * 100.
Time Frame Baseline (Days -28 to Day -1), Treatment: Month 1, Month 2, Month 3, Month 1-3 (Days 1 – Week 12)
Hide Outcome Measure Data
Hide Analysis Population Description
FAS. One participant in the Placebo and Fremanezumab 675/225/225 mg treatment arms had 0 headache days of >= moderate severity during baseline and treatment and therefore was not included.
Arm/Group Title Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 675/225/225 mg
Hide Arm/Group Description:
Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56 .
Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.
Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
Overall Number of Participants Analyzed 370 375 374
Measure Type: Number
Unit of Measure: percentage of total participants
Month 1 Number Analyzed 370 participants 375 participants 374 participants
21.6 41.3 40.0
Month 2 Number Analyzed 355 participants 365 participants 361 participants
24.3 39.7 41.9
Month 3 Number Analyzed 342 participants 350 participants 345 participants
26.4 40.5 44.5
Overall - Months 1-3 Number Analyzed 370 participants 375 participants 374 participants
18.1 37.6 40.8
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Fremanezumab 675 mg/Placebo/Placebo
Comments Month 1: Active 675/placebo/placebo to Placebo
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 0.05 level of significance. P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Fremanezumab 675/225/225 mg
Comments Month 1: Active 675/225/225 to Placebo
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 0.05 level of significance. P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Placebo, Fremanezumab 675 mg/Placebo/Placebo
Comments Month 2
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 0.05 level of significance. P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Placebo, Fremanezumab 675/225/225 mg
Comments Month 2
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 0.05 level of significance. P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Placebo, Fremanezumab 675 mg/Placebo/Placebo
Comments Month 3
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 0.05 level of significance. P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Placebo, Fremanezumab 675/225/225 mg
Comments Month 3
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 0.05 level of significance. P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Placebo, Fremanezumab 675 mg/Placebo/Placebo
Comments Overall
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 0.05 level of significance. P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Placebo, Fremanezumab 675/225/225 mg
Comments Overall
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 0.05 level of significance. P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use.
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
5.Secondary Outcome
Title Change From Baseline in the Monthly Average Number of Days of Use of Any Acute Headache Medicine During the 12 Week Period After the First Dose of Study Drug
Hide Description Participants recorded any migraine medications (name of drug, number of tablets/capsules, and the dose in milligrams per tablet/capsule) taken on each day in their electronic headache diary device. Acute migraine-specific medication included triptans or ergots. Monthly averages are derived and normalized to 28 days equivalent by the following formula: (# days of efficacy variable over relevant period / # days with assessments recorded in the e-diary over the relevant period) * 28. The change is calculated as post-baseline value – baseline value.
Time Frame Baseline (Days -28 to Day -1), Treatment (Days 1 – Week 12)
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set
Arm/Group Title Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 675/225/225 mg
Hide Arm/Group Description:
Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56.
Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.
Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
Overall Number of Participants Analyzed 371 375 375
Median (Inter-Quartile Range)
Unit of Measure: days
-2.0
(-5.3 to 0.2)
-3.6
(-7.3 to -0.7)
-4.2
(-7.6 to -1.1)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Fremanezumab 675 mg/Placebo/Placebo
Comments Due to the deviation from the normal distribution assumption of the data, the primary analysis was conducted using the Wilcoxon rank-sum test as outlined in the SAP.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 0.05 level of significance
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Fremanezumab 675/225/225 mg
Comments Due to the deviation from the normal distribution assumption of the data, the primary analysis was conducted using the Wilcoxon rank-sum test as outlined in the SAP.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 0.05 level of significance
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
6.Secondary Outcome
Title Change From Baseline in the Number of Headache Days of At Least Moderate Severity During the 4 Week Period After the First Dose of Study Drug
Hide Description Headaches were subjectively rated by participants as mild, moderate or severe. A headache day of at least moderate severity was defined as a calendar day (00:00 to 23:59) where the patient (using the electronic headache diary device) reports: - a day with headache pain that lasts ≥4 hours with a peak severity of at least moderate severity or - a day when the patient used acute migraine-specific medication (triptans or ergots) to treat a headache of any severity or duration. The change is calculated as post-baseline value – baseline value.
Time Frame Baseline (Days -28 to Day -1), Treatment (Days 1 – Week 4)
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Hide Analysis Population Description
Full analysis set (FAS) included those in the ITT population who received at least 1 dose of study drug and had at least 10 days of post-baseline efficacy assessments on the primary endpoint.
Arm/Group Title Placebo Fremanezumab 675 mg
Hide Arm/Group Description:
Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56.
Participants randomized to both fremanezumab treatment arms received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0. Later treatments are beyond the timeframe for this outcome. Therefore the data from both active treatment arms were combined for this comparison.
Overall Number of Participants Analyzed 371 750
Least Squares Mean (Standard Error)
Unit of Measure: days
-2.3  (0.33) -4.6  (0.27)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Fremanezumab 675 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 0.05 level of significance
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter LSM difference from placebo
Estimated Value -2.3
Confidence Interval (2-Sided) 95%
-2.95 to -1.73
Parameter Dispersion
Type: Standard Error of the Mean
Value: 0.31
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Change From Baseline in the Monthly Average Number of Headache Days of At Least Moderate Severity During the 12 Week Period After the First Dose of Study Medication in Patients Not Receiving Concomitant Preventive Migraine Medications
Hide Description A subset of patients (specified in the protocol not to exceed 30%) were allowed to use 1 concomitant migraine preventive medication. This outcome only includes those participants who did not take concomitant preventive migraine medication during this study. Headaches were subjectively rated by participants as mild, moderate or severe. A headache day of >= moderate severity was defined as a calendar day where the patient (using the electronic headache diary device) reports: - a day with headache pain that lasts ≥4 hours with a peak severity of >= moderate severity or - a day when the patient used acute migraine-specific medication (triptans or ergots) to treat a headache of any severity or duration. Monthly averages are derived and normalized to 28 days equivalent by the following formula: (# days of efficacy variable over relevant period / # days with assessments recorded in the e-diary over the relevant period) * 28. Change is post-baseline value – baseline value.
Time Frame Baseline (Days -28 to Day -1), Treatment (Days 1 – Week 12)
Hide Outcome Measure Data
Hide Analysis Population Description
FAS of participants who did not receive concomitant preventive migraine medications.
Arm/Group Title Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 675/225/225 mg
Hide Arm/Group Description:
Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56.
Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.
Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
Overall Number of Participants Analyzed 294 298 290
Median (Inter-Quartile Range)
Unit of Measure: days
-2.4
(-5.3 to 0.0)
-4.4
(-8.0 to -1.7)
-4.6
(-7.8 to -1.5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Fremanezumab 675 mg/Placebo/Placebo
Comments Due to the deviation from the normal distribution assumption of the data, the primary analysis was conducted using the Wilcoxon rank-sum test as outlined in the SAP.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 0.05 level of significance
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Fremanezumab 675/225/225 mg
Comments Due to the deviation from the normal distribution assumption of the data, the primary analysis was conducted using the Wilcoxon rank-sum test as outlined in the SAP.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 0.05 level of significance
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
8.Secondary Outcome
Title Change From Baseline in Migraine-Related Disability Score, As Measured by the 6-Item Headache Impact Test (HIT) At Week 12
Hide Description The HIT-6 was developed by Kosinski et al (2003) as a short form for reliably assessing the adverse headache impact in clinical practice and clinical research settings. The questionnaire measures the adverse impact of headache on social functioning, role functioning, vitality, cognitive functioning, and psychological distress. It also assesses headache severity. Scores range from 36 to 78, where a higher score indicates a greater impact of headache on the daily life of the patient, i.e. scores ≤49 represent little or no impact, scores between 50 and 55 represent some impact, scores between 56 and 59 represent substantial impact; and scores ≥60 indicate severe impact. Negative change from baseline values indicate less adverse impact of headache.
Time Frame Baseline, 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set
Arm/Group Title Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 675/225/225 mg
Hide Arm/Group Description:
Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56.
Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.
Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
Overall Number of Participants Analyzed 371 375 375
Median (Inter-Quartile Range)
Unit of Measure: units on a scale
-4.0
(-7.0 to 0.0)
-5.0
(-10.0 to -2.0)
-6.0
(-11.0 to -2.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Fremanezumab 675 mg/Placebo/Placebo
Comments Due to the deviation from the normal distribution assumption of the data, the primary analysis was conducted using the Wilcoxon rank-sum test as outlined in the SAP.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0004
Comments 0.05 level of significance
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Fremanezumab 675/225/225 mg
Comments Due to the deviation from the normal distribution assumption of the data, the primary analysis was conducted using the Wilcoxon rank-sum test as outlined in the SAP.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments 0.05 level of significance
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
9.Secondary Outcome
Title Electrocardiogram (ECG) Findings Shifts From Baseline to Overall
Hide Description 12-lead ECGs were performed before other assessments (eg, blood draws and administration of questionnaires) and performed in triplicate. The worst post-baseline finding for the participant is summarized. Only participants with both baseline and post-baseline ECGs are included. The ECG was evaluated by the investigator at the time of recording (signed and dated), and the printout was kept in the source documentation file. When potentially clinically significant findings were detected by the investigator, a cardiologist at a central diagnostic center was consulted for a definitive interpretation. Any ECG finding that was judged by the investigator as a potentially clinically significant change (worsening) compared with a baseline value was considered an adverse event. - NCS = abnormal, not clinically significant. - CS= abnormal, clinically significant. Shift format is: baseline finding / worst post-baseline finding.
Time Frame Baseline (Day 0), Treatment Week 12 (or endpoint)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population of participants with both baseline and post-treatment ECGs.
Arm/Group Title Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 675/225/225 mg
Hide Arm/Group Description:
Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56.
Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.
Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
Overall Number of Participants Analyzed 360 361 362
Measure Type: Count of Participants
Unit of Measure: Participants
Normal / Normal
215
  59.7%
220
  60.9%
223
  61.6%
Normal / NCS
54
  15.0%
48
  13.3%
43
  11.9%
Normal / CS
1
   0.3%
0
   0.0%
0
   0.0%
NCS / Normal
31
   8.6%
34
   9.4%
34
   9.4%
NCS / NCS
59
  16.4%
59
  16.3%
62
  17.1%
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%
10.Secondary Outcome
Title Participants With Vital Signs Potentially Clinically Significant Abnormal Values
Hide Description Vital signs were performed before other assessments (eg, blood draws and administration of questionnaires). Vital signs with potentially clinically significant abnormal findings included: - Pulse Rate High: >=120 and increase of >=15 beats per minute - Pulse Rate Low: <=50 and decrease of >=15 beats per minute - Systolic Blood Pressure Low: <=90 mmHg and decrease of >=20 mmHg - Diastolic Blood Pressure High: >=105 mmHg and increase of >=15 mmHg - Diastolic Blood Pressure Low: <=50 mmHg and decrease of >=15 mmHg - Respiratory Rate Low: <10 breaths / minute
Time Frame Treatment Days 28, 56 and 84 (or endpoint). Changes from previous reading may reflect the baseline reading performed on Day 0.
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population of participants with both baseline and post-treatment values for each vital sign.
Arm/Group Title Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 675/225/225 mg
Hide Arm/Group Description:
Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56.
Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.
Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
Overall Number of Participants Analyzed 366 373 372
Measure Type: Count of Participants
Unit of Measure: Participants
Participants with at least 1 abnormality
7
   1.9%
10
   2.7%
14
   3.8%
Pulse Rate High
0
   0.0%
0
   0.0%
1
   0.3%
Pulse Rate Low
1
   0.3%
1
   0.3%
0
   0.0%
Systolic Blood Pressure Low
2
   0.5%
4
   1.1%
6
   1.6%
Diastolic Blood Pressure High
1
   0.3%
2
   0.5%
3
   0.8%
Diastolic Blood Pressure Low
0
   0.0%
1
   0.3%
2
   0.5%
Respiratory Rate Low
3
   0.8%
2
   0.5%
3
   0.8%
11.Secondary Outcome
Title Participants With Serum Chemistry and Hematology Potentially Clinically Significant Abnormal Results
Hide Description Serum chemistry and hematology laboratory tests with potentially clinically significant abnormal findings included: - Blood Urea Nitrogen (BUN) High: >=10.71 mmol/L - Creatinine High: >=177 umol/L - Bilirubin High: >=34.2 umol/L - Alanine Aminotransferase (ALT): >=3*upper limit of normal (ULN) - Aspartate Aminotransferase (AST): >=3*upper limit of normal (ULN) - Gamma Glutamyl Transferase (GGT): >=3*upper limit of normal (ULN) - Hemoglobin: Male: <115 g/L or Female: <=95 g/L - Hematocrit: Male: <0.37 L/L or Female: <0.32 L/L - Leukocytes: >=20*10^9/L or <=3*10^9/L - Eosinophils/Leukocytes: >=10% - Platelets: >=700*10^9/L or <=75*10^9/L
Time Frame Treatment Days 28, 56 and 84 (or endpoint)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population of participants with at least one post-baseline result for the tests
Arm/Group Title Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 675/225/225 mg
Hide Arm/Group Description:
Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56.
Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.
Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
Overall Number of Participants Analyzed 366 373 371
Measure Type: Count of Participants
Unit of Measure: Participants
BUN Number Analyzed 366 participants 373 participants 371 participants
1
   0.3%
1
   0.3%
1
   0.3%
Creatinine Number Analyzed 366 participants 373 participants 371 participants
2
   0.5%
0
   0.0%
0
   0.0%
Bilirubin Number Analyzed 366 participants 373 participants 371 participants
0
   0.0%
2
   0.5%
0
   0.0%
ALT Number Analyzed 366 participants 373 participants 371 participants
2
   0.5%
2
   0.5%
7
   1.9%
AST Number Analyzed 366 participants 373 participants 371 participants
0
   0.0%
3
   0.8%
4
   1.1%
GGT Number Analyzed 366 participants 373 participants 371 participants
7
   1.9%
7
   1.9%
8
   2.2%
Hemoglobin Number Analyzed 366 participants 373 participants 371 participants
2
   0.5%
5
   1.3%
3
   0.8%
Hematocrit Number Analyzed 366 participants 373 participants 371 participants
8
   2.2%
9
   2.4%
7
   1.9%
Leukocytes Number Analyzed 366 participants 373 participants 371 participants
2
   0.5%
9
   2.4%
5
   1.3%
Eosinophils/Leukocytes Number Analyzed 366 participants 373 participants 371 participants
4
   1.1%
5
   1.3%
4
   1.1%
Platelets Number Analyzed 366 participants 371 participants 371 participants
1
   0.3%
2
   0.5%
0
   0.0%
12.Secondary Outcome
Title Participants With Urinalysis Laboratory Tests Potentially Clinically Significant Abnormal Results
Hide Description Urinalysis with potentially clinically significant abnormal findings included: - Blood: >=2 unit increase from baseline - Urine Glucose (mg/dL): >=2 unit increase from baseline - Ketones (mg/dL): >=2 unit increase from baseline - Urine Protein (mg/dL): >=2 unit increase from baseline
Time Frame Treatment Days 28, 56 and 84 (or endpoint). Changes from previous reading reflect the baseline reading performed on Day 0.
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population of participants with at least one post-baseline result for the tests.
Arm/Group Title Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 675/225/225 mg
Hide Arm/Group Description:
Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56.
Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.
Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
Overall Number of Participants Analyzed 365 373 372
Measure Type: Count of Participants
Unit of Measure: Participants
Participants with at least 1 abnormality
78
  21.4%
57
  15.3%
68
  18.3%
Blood
33
   9.0%
32
   8.6%
35
   9.4%
Urine glucose
7
   1.9%
7
   1.9%
5
   1.3%
Ketones
7
   1.9%
7
   1.9%
7
   1.9%
Urine protein
40
  11.0%
19
   5.1%
34
   9.1%
13.Secondary Outcome
Title Prothrombin Time Shifts From Baseline to Endpoint
Hide Description Shifts in prothrombin time from baseline to endpoint were summarized using patient counts grouped into three categories: - Low (below normal range) - Normal (within the normal range of 9.4 to 12.5 seconds) - High (above normal range) Shift format is: baseline finding / endpoint finding
Time Frame Baseline (Day 0), Treatment Endpoint (Week 12)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population of participants with both baseline and post-treatment values
Arm/Group Title Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 675/225/225 mg
Hide Arm/Group Description:
Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56.
Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.
Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
Overall Number of Participants Analyzed 366 373 370
Measure Type: Count of Participants
Unit of Measure: Participants
Low / Low
0
   0.0%
0
   0.0%
0
   0.0%
Low / Normal
2
   0.5%
0
   0.0%
1
   0.3%
Low / High
0
   0.0%
0
   0.0%
0
   0.0%
Normal / Low
0
   0.0%
1
   0.3%
2
   0.5%
Normal / Normal
330
  90.2%
318
  85.3%
327
  88.4%
Normal / High
13
   3.6%
17
   4.6%
19
   5.1%
High / Low
0
   0.0%
0
   0.0%
0
   0.0%
High / Normal
14
   3.8%
19
   5.1%
12
   3.2%
High / High
7
   1.9%
18
   4.8%
9
   2.4%
14.Secondary Outcome
Title Injection Site Reaction Adverse Events
Hide Description Counts of participants who reported treatment-emergent injection site reactions as AEs are summarized. Preferred terms from MedDRA version 18.1 are offered without a threshold applied.
Time Frame Day 1 to Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population
Arm/Group Title Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 675/225/225 mg
Hide Arm/Group Description:
Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56.
Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.
Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
Overall Number of Participants Analyzed 375 376 379
Measure Type: Count of Participants
Unit of Measure: Participants
Participants with >= 1 injection site reaction
151
  40.3%
176
  46.8%
183
  48.3%
Injection site pain
104
  27.7%
114
  30.3%
99
  26.1%
Injection site induration
68
  18.1%
74
  19.7%
90
  23.7%
Injection site erythema
60
  16.0%
80
  21.3%
75
  19.8%
Injection site haemorrhage
10
   2.7%
7
   1.9%
8
   2.1%
Injection site pruritus
0
   0.0%
6
   1.6%
8
   2.1%
Injection site rash
0
   0.0%
4
   1.1%
3
   0.8%
Injection site bruising
2
   0.5%
1
   0.3%
2
   0.5%
Injection site swelling
0
   0.0%
2
   0.5%
1
   0.3%
Injection site dermatitis
0
   0.0%
1
   0.3%
0
   0.0%
Injection site discomfort
0
   0.0%
1
   0.3%
0
   0.0%
Injection site haematoma
0
   0.0%
0
   0.0%
1
   0.3%
Injection site hypoaesthesia
0
   0.0%
0
   0.0%
1
   0.3%
Injection site inflammation
0
   0.0%
0
   0.0%
1
   0.3%
Injection site oedema
0
   0.0%
1
   0.3%
0
   0.0%
Injection site paraesthesia
0
   0.0%
0
   0.0%
1
   0.3%
Injection site urticaria
2
   0.5%
0
   0.0%
1
   0.3%
Injection site warmth
2
   0.5%
0
   0.0%
1
   0.3%
15.Secondary Outcome
Title Participants With Positive Electronic Columbia Suicide Severity Rating Scale (eC-SSRS) Results After the First Dose of Study Drug
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The electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) was used to assess the participant’s suicidal ideation (severity and intensity) and behavior (Posner et al 2011). Suicidal behavior is defined as a "yes" answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation is defined as a "yes" answer to any one of 5 suicidal ideation questions: wish to be dead, and 4 different categories of active suicidal ideation.

The eC-SSRS Baseline/Screening version was completed by the participant at baseline, and the eC-SSRS Since Last Visit version was completed by the participant at all other time points. Any positive findings on the eC-SSRS Since Last Visit version required evaluation by a physician or doctoral-level psychologist. Findings after the first dose of study drug using the eC-SSRS Since Last Visit version are summarized.

Time Frame Baseline (Day 0), Treatment Days 28, 56, 84
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Safety population
Arm/Group Title Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 675/225/225 mg
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Participants randomized to the placebo treatment arm received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56.
Participants randomized to the fremanezumab 675 mg/placebo/placebo treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.
Participants randomized to the fremanezumab 675/225/225 mg treatment arm received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
Overall Number of Participants Analyzed 375 376 379
Measure Type: Count of Participants
Unit of Measure: Participants
Participants with positive eC-SSRS responses
1
   0.3%
1
   0.3%
1
   0.3%
Specific finding: interrupted suicide attempt
1
   0.3%
1
   0.3%
0
   0.0%
Specific finding: suicidal ideation
0
   0.0%
0
   0.0%
1
   0.3%
Time Frame Day 1 to Week 12
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 675/225/225 mg
Hide Arm/Group Description Participants randomized to receive placebo received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56. Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56. Participants randomized to receive fremanezumab 675/225/225 mg received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56.
All-Cause Mortality
Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 675/225/225 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/375 (0.00%)      1/376 (0.27%)      0/379 (0.00%)    
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Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 675/225/225 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   6/375 (1.60%)      3/376 (0.80%)      5/379 (1.32%)    
Eye disorders       
Diplopia  1  1/375 (0.27%)  1 0/376 (0.00%)  0 0/379 (0.00%)  0
General disorders       
Oedema peripheral  1  1/375 (0.27%)  1 0/376 (0.00%)  0 0/379 (0.00%)  0
Immune system disorders       
Drug hypersensitivity  1  1/375 (0.27%)  1 0/376 (0.00%)  0 0/379 (0.00%)  0
Infections and infestations       
Pneumonia  1  0/375 (0.00%)  0 1/376 (0.27%)  1 0/379 (0.00%)  0
Injury, poisoning and procedural complications       
Accident  1  1/375 (0.27%)  1 0/376 (0.00%)  0 0/379 (0.00%)  0
Clavicle fracture  1  1/375 (0.27%)  1 0/376 (0.00%)  0 0/379 (0.00%)  0
Fall  1  0/375 (0.00%)  0 0/376 (0.00%)  0 1/379 (0.26%)  1
Radius fracture  1  0/375 (0.00%)  0 0/376 (0.00%)  0 1/379 (0.26%)  1
Road traffic accident  1  0/375 (0.00%)  0 1/376 (0.27%)  1 0/379 (0.00%)  0
Ulna fracture  1  0/375 (0.00%)  0 0/376 (0.00%)  0 1/379 (0.26%)  1
Wrist fracture  1  0/375 (0.00%)  0 1/376 (0.27%)  1 0/379 (0.00%)  0
Musculoskeletal and connective tissue disorders       
Back pain  1  0/375 (0.00%)  0 0/376 (0.00%)  0 1/379 (0.26%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Uterine leiomyoma  1  1/375 (0.27%)  1 0/376 (0.00%)  0 0/379 (0.00%)  0
Nervous system disorders       
Migraine  1  1/375 (0.27%)  1 0/376 (0.00%)  0 0/379 (0.00%)  0
Psychiatric disorders       
Suicidal ideation  1  0/375 (0.00%)  0 0/376 (0.00%)  0 1/379 (0.26%)  1
Renal and urinary disorders       
Calculus urinary  1  0/375 (0.00%)  0 0/376 (0.00%)  0 1/379 (0.26%)  1
Nephrolithiasis  1  1/375 (0.27%)  1 0/376 (0.00%)  0 0/379 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
Asthma  1  1/375 (0.27%)  1 0/376 (0.00%)  0 0/379 (0.00%)  0
Chronic obstructive pulmonary disease  1  0/375 (0.00%)  0 1/376 (0.27%)  1 0/379 (0.00%)  0
Dyspnoea  1  1/375 (0.27%)  1 0/376 (0.00%)  0 0/379 (0.00%)  0
Vascular disorders       
Hypertensive crisis  1  0/375 (0.00%)  0 0/376 (0.00%)  0 1/379 (0.26%)  1
1
Term from vocabulary, MedDRA (18.1)
Indicates events were collected by systematic assessment
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Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Fremanezumab 675 mg/Placebo/Placebo Fremanezumab 675/225/225 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   160/375 (42.67%)      185/376 (49.20%)      178/379 (46.97%)    
General disorders       
Injection site erythema  1  60/375 (16.00%)  129 80/376 (21.28%)  172 75/379 (19.79%)  166
Injection site induration  1  68/375 (18.13%)  130 74/376 (19.68%)  159 90/379 (23.75%)  196
Injection site pain  1  104/375 (27.73%)  288 114/376 (30.32%)  296 99/379 (26.12%)  271
Infections and infestations       
Nasopharyngitis  1  20/375 (5.33%)  24 19/376 (5.05%)  20 15/379 (3.96%)  16
1
Term from vocabulary, MedDRA (18.1)
Indicates events were collected by systematic assessment
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
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Name/Title: Director, Clinical Research
Organization: Teva Branded Pharmaceutical Products, R&D Inc
Phone: 1-888-483-8279
EMail: USMedInfo@tevapharm.com
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Responsible Party: Teva Pharmaceutical Industries ( Teva Branded Pharmaceutical Products, R&D Inc. )
ClinicalTrials.gov Identifier: NCT02621931     History of Changes
Other Study ID Numbers: TV48125-CNS-30049
2015-004549-23 ( EudraCT Number )
First Submitted: December 2, 2015
First Posted: December 4, 2015
Results First Submitted: October 10, 2018
Results First Posted: December 6, 2018
Last Update Posted: December 6, 2018