Efficacy and Safety of 2 Dose Regimens of TEV-48125 Versus Placebo for the Preventive Treatment of Episodic Migraine

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02629861
• Collaborator: (none)
• Enrollment: 875
• Locations: 275
• Arms: 3
• Actual Duration (Months): 12.6
• Patients Per Site: 3.2
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The study is being conducted to evaluate two doses of TEV-48125 in adult patients with episodic migraine

Condition or Disease	Intervention/Treatment	Phase
Migraine	Drug: Fremanezumab; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 875 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study Comparing the Efficacy and Safety of 2 Dose Regimens of Subcutaneous Administration of Fremanezumab (TEV-48125) vs Placebo for the Preventive Treatment of Episodic Migraine
• Actual Study Start Date: Mar 23, 2016
• Actual Primary Completion Date: Apr 10, 2017
• Actual Study Completion Date: Apr 10, 2017

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Matching Placebo	Drug: Placebo; Placebo 1.5 mL pre-filled syringes identical in appearance to active intervention. Study drug was administered at the clinical site.
Experimental: Fremanezumab 675 mg/placebo/placebo Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Drug: Fremanezumab; Fremanezumab was provided as a sterile, unpreserved, aqueous solution for injection, 225 mg/1.5 mL pre-filled syringe for single-use administration. The 675 mg dose was given as 3 injections; doses of 225 mg were given as a single injection. Study drug was administered at the clinical site.; Other Names: TEV-48125, anti-calcitonin gene-related peptide (anti-CGRP) ; Drug: Placebo; Placebo 1.5 mL pre-filled syringes identical in appearance to active intervention. Study drug was administered at the clinical site.
Experimental: Fremanezumab 225/225/225 mg Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.	Drug: Fremanezumab; Fremanezumab was provided as a sterile, unpreserved, aqueous solution for injection, 225 mg/1.5 mL pre-filled syringe for single-use administration. The 675 mg dose was given as 3 injections; doses of 225 mg were given as a single injection. Study drug was administered at the clinical site.; Other Names: TEV-48125, anti-calcitonin gene-related peptide (anti-CGRP)

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in the Monthly Average Number of Migraine Days During the 12-Week Period After the First Dose of Study Drug [Baseline (Days -28 to Day -1), Treatment (Days 1 - Week 12)]

   A migraine day was defined as when at least 1 of the following situations occurred: - a calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache endorsing criteria for migraine with or without aura - a calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache endorsing criteria for probable migraine, a migraine subtype where only 1 migraine criterion is missing - a calendar day (0:00 to 23:59) demonstrating a headache of any duration that was treated with migraine-specific medications (triptans and ergot compounds) Monthly averages are derived and normalized to 28 days equivalent by the following formula: (# days of efficacy variable over relevant period / # days with assessments recorded in the e-diary over the relevant period) * 28. The change is calculated as postbaseline value - baseline value.

2. Participants With Adverse Events [Day 1 to Week 12]

   An adverse event was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents usual activities. Relationship of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.

Secondary Outcome Measures

1. Percentage of Participants With At Least 50% Reduction In Monthly Average Number of Migraine Days During the 12-Week Period After the First Dose of Study Drug [Baseline (Days -28 to Day -1), Treatment Month 1, Month 2, Month 3, Month 1-3 (Days 1 - Week 12)]

   Responder rates were defined as the percentage of total subjects who reached at least a 50% reduction in the monthly average of headache days (as subjectively reported by participants in the study diary) of at least moderate severity relative to the baseline period. For the overall analysis (Month 1-3), patients who discontinued early were considered nonresponders. Monthly averages are derived and normalized to 28 days equivalent by the following formula: (# days of efficacy variable over relevant period / # days with assessments recorded in the e-diary over the relevant period) * 28. The percentage reduction in monthly average is calculated as: ((baseline value - postbaseline value) / baseline value) * 100

2. 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 [Baseline (Days -28 to Day -1), Treatment (Days 1 - Week 12)]

   Patients recorded any migraine medications (name of drug, number of tablets/capsules, and the dose in milligrams per tablet/capsule) taken on each day in their electronic headache diary device. Acute migraine-specific medication included triptans or ergots. Monthly averages are derived and normalized to 28 days equivalent by the following formula: (# days of efficacy variable over relevant period / # days with assessments recorded in the e-diary over the relevant period) * 28. The change is calculated as postbaseline value - baseline value.

3. Change From Baseline in the Number of Migraine Days During the 4 Week Period After the First Dose of Study Drug [Baseline (Days -28 to Day -1), Treatment (Days 1 - Week 4)]

   A migraine day was defined as when at least 1 of the following situations occurred: - a calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache endorsing criteria for migraine with or without aura - a calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache endorsing criteria for probable migraine, a migraine subtype where only 1 migraine criterion is missing - a calendar day (0:00 to 23:59) demonstrating a headache of any duration that was treated with migraine-specific medications (triptans and ergot compounds) Monthly averages are derived and normalized to 28 days equivalent by the following formula: (# days of efficacy variable over relevant period / # days with assessments recorded in the e-diary over the relevant period) * 28. The change is calculated as postbaseline value - baseline value.

4. Change From Baseline in the Monthly Average Number of Migraine Days During the 12 Week Period After the First Dose of Study Medication in Patients Not Receiving Concomitant Preventive Migraine Medications [Baseline (Days -28 to Day -1), Treatment (Days 1 - Week 12)]

   A subset of patients (specified in the protocol not to exceed 30%) were allowed to use 1 concomitant migraine preventive medication. This outcome only includes those participants who did not take concomitant preventive migraine medication during this study. A migraine day has been previously defined. Monthly averages are derived and normalized to 28 days equivalent by the following formula: (# days of efficacy variable over relevant period / # days with assessments recorded in the e-diary over the relevant period) * 28. The change is calculated as postbaseline value - baseline value.

5. Change From Baseline in Migraine-Related Disability Score (MIDAS), As Measured by the Migraine Disability Assessment At 4 Weeks After the Last (3rd) Dose of Study Drug [Baseline (Day 0), Treatment Week 12 (4 weeks after the 3rd dose)]

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

6. Electrocardiogram Finding Shifts From Baseline to Overall [Baseline (Day 0), Treatment Week 12 (or early withdrawal)]

   12-lead ECGs were performed before other assessments (eg, blood draws and administration of questionnaires) and performed in triplicate. The worst post-baseline finding for the patient is summarized. Only patients with both baseline and post-baseline ECGs are included. The ECG was evaluated by the investigator at the time of recording (signed and dated), and the printout was kept in the source documentation file. When potentially clinically significant findings were detected by the investigator, a cardiologist at a central diagnostic center was consulted for a definitive interpretation. Any ECG finding that was judged by the investigator as a potentially clinically significant change (worsening) compared with a baseline value was considered an adverse event. - NCS = abnormal, not clinically significant - CS = abnormal, clinically significant Shift format is: baseline finding / worst post-baseline finding

7. Participants With Vital Signs Potentially Clinically Significant Abnormal Values [Treatment Days 28, 56 and 84. Changes from previous reading may reflect the baseline reading performed on Day 0.]

   Vital signs were performed before other assessments (eg, blood draws and administration of questionnaires). Vital signs with at least one participant showing potentially clinically significant abnormal findings included: - Pulse Rate Low: <=50 and decrease of >=15 beats per minute - Systolic Blood Pressure Low: <=90 mmHg and decrease of >=20 mmHg - Diastolic Blood Pressure High: >=105 mmHg and increase of >=15 mmHg - Diastolic Blood Pressure Low: <=50 mmHg and decrease of >=15 mmHg - Respiratory Rate Low: <10 breaths / minute

8. Participants With Serum Chemistry and Hematology Potentially Clinically Significant Abnormal Results [Treatment Days 28, 56 and 84 (or early withdrawal)]

   Serum chemistry and hematology laboratory tests with potentially clinically significant abnormal findings included: - Blood Urea Nitrogen (BUN) High: >=10.71 mmol/L - Bilirubin High: >=34.2 umol/L - Alanine Aminotransferase (ALT): >=3*upper limit of normal (ULN) - Aspartate Aminotransferase (AST): >=3*upper limit of normal (ULN) - Gamma Glutamyl Transferase (GGT): >=3*upper limit of normal (ULN) - Hemoglobin: Male: <115 g/L or Female: <=95 g/L - Hematocrit: Male: <0.37 L/L or Female: <0.32 L/L - Leukocytes: >=20*10^9/L or <=3*10^9/L - Eosinophils/Leukocytes: >=10% - Platelets: >=700*10^9/L or <=75*10^9/L

9. Participants With Urinalysis Laboratory Tests Potentially Clinically Significant Abnormal Results [Treatment Days 28, 56 and 84. Changes from previous reading reflect the baseline reading performed on Day 0.]

   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

10. Prothrombin Time Shifts From Baseline to Endpoint [Baseline (Day 0), Treatment Endpoint (Week 12)]

    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

11. Injection Site Reaction Adverse Events [Day 1 to Week 12]

    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.

12. Participants With Positive Electronic Columbia Suicide Severity Rating Scale Results After the First Dose of Study Drug [Day 1 to Week 12]

    The electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) was used to assess the patient's suicidal ideation (severity and intensity) and behavior (Posner et al 2011). The eC-SSRS Baseline/Screening version was completed by the patient at visit 2, and the eC-SSRS Since Last Visit version was completed by the patient at all other time points. Any positive findings on the eC-SSRS Since Last Visit version required evaluation by a physician or doctoral-level psychologist. Findings after the first dose of study drug using the eC-SSRS Since Last Visit version are summarized.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Males or females aged 18 to 70 years, inclusive, with migraine onset at ≤50 years of age

• Patient signs and dates the informed consent document

• Patient has history of migraine according to International Classification of Headache Disorders, or clinical judgment suggests a migraine diagnosis

• 85% e-diary compliance

• Total body weight between 99 and 265 lbs, inclusive

• Additional criteria apply, please contact the investigator for more information

Exclusion Criteria:

• Clinically significant hematological, cardiac, renal, endocrine, pulmonary, gastrointestinal, genitourinary, neurologic, hepatic, or ocular disease, at the discretion of the investigator

• Evidence or medical history of clinically significant psychiatric issues, including any suicide attempt in the past, or suicidal ideation with a specific plan in the past 2 years

• History of clinically significant cardiovascular disease or vascular ischemia (such as myocardial, neurological [eg, cerebral ischemia], peripheral extremity ischemia, or other ischemic event) or thromboembolic events (arterial or venous thrombotic or embolic events), such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism

• Known infection or history of human immunodeficiency virus, tuberculosis, or chronic hepatitis B or C infection

• Past or current history of cancer in the last 5 years, except for appropriately treated nonmelanoma skin carcinoma

• Pregnant or nursing females

• History of hypersensitivity reactions to injected proteins, including monoclonal antibodies

• Participation in a clinical study of a new chemical entity or a prescription medicine within 2 months or 5 half-lives, whichever is longer

• Additional criteria apply, please contact the investigator for more information

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Teva Investigational Site 13628	Birmingham	Alabama	United States	35211
2	Teva Investigational Site 13577	Birmingham	Alabama	United States	35216
3	Teva Investigational Site 13577	Birmingham	Alabama	United States
4	Teva Investigational Site 13628	Birmingham	Alabama	United States
5	Teva Investigational Site 13606	Phoenix	Arizona	United States	85018
6	Teva Investigational Site 13579	Phoenix	Arizona	United States	85023
7	Teva Investigational Site 13579	Phoenix	Arizona	United States
8	Teva Investigational Site 13606	Phoenix	Arizona	United States
9	Teva Investigational Site 13602	Little Rock	Arkansas	United States	72205
10	Teva Investigational Site 13602	Little Rock	Arkansas	United States
11	Teva Investigational Site 13568	Encino	California	United States	91316
12	Teva Investigational Site 13568	Encino	California	United States
13	Teva Investigational Site 13546	Fullerton	California	United States	92835
14	Teva Investigational Site 13546	Fullerton	California	United States
15	Teva Investigational Site 13540	Long Beach	California	United States	90806
16	Teva Investigational Site 13540	Long Beach	California	United States
17	Teva Investigational Site 13632	Redlands	California	United States	92374
18	Teva Investigational Site 13632	Redlands	California	United States
19	Teva Investigational Site 13571	Redondo Beach	California	United States	90277
20	Teva Investigational Site 13571	Redondo Beach	California	United States
21	Teva Investigational Site 13573	San Diego	California	United States	92103
22	Teva Investigational Site 13573	San Diego	California	United States
23	Teva Investigational Site 13538	Santa Monica	California	United States	90404
24	Teva Investigational Site 13538	Santa Monica	California	United States
25	Teva Investigational Site 13594	Santa Rosa	California	United States	95405
26	Teva Investigational Site 13594	Santa Rosa	California	United States
27	Teva Investigational Site 13595	Walnut Creek	California	United States	94598
28	Teva Investigational Site 13595	Walnut Creek	California	United States
29	Teva Investigational Site 13629	Aurora	Colorado	United States	80014
30	Teva Investigational Site 13629	Aurora	Colorado	United States
31	Teva Investigational Site 13557	Boulder	Colorado	United States	80301
32	Teva Investigational Site 13557	Boulder	Colorado	United States
33	Teva Investigational Site 13593	Colorado Springs	Colorado	United States	80918
34	Teva Investigational Site 13593	Colorado Springs	Colorado	United States
35	Teva Investigational Site 13633	Denver	Colorado	United States	80210
36	Teva Investigational Site 13612	Denver	Colorado	United States	80239
37	Teva Investigational Site 13612	Denver	Colorado	United States
38	Teva Investigational Site 13633	Denver	Colorado	United States
39	Teva Investigational Site 13631	Englewood	Colorado	United States	80113
40	Teva Investigational Site 13631	Englewood	Colorado	United States
41	Teva Investigational Site 13563	East Hartford	Connecticut	United States	06118
42	Teva Investigational Site 13563	East Hartford	Connecticut	United States
43	Teva Investigational Site 13550	Stamford	Connecticut	United States	06905
44	Teva Investigational Site 13550	Stamford	Connecticut	United States
45	Teva Investigational Site 13635	Bradenton	Florida	United States	34201
46	Teva Investigational Site 13635	Bradenton	Florida	United States
47	Teva Investigational Site 13597	Gainesville	Florida	United States	32607
48	Teva Investigational Site 13597	Gainesville	Florida	United States
49	Teva Investigational Site 13607	Hialeah	Florida	United States	33012
50	Teva Investigational Site 13607	Hialeah	Florida	United States
51	Teva Investigational Site 13559	Jacksonville	Florida	United States	32205
52	Teva Investigational Site 13559	Jacksonville	Florida	United States
53	Teva Investigational Site 13584	Ocala	Florida	United States	34471
54	Teva Investigational Site 13584	Ocala	Florida	United States
55	Teva Investigational Site 13587	Orlando	Florida	United States	32806
56	Teva Investigational Site 13551	Orlando	Florida	United States
57	Teva Investigational Site 13555	Orlando	Florida	United States
58	Teva Investigational Site 13587	Orlando	Florida	United States
59	Teva Investigational Site 13599	Orlando	Florida	United States
60	Teva Investigational Site 13553	Pembroke Pines	Florida	United States	33026
61	Teva Investigational Site 13553	Pembroke Pines	Florida	United States
62	Teva Investigational Site 13616	Pinellas Park	Florida	United States	33781
63	Teva Investigational Site 13616	Pinellas Park	Florida	United States
64	Teva Investigational Site 13567	West Palm Beach	Florida	United States	33407
65	Teva Investigational Site 13567	West Palm Beach	Florida	United States
66	Teva Investigational Site 13620	Atlanta	Georgia	United States	30312
67	Teva Investigational Site 13537	Atlanta	Georgia	United States	30342
68	Teva Investigational Site 13537	Atlanta	Georgia	United States
69	Teva Investigational Site 13620	Atlanta	Georgia	United States
70	Teva Investigational Site 13604	Boise	Idaho	United States	83642
71	Teva Investigational Site 13604	Meridian	Idaho	United States
72	Teva Investigational Site 13585	Chicago	Illinois	United States	60607
73	Teva Investigational Site 13621	Chicago	Illinois	United States	60654
74	Teva Investigational Site 13585	Chicago	Illinois	United States
75	Teva Investigational Site 13621	Chicago	Illinois	United States
76	Teva Investigational Site 13627	Evanston	Illinois	United States	60201
77	Teva Investigational Site 13627	Evanston	Illinois	United States
78	Teva Investigational Site 13596	Indianapolis	Indiana	United States	46254
79	Teva Investigational Site 13596	Indianapolis	Indiana	United States
80	Teva Investigational Site 13617	Wichita	Kansas	United States	67207
81	Teva Investigational Site 13598	Wichita	Kansas	United States	67211
82	Teva Investigational Site 13598	Wichita	Kansas	United States
83	Teva Investigational Site 13617	Wichita	Kansas	United States
84	Teva Investigational Site 13566	Louisville	Kentucky	United States	40207
85	Teva Investigational Site 13566	Louisville	Kentucky	United States
86	Teva Investigational Site 13603	Metairie	Louisiana	United States	70006
87	Teva Investigational Site 13603	Metairie	Louisiana	United States
88	Teva Investigational Site 13582	Baltimore	Maryland	United States
89	Teva Investigational Site 13582	Pikesville	Maryland	United States	21208
90	Teva Investigational Site 13590	Boston	Massachusetts	United States	02131
91	Teva Investigational Site 13590	Boston	Massachusetts	United States
92	Teva Investigational Site 13589	New Bedford	Massachusetts	United States	02301
93	Teva Investigational Site 13589	New Bedford	Massachusetts	United States
94	Teva Investigational Site 13543	Wellesley Hills	Massachusetts	United States	02481
95	Teva Investigational Site 13543	Wellesley Hills	Massachusetts	United States
96	Teva Investigational Site 13539	Ann Arbor	Michigan	United States	48104
97	Teva Investigational Site 13539	Ann Arbor	Michigan	United States
98	Teva Investigational Site 13542	Golden Valley	Minnesota	United States	55422
99	Teva Investigational Site 13542	Golden Valley	Minnesota	United States
100	Teva Investigational Site 13534	Kansas City	Missouri	United States	64114
101	Teva Investigational Site 13534	Kansas City	Missouri	United States
102	Teva Investigational Site 13619	Saint Louis	Missouri	United States	63141
103	Teva Investigational Site 13619	Saint Louis	Missouri	United States
104	Teva Investigational Site 13536	Springfield	Missouri	United States
105	Teva Investigational Site 13618	Fremont	Nebraska	United States	68025
106	Teva Investigational Site 13618	Fremont	Nebraska	United States
107	Teva Investigational Site 13605	Las Vegas	Nevada	United States	89106
108	Teva Investigational Site 13605	Las Vegas	Nevada	United States
109	Teva Investigational Site 13578	Lebanon	New Hampshire	United States	03756
110	Teva Investigational Site 13578	Lebanon	New Hampshire	United States
111	Teva Investigational Site 13575	Martinsville	New Jersey	United States
112	Teva Investigational Site 13575	Raritan	New Jersey	United States	08869
113	Teva Investigational Site 13588	Albuquerque	New Mexico	United States	87102
114	Teva Investigational Site 13588	Albuquerque	New Mexico	United States
115	Teva Investigational Site 13576	Amherst	New York	United States	14226
116	Teva Investigational Site 13576	Amherst	New York	United States
117	Teva Investigational Site 13565	Plainview	New York	United States	11803
118	Teva Investigational Site 13565	Plainview	New York	United States
119	Teva Investigational Site 13544	Greensboro	North Carolina	United States	27401
120	Teva Investigational Site 13574	Greensboro	North Carolina	United States	27408
121	Teva Investigational Site 13544	Greensboro	North Carolina	United States
122	Teva Investigational Site 13574	Greensboro	North Carolina	United States
123	Teva Investigational Site 13545	Raleigh	North Carolina	United States	27607
124	Teva Investigational Site 13545	Raleigh	North Carolina	United States
125	Teva Investigational Site 13609	Akron	Ohio	United States	44311
126	Teva Investigational Site 13634	Akron	Ohio	United States	44311
127	Teva Investigational Site 13609	Akron	Ohio	United States
128	Teva Investigational Site 13634	Akron	Ohio	United States
129	Teva Investigational Site 13533	Cincinnati	Ohio	United States	45227
130	Teva Investigational Site 13624	Cincinnati	Ohio	United States	45249
131	Teva Investigational Site 13533	Cincinnati	Ohio	United States
132	Teva Investigational Site 13624	Cincinnati	Ohio	United States
133	Teva Investigational Site 13569	Cleveland	Ohio	United States	44195
134	Teva Investigational Site 13569	Cleveland	Ohio	United States
135	Teva Investigational Site 13626	Columbus	Ohio	United States	43212
136	Teva Investigational Site 13626	Columbus	Ohio	United States
137	Teva Investigational Site 13625	Mogadore	Ohio	United States	44260
138	Teva Investigational Site 13625	Mogadore	Ohio	United States
139	Teva Investigational Site 13561	Oklahoma City	Oklahoma	United States	73112
140	Teva Investigational Site 13561	Oklahoma City	Oklahoma	United States
141	Teva Investigational Site 13601	Eugene	Oregon	United States	97401
142	Teva Investigational Site 13601	Eugene	Oregon	United States
143	Teva Investigational Site 13591	Jenkintown	Pennsylvania	United States	19046
144	Teva Investigational Site 13591	Jenkintown	Pennsylvania	United States
145	Teva Investigational Site 13554	Philadelphia	Pennsylvania	United States	19107
146	Teva Investigational Site 13554	Philadelphia	Pennsylvania	United States
147	Teva Investigational Site 13608	Uniontown	Pennsylvania	United States	15401
148	Teva Investigational Site 13608	Uniontown	Pennsylvania	United States
149	Teva Investigational Site 13615	Greer	South Carolina	United States	29650
150	Teva Investigational Site 13615	Greer	South Carolina	United States
151	Teva Investigational Site 13556	Mount Pleasant	South Carolina	United States	29464
152	Teva Investigational Site 13556	Mount Pleasant	South Carolina	United States
153	Teva Investigational Site 13560	Bristol	Tennessee	United States	37620
154	Teva Investigational Site 13560	Bristol	Tennessee	United States
155	Teva Investigational Site 13532	Nashville	Tennessee	United States	37203
156	Teva Investigational Site 13552	Nashville	Tennessee	United States	37203
157	Teva Investigational Site 13532	Nashville	Tennessee	United States
158	Teva Investigational Site 13552	Nashville	Tennessee	United States
159	Teva Investigational Site 13541	Austin	Texas	United States	78731
160	Teva Investigational Site 13541	Austin	Texas	United States
161	Teva Investigational Site 13623	Dallas	Texas	United States	75214
162	Teva Investigational Site 13623	Dallas	Texas	United States
163	Teva Investigational Site 13611	Plano	Texas	United States	75024
164	Teva Investigational Site 13611	Plano	Texas	United States
165	Teva Investigational Site 13572	San Antonio	Texas	United States	78229
166	Teva Investigational Site 13572	San Antonio	Texas	United States
167	Teva Investigational Site 13614	Murray	Utah	United States	84107
168	Teva Investigational Site 13614	Murray	Utah	United States
169	Teva Investigational Site 13581	West Jordan	Utah	United States	84088
170	Teva Investigational Site 13581	West Jordan	Utah	United States
171	Teva Investigational Site 13630	Virginia Beach	Virginia	United States	23454
172	Teva Investigational Site 13630	Virginia Beach	Virginia	United States
173	Teva Investigational Site 13564	Seattle	Washington	United States	98105
174	Teva Investigational Site 13586	Seattle	Washington	United States	98105
175	Teva Investigational Site 13564	Seattle	Washington	United States
176	Teva Investigational Site 13586	Seattle	Washington	United States
177	Teva Investigational Site 13600	Morgantown	West Virginia	United States	26506
178	Teva Investigational Site 13600	Morgantown	West Virginia	United States
179	Teva Investigational Site 11124	Hamilton	Ontario	Canada	L8N 1Y2
180	Teva Investigational Site 11124	Hamilton	Ontario	Canada
181	Teva Investigational Site 11120	Calgary		Canada	T3M 1M4
182	Teva Investigational Site 11120	Calgary		Canada
183	Teva Investigational Site 11121	Montreal		Canada	H2W 1V1
184	Teva Investigational Site 11121	Montreal		Canada
185	Teva Investigational Site 11122	Newmarket		Canada	L3Y5G8
186	Teva Investigational Site 11122	Newmarket		Canada
187	Teva Investigational Site 11123	Sarnia		Canada	N7T 4X3
188	Teva Investigational Site 11123	Sarnia		Canada
189	Teva Investigational Site 54144	Brno		Czechia	602 00
190	Teva Investigational Site 54144	Brno		Czechia
191	Teva Investigational Site 54141	Kunratice		Czechia	14800
192	Teva Investigational Site 54141	Kunratice		Czechia
193	Teva Investigational Site 54145	Pardubice		Czechia	53002
194	Teva Investigational Site 54145	Pardubice		Czechia
195	Teva Investigational Site 54142	Prague 4		Czechia	140 59
196	Teva Investigational Site 54142	Prague-4-Krc		Czechia
197	Teva Investigational Site 54146	Praha 3		Czechia	130 00
198	Teva Investigational Site 54146	Praha 3		Czechia
199	Teva Investigational Site 54143	Praha		Czechia	100 00
200	Teva Investigational Site 54143	Praha		Czechia
201	Teva Investigational Site 40018	Helsinki		Finland	00100
202	Teva Investigational Site 40017	Helsinki		Finland	00930
203	Teva Investigational Site 40017	Helsinki		Finland
204	Teva Investigational Site 40018	Helsinki		Finland
205	Teva Investigational Site 40016	Turku		Finland	20100
206	Teva Investigational Site 40016	Turku		Finland
207	Teva Investigational Site 80096	Holon		Israel	58100
208	Teva Investigational Site 80096	Holon		Israel
209	Teva Investigational Site 80099	Jerusalem		Israel	9112001
210	Teva Investigational Site 80099	Jerusalem		Israel
211	Teva Investigational Site 80098	Nahariya		Israel	221001
212	Teva Investigational Site 80098	Nahariya		Israel
213	Teva Investigational Site 80097	Netanya		Israel	4244916
214	Teva Investigational Site 80097	Netanya		Israel
215	Teva Investigational Site 80100	Ramat Gan		Israel	5262160
216	Teva Investigational Site 80100	Ramat Gan		Israel
217	Teva Investigational Site 80095	Tel Aviv		Israel	64239
218	Teva Investigational Site 80095	Tel Aviv		Israel
219	Teva Investigational Site 84072	Chofu-shi		Japan	182-0006
220	Teva Investigational Site 84064	Chofu-shi		Japan
221	Teva Investigational Site 84072	Chofu-shi		Japan
222	Teva Investigational Site 84066	Kagoshima-shi		Japan
223	Teva Investigational Site 84066	Kagoshima		Japan	892-0844
224	Teva Investigational Site 84069	Kai-shi		Japan
225	Teva Investigational Site 84069	Kai		Japan	400-0124
226	Teva Investigational Site 84073	Kawasaki-shi		Japan
227	Teva Investigational Site 84073	Kawasaki		Japan	211-8588
228	Teva Investigational Site 84067	Kyoto		Japan	600-8811
229	Teva Investigational Site 84067	Kyoto		Japan
230	Teva Investigational Site 84062	Osaka-shi		Japan	556-0015
231	Teva Investigational Site 84062	Osaka-shi		Japan
232	Teva Investigational Site 84070	Saitama-shi		Japan
233	Teva Investigational Site 84070	Saitama		Japan	338-8577
234	Teva Investigational Site 84061	Sendai-shi		Japan	982-0014
235	Teva Investigational Site 84061	Sendai-shi		Japan
236	Teva Investigational Site 84065	Shimotsuma		Japan
237	Teva Investigational Site 84063	Shinjuku-ku		Japan	160-8582
238	Teva Investigational Site 84068	Shizuoka-shi		Japan
239	Teva Investigational Site 84068	Shizuoka		Japan	4200-853
240	Teva Investigational Site 84065	Tochigi		Japan	321-0293
241	Teva Investigational Site 84064	Tokyo		Japan	182-0006
242	Teva Investigational Site 84071	Toyonaka-shi		Japan
243	Teva Investigational Site 84071	Toyonaka		Japan
244	Teva Investigational Site 53364	Krakow		Poland	31-523
245	Teva Investigational Site 53363	Krakow		Poland	33-332
246	Teva Investigational Site 53363	Krakow		Poland
247	Teva Investigational Site 53364	Krakow		Poland
248	Teva Investigational Site 53366	Lublin		Poland	20-022
249	Teva Investigational Site 53366	Lublin		Poland
250	Teva Investigational Site 53365	Poznan		Poland	60-529
251	Teva Investigational Site 53365	Poznan		Poland
252	Teva Investigational Site 53367	Warsaw		Poland	04-730
253	Teva Investigational Site 53367	Warsaw		Poland
254	Teva Investigational Site 50399	Kazan		Russian Federation	420012
255	Teva Investigational Site 50395	Kazan		Russian Federation	420021
256	Teva Investigational Site 50395	Kazan		Russian Federation
257	Teva Investigational Site 50399	Kazan		Russian Federation
258	Teva Investigational Site 50394	Moscow		Russian Federation	121467
259	Teva Investigational Site 50400	Moscow		Russian Federation	129128
260	Teva Investigational Site 50394	Moscow		Russian Federation
261	Teva Investigational Site 50400	Moscow		Russian Federation
262	Teva Investigational Site 50398	Nizhniy Novgorod		Russian Federation	603126
263	Teva Investigational Site 50396	Nizhniy Novgorod		Russian Federation	603137
264	Teva Investigational Site 50396	Nizhniy Novgorod		Russian Federation
265	Teva Investigational Site 50398	Nizhniy Novgorod		Russian Federation
266	Teva Investigational Site 50397	Ufa		Russian Federation	450007
267	Teva Investigational Site 50397	Ufa		Russian Federation
268	Teva Investigational Site 31207	Madrid		Spain	28046
269	Teva Investigational Site 31207	Madrid		Spain
270	Teva Investigational Site 31208	Pamplona		Spain	31008
271	Teva Investigational Site 31208	Pamplona		Spain
272	Teva Investigational Site 31205	Valladolid		Spain	47003
273	Teva Investigational Site 31205	Valladolid		Spain
274	Teva Investigational Site 31206	Zaragoza		Spain	50009
275	Teva Investigational Site 31206	Zaragoza		Spain

Sponsors and Collaborators

• Teva Branded Pharmaceutical Products R&D, Inc.

Investigators

• Study Director: Teva Medical Expert, MD, Teva Branded Pharmaceutical Products R&D, Inc.

Study Documents (Full-Text)

• Study Protocol - Mar 30, 2016
• Statistical Analysis Plan - May 26, 2017

More Information

Publications

None provided.

• Responsible Party: Teva Branded Pharmaceutical Products R&D, Inc.
• ClinicalTrials.gov Identifier: NCT02629861
• Other Study ID Numbers: TV48125-CNS-30050; 2015-004598-34
• First Posted: Dec 14, 2015
• Last Update Posted: Nov 9, 2021
• Last Verified: Nov 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Migraine Disorders; Calcitonin; Calcitonin Gene-Related Peptide; Katacalcin

Study Results

Participant Flow

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

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

Baseline Characteristics

Arm/Group Title	Placebo	Fremanezumab 675 mg/Placebo/Placebo	Fremanezumab 225/225/225 mg	Total
Arm/Group Description	Participants randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.	Total of all reporting groups
Overall Participants	294	291	290	875
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41.3 (12.04)	41.1 (11.41)	42.9 (12.67)	41.8 (12.06)
Age, Customized (Count of Participants)
18-45 years	184 62.6%	178 61.2%	163 56.2%	525 60%
46-65 years	102 34.7%	110 37.8%	120 41.4%	332 37.9%
>65 years	8 2.7%	3 1%	7 2.4%	18 2.1%
Sex: Female, Male (Count of Participants)
Female	247 84%	251 86.3%	244 84.1%	742 84.8%
Male	47 16%	40 13.7%	46 15.9%	133 15.2%
Race/Ethnicity, Customized (Count of Participants)
White	225 76.5%	232 79.7%	243 83.8%	700 80%
Black	40 13.6%	28 9.6%	18 6.2%	86 9.8%
Asian	25 8.5%	27 9.3%	25 8.6%	77 8.8%
American Indian or Alaska Native	0 0%	1 0.3%	3 1%	4 0.5%
Native Hawaiian or Other Pacific Islander	0 0%	1 0.3%	0 0%	1 0.1%
Other	4 1.4%	2 0.7%	1 0.3%	7 0.8%
Race/Ethnicity, Customized (Count of Participants)
Not Hispanic or Latino	267 90.8%	251 86.3%	252 86.9%	770 88%
Hispanic or Latino	27 9.2%	39 13.4%	37 12.8%	103 11.8%
Unknown	0 0%	1 0.3%	1 0.3%	2 0.2%
Preventive Medication Use During Baseline Period (Count of Participants)
Yes	62 21.1%	58 19.9%	62 21.4%	182 20.8%
No	232 78.9%	233 80.1%	228 78.6%	693 79.2%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	75.3 (16.01)	74.2 (15.42)	72.1 (15.77)	73.9 (15.77)
Time Since Initial Migraine Diagnosis (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	19.9 (11.87)	20.0 (12.14)	20.7 (12.85)	20.2 (12.28)
Total Number of Headache Days of Any Duration And Any Severity During the 28 Day Baseline Period (days) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [days]	11.2 (2.45)	11.1 (2.42)	11.0 (2.49)	11.1 (2.45)
Number of Migraine Days (days) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [days]	9.1 (2.65)	9.3 (2.65)	8.9 (2.63)	9.1 (2.64)
Number of Headache Days of At Least Moderate Severity (days) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [days]	6.9 (3.12)	7.2 (3.14)	6.8 (2.90)	7.0 (3.06)
Number of Days of Use of Any Acute Headache Medications (days) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [days]	7.7 (3.60)	7.8 (3.74)	7.7 (3.37)	7.8 (3.57)
Migraine Disability Assessment (MIDAS) Total Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	37.3 (27.59)	41.7 (32.96)	38.0 (33.19)	39.0 (31.36)

Outcome Measures

1. Primary 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
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 postbaseline value - baseline value.
Time Frame	Baseline (Days -28 to Day -1), Treatment (Days 1 - Week 12)

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Placebo	Fremanezumab 675 mg/Placebo/Placebo	Fremanezumab 225/225/225 mg
Arm/Group Description	Participants randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.
Measure Participants	290	288	287
Median (Inter-Quartile Range) [days]	-2.7	-4.0	-4.2

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
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	0.05 level of significance
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Fremanezumab 225/225/225 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
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	0.05 level of significance
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Primary Outcome

Title	Participants With Adverse Events
Description	An adverse event was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents usual activities. Relationship of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.
Time Frame	Day 1 to Week 12

Outcome Measure Data

Analysis Population Description

Safety population

Arm/Group Title	Placebo	Fremanezumab 675 mg/Placebo/Placebo	Fremanezumab 225/225/225 mg
Arm/Group Description	Participants randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.
Measure Participants	293	291	290
Any AEs	171 58.2%	193 66.3%	192 66.2%
Severe AEs	11 3.7%	16 5.5%	10 3.4%
Treatment-related AEs	109 37.1%	137 47.1%	138 47.6%
Serious adverse events	7 2.4%	3 1%	3 1%
Deaths	0 0%	1 0.3%	0 0%
Discontinued from study due to AE	5 1.7%	5 1.7%	5 1.7%

3. Secondary Outcome

Title	Percentage of Participants With At Least 50% Reduction In Monthly Average Number of Migraine Days During the 12-Week Period After the First Dose of Study Drug
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 nonresponders. Monthly averages are derived and normalized to 28 days equivalent by the following formula: (# days of efficacy variable over relevant period / # days with assessments recorded in the e-diary over the relevant period) * 28. The percentage reduction in monthly average is calculated as: ((baseline value - postbaseline value) / baseline value) * 100
Time Frame	Baseline (Days -28 to Day -1), Treatment Month 1, Month 2, Month 3, Month 1-3 (Days 1 - Week 12)

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Placebo	Fremanezumab 675 mg/Placebo/Placebo	Fremanezumab 225/225/225 mg
Arm/Group Description	Participants randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.
Measure Participants	290	288	287
Month 1	25.2 8.6%	44.1 15.2%	47.0 16.2%
Month 2	34.8 11.8%	46.9 16.1%	48.4 16.7%
Month 3	37.2 12.7%	49.0 16.8%	51.2 17.7%
Overall - Months 1-3	27.9 9.5%	44.4 15.3%	47.7 16.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Fremanezumab 675 mg/Placebo/Placebo
	Comments	Month 1 P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	0.05 level of significance
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Fremanezumab 225/225/225 mg
	Comments	Month 1 P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	0.05 level of significance
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Fremanezumab 675 mg/Placebo/Placebo
	Comments	Month 2 P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0032
	Comments	0.05 level of significance
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Fremanezumab 225/225/225 mg
	Comments	Month 2 P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0010
	Comments	0.05 level of significance
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Fremanezumab 675 mg/Placebo/Placebo
	Comments	Month 3 P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0048
	Comments	0.05 level of significance
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Placebo, Fremanezumab 225/225/225 mg
	Comments	Month 3 P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments	0.05 level of significance
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Placebo, Fremanezumab 675 mg/Placebo/Placebo
	Comments	Overall P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	0.05 level of significance
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Placebo, Fremanezumab 225/225/225 mg
	Comments	Overall P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	0.05 level of significance
	Method	Cochran-Mantel-Haenszel
	Comments

4. 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
Description	Patients recorded any migraine medications (name of drug, number of tablets/capsules, and the dose in milligrams per tablet/capsule) taken on each day in their electronic headache diary device. Acute migraine-specific medication included triptans or ergots. Monthly averages are derived and normalized to 28 days equivalent by the following formula: (# days of efficacy variable over relevant period / # days with assessments recorded in the e-diary over the relevant period) * 28. The change is calculated as postbaseline value - baseline value.
Time Frame	Baseline (Days -28 to Day -1), Treatment (Days 1 - Week 12)

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Placebo	Fremanezumab 675 mg/Placebo/Placebo	Fremanezumab 225/225/225 mg
Arm/Group Description	Participants randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.
Measure Participants	290	288	287
Median (Inter-Quartile Range) [days]	-1.7	-3.0	-3.2

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 Wilcoxon rank-sum test was conducted as the primary analysis for each active treatment group and placebo treatment group for this endpoint
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	0.05 level of significance
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Fremanezumab 225/225/225 mg
	Comments	Due to the deviation from the normal distribution assumption of the data, the Wilcoxon rank-sum test was conducted as the primary analysis for each active treatment group and placebo treatment group for this endpoint
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	0.05 level of significance
	Method	Wilcoxon (Mann-Whitney)
	Comments

5. Secondary Outcome

Title	Change From Baseline in the Number of Migraine Days During the 4 Week Period After the First Dose of Study Drug
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 postbaseline value - baseline value.
Time Frame	Baseline (Days -28 to Day -1), Treatment (Days 1 - Week 4)

Outcome Measure Data

Analysis Population Description

Full analysis set; includes participants with observations

Arm/Group Title	Placebo	Fremanezumab 675 mg/Placebo/Placebo	Fremanezumab 225/225/225 mg
Arm/Group Description	Participants randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.
Measure Participants	290	285	286
Median (Inter-Quartile Range) [days]	-2.0	-4.0	-4.0

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 Wilcoxon rank-sum test was conducted as the primary analysis for each active treatment group and placebo treatment group for this endpoint
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	0.05 level of significance
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Fremanezumab 225/225/225 mg
	Comments	Due to the deviation from the normal distribution assumption of the data, the Wilcoxon rank-sum test was conducted as the primary analysis for each active treatment group and placebo treatment group for this endpoint
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	0.05 level of significance
	Method	Wilcoxon (Mann-Whitney)
	Comments

6. 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 Medication in Patients Not Receiving Concomitant Preventive Migraine Medications
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. A migraine day has been previously defined. Monthly averages are derived and normalized to 28 days equivalent by the following formula: (# days of efficacy variable over relevant period / # days with assessments recorded in the e-diary over the relevant period) * 28. The change is calculated as postbaseline value - baseline value.
Time Frame	Baseline (Days -28 to Day -1), Treatment (Days 1 - Week 12)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo	Fremanezumab 675 mg/Placebo/Placebo	Fremanezumab 225/225/225 mg
Arm/Group Description	Participants randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.
Measure Participants	230	230	225
Median (Inter-Quartile Range) [days]	-2.9	-4.0	-4.2

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 Wilcoxon rank-sum test was conducted as the primary analysis for each active treatment group and placebo treatment group for this endpoint.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	0.05 level of significance
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Fremanezumab 225/225/225 mg
	Comments	Due to the deviation from the normal distribution assumption of the data, the Wilcoxon rank-sum test was conducted as the primary analysis for each active treatment group and placebo treatment group for this endpoint.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	0.05 level of significance
	Method	Wilcoxon (Mann-Whitney)
	Comments

7. Secondary Outcome

Title	Change From Baseline in Migraine-Related Disability Score (MIDAS), As Measured by the Migraine Disability Assessment At 4 Weeks After the Last (3rd) Dose of Study Drug
Description	The MIDAS questionnaire is a 5-item instrument developed to assess headache-related disability based on lost days of activity in 3 domains (work, household work, and nonwork) over the previous 3 months. The total score, ie, the sum of the # lost days answered for the first 5 questions, is used for grading of disability, with scores of 0-5 lost days = grade 1 (little or no disability), 6-10 lost days =grade 2 (mild disability), 11-20 lost days = grade 3 (moderate disability), and ≥21 lost days interpreted as grade 4 (severe disability). Negative change from baseline scores indicate a reduction (improvement) in headache-related disability.
Time Frame	Baseline (Day 0), Treatment Week 12 (4 weeks after the 3rd dose)

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Placebo	Fremanezumab 675 mg/Placebo/Placebo	Fremanezumab 225/225/225 mg
Arm/Group Description	Participants randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.
Measure Participants	290	288	287
Median (Inter-Quartile Range) [lost days]	-12.5	-18.0	-19.0

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 Wilcoxon rank-sum test was conducted as the primary analysis for each active treatment group and placebo treatment group for this endpoint.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0023
	Comments	0.05 level of significance
	Method	Wilcoxon (Mann-Whitney)
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Fremanezumab 225/225/225 mg
	Comments	Due to the deviation from the normal distribution assumption of the data, the Wilcoxon rank-sum test was conducted as the primary analysis for each active treatment group and placebo treatment group for this endpoint.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0021
	Comments	0.05 level of significance
	Method	Wilcoxon (Mann-Whitney)
	Comments

8. Secondary Outcome

Title	Electrocardiogram Finding Shifts From Baseline to Overall
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 patient is summarized. Only patients with both baseline and post-baseline ECGs are included. The ECG was evaluated by the investigator at the time of recording (signed and dated), and the printout was kept in the source documentation file. When potentially clinically significant findings were detected by the investigator, a cardiologist at a central diagnostic center was consulted for a definitive interpretation. Any ECG finding that was judged by the investigator as a potentially clinically significant change (worsening) compared with a baseline value was considered an adverse event. - NCS = abnormal, not clinically significant - CS = abnormal, clinically significant Shift format is: baseline finding / worst post-baseline finding
Time Frame	Baseline (Day 0), Treatment Week 12 (or early withdrawal)

Outcome Measure Data

Analysis Population Description

Safety population of participants with both baseline and post-treatment ECGs

Arm/Group Title	Placebo	Fremanezumab 675 mg/Placebo/Placebo	Fremanezumab 225/225/225 mg
Arm/Group Description	Participants randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.
Measure Participants	278	276	281
Normal / Normal	161 54.8%	169 58.1%	181 62.4%
Normal / NCS	32 10.9%	41 14.1%	25 8.6%
Normal / CS	0 0%	0 0%	0 0%
NCS / Normal	27 9.2%	23 7.9%	29 10%
NCS / NCS	58 19.7%	43 14.8%	46 15.9%
NCS / CS	0 0%	0 0%	0 0%
CS / Normal	0 0%	0 0%	0 0%
CS / NCS	0 0%	0 0%	0 0%
CS / CS	0 0%	0 0%	0 0%

9. Secondary Outcome

Title	Participants With Vital Signs Potentially Clinically Significant Abnormal Values
Description	Vital signs were performed before other assessments (eg, blood draws and administration of questionnaires). Vital signs with at least one participant showing potentially clinically significant abnormal findings included: - Pulse Rate Low: <=50 and decrease of >=15 beats per minute - Systolic Blood Pressure Low: <=90 mmHg and decrease of >=20 mmHg - Diastolic Blood Pressure High: >=105 mmHg and increase of >=15 mmHg - Diastolic Blood Pressure Low: <=50 mmHg and decrease of >=15 mmHg - Respiratory Rate Low: <10 breaths / minute
Time Frame	Treatment Days 28, 56 and 84. Changes from previous reading may reflect the baseline reading performed on Day 0.

Outcome Measure Data

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 225/225/225 mg
Arm/Group Description	Participants randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.
Measure Participants	285	285	285
Participants with at least 1 abnormality	3 1%	4 1.4%	5 1.7%
Pulse Rate Low	0 0%	1 0.3%	0 0%
Systolic Blood Pressure Low	0 0%	2 0.7%	1 0.3%
Diastolic Blood Pressure High	0 0%	1 0.3%	2 0.7%
Diastolic Blood Pressure Low	2 0.7%	1 0.3%	0 0%
Respiratory Rate Low	1 0.3%	0 0%	2 0.7%

10. Secondary Outcome

Title	Participants With Serum Chemistry and Hematology Potentially Clinically Significant Abnormal Results
Description	Serum chemistry and hematology laboratory tests with potentially clinically significant abnormal findings included: - Blood Urea Nitrogen (BUN) High: >=10.71 mmol/L - Bilirubin High: >=34.2 umol/L - Alanine Aminotransferase (ALT): >=3*upper limit of normal (ULN) - Aspartate Aminotransferase (AST): >=3*upper limit of normal (ULN) - Gamma Glutamyl Transferase (GGT): >=3*upper limit of normal (ULN) - Hemoglobin: Male: <115 g/L or Female: <=95 g/L - Hematocrit: Male: <0.37 L/L or Female: <0.32 L/L - Leukocytes: >=20*10^9/L or <=3*10^9/L - Eosinophils/Leukocytes: >=10% - Platelets: >=700*10^9/L or <=75*10^9/L
Time Frame	Treatment Days 28, 56 and 84 (or early withdrawal)

Outcome Measure Data

Analysis Population Description

Safety population of participants with at least one postbaseline result for the tests.

Arm/Group Title	Placebo	Fremanezumab 675 mg/Placebo/Placebo	Fremanezumab 225/225/225 mg
Arm/Group Description	Participants randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.
Measure Participants	285	285	285
Blood Urea Nitrogen (BUN)	1 0.3%	0 0%	1 0.3%
Bilirubin	1 0.3%	0 0%	1 0.3%
Alanine Aminotransferase (ALT)	0 0%	1 0.3%	0 0%
Aspartate Aminotransferase (AST)	0 0%	0 0%	1 0.3%
Gamma Glutamyl Transferase (GGT)	4 1.4%	4 1.4%	8 2.8%
Hemoglobin	1 0.3%	4 1.4%	2 0.7%
Hematocrit	3 1%	6 2.1%	6 2.1%
Leukocytes	4 1.4%	1 0.3%	6 2.1%
Eosinophils/Leukocytes	7 2.4%	3 1%	5 1.7%
Platelets	1 0.3%	0 0%	0 0%

11. Secondary Outcome

Title	Participants With Urinalysis Laboratory Tests Potentially Clinically Significant Abnormal Results
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. Changes from previous reading reflect the baseline reading performed on Day 0.

Outcome Measure Data

Analysis Population Description

Safety population of participants with at least one postbaseline result for the tests

Arm/Group Title	Placebo	Fremanezumab 675 mg/Placebo/Placebo	Fremanezumab 225/225/225 mg
Arm/Group Description	Participants randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.
Measure Participants	285	285	285
Participants with at least 1 abnormality	55 18.7%	54 18.6%	49 16.9%
Blood	29 9.9%	30 10.3%	23 7.9%
Urine glucose	5 1.7%	8 2.7%	2 0.7%
Ketones	5 1.7%	7 2.4%	9 3.1%
Urine protein	25 8.5%	19 6.5%	23 7.9%

12. Secondary Outcome

Title	Prothrombin Time Shifts From Baseline to Endpoint
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)

Outcome Measure Data

Analysis Population Description

Safety population of participants with both baseline and posttreatment values

Arm/Group Title	Placebo	Fremanezumab 675 mg/Placebo/Placebo	Fremanezumab 225/225/225 mg
Arm/Group Description	Participants randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.
Measure Participants	284	285	284
Low / Low	0 0%	0 0%	0 0%
Low / Normal	0 0%	1 0.3%	1 0.3%
Low / High	0 0%	0 0%	0 0%
Normal / Low	0 0%	1 0.3%	0 0%
Normal / Normal	254 86.4%	248 85.2%	250 86.2%
Normal / High	14 4.8%	10 3.4%	13 4.5%
High / Low	0 0%	0 0%	0 0%
High / Normal	8 2.7%	15 5.2%	12 4.1%
High / High	8 2.7%	10 3.4%	8 2.8%

13. Secondary Outcome

Title	Injection Site Reaction Adverse Events
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

Outcome Measure Data

Analysis Population Description

Safety population

Arm/Group Title	Placebo	Fremanezumab 675 mg/Placebo/Placebo	Fremanezumab 225/225/225 mg
Arm/Group Description	Participants randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.
Measure Participants	293	291	290
Participants with >=1 injection site reaction	106 36.1%	131 45%	130 44.8%
Injection site pain	76 25.9%	86 29.6%	87 30%
Injection site induration	45 15.3%	57 19.6%	71 24.5%
Injection site erythema	41 13.9%	55 18.9%	52 17.9%
Injection site haemorrhage	6 2%	9 3.1%	3 1%
Injection site pruritus	2 0.7%	4 1.4%	4 1.4%
Injection site swelling	0 0%	2 0.7%	3 1%
Injection site urticaria	2 0.7%	2 0.7%	1 0.3%
Injection site rash	0 0%	1 0.3%	3 1%
Fatigue	0 0%	1 0.3%	0 0%
Injection site bruising	1 0.3%	0 0%	0 0%
Injection site dermatitis	0 0%	0 0%	1 0.3%
Injection site hypersensitivity	0 0%	0 0%	1 0.3%
Injection site nodule	0 0%	0 0%	1 0.3%
Injection site oedema	0 0%	0 0%	1 0.3%
Injection site warmth	0 0%	1 0.3%	0 0%

14. Secondary Outcome

Title	Participants With Positive Electronic Columbia Suicide Severity Rating Scale Results After the First Dose of Study Drug
Description	The electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) was used to assess the patient's suicidal ideation (severity and intensity) and behavior (Posner et al 2011). The eC-SSRS Baseline/Screening version was completed by the patient at visit 2, and the eC-SSRS Since Last Visit version was completed by the patient at all other time points. Any positive findings on the eC-SSRS Since Last Visit version required evaluation by a physician or doctoral-level psychologist. Findings after the first dose of study drug using the eC-SSRS Since Last Visit version are summarized.
Time Frame	Day 1 to Week 12

Outcome Measure Data

Analysis Population Description

Safety population

Arm/Group Title	Placebo	Fremanezumab 675 mg/Placebo/Placebo	Fremanezumab 225/225/225 mg
Arm/Group Description	Participants randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.	Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56.	Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.
Measure Participants	294	291	289
Suicidal Ideation	0 0%	0 0%	2 0.7%
Suicidal Behaviour	0 0%	0 0%	0 0%

Adverse Events

Time Frame	Day 1 to Week 12
Arm/Group Title	Placebo		Fremanezumab 225/225/225 mg		Fremanezumab 675 mg/Placebo/Placebo
Arm/Group Description	Participants randomized to receive placebo received three 1.5-mL placebo injections Day 0, and a single 1.5-mL placebo injection on Days 28 and 56.		Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.		Participants 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.
All Cause Mortality
	Placebo		Fremanezumab 225/225/225 mg		Fremanezumab 675 mg/Placebo/Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/294 (0%)		0/289 (0%)		1/291 (0.3%)
Serious Adverse Events
	Placebo		Fremanezumab 225/225/225 mg		Fremanezumab 675 mg/Placebo/Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/294 (2.4%)		3/289 (1%)		3/291 (1%)
Gastrointestinal disorders
Intestinal haemorrhage	0/294 (0%)	0	0/289 (0%)	0	1/291 (0.3%)	1
General disorders
Death	0/294 (0%)	0	0/289 (0%)	0	1/291 (0.3%)	1
Immune system disorders
Drug hypersensitivity	1/294 (0.3%)	1	0/289 (0%)	0	0/291 (0%)	0
Infections and infestations
Appendicitis	0/294 (0%)	0	1/289 (0.3%)	1	0/291 (0%)	0
Injury, poisoning and procedural complications
Fall	1/294 (0.3%)	1	0/289 (0%)	0	0/291 (0%)	0
Road traffic accident	1/294 (0.3%)	1	0/289 (0%)	0	0/291 (0%)	0
Tendon injury	0/294 (0%)	0	0/289 (0%)	0	1/291 (0.3%)	1
Wrist fracture	1/294 (0.3%)	1	0/289 (0%)	0	0/291 (0%)	0
Metabolism and nutrition disorders
Hypoglycaemia	1/294 (0.3%)	1	0/289 (0%)	0	0/291 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lentigo maligna	1/294 (0.3%)	1	0/289 (0%)	0	0/291 (0%)	0
Nervous system disorders
Dizziness	1/294 (0.3%)	1	0/289 (0%)	0	0/291 (0%)	0
Generalised tonic-clonic seizure	0/294 (0%)	0	1/289 (0.3%)	1	0/291 (0%)	0
Status migrainosus	1/294 (0.3%)	2	0/289 (0%)	0	0/291 (0%)	0
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	1/294 (0.3%)	1	0/289 (0%)	0	0/291 (0%)	0
Reproductive system and breast disorders
Menorrhagia	0/294 (0%)	0	1/289 (0.3%)	1	0/291 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Fremanezumab 225/225/225 mg		Fremanezumab 675 mg/Placebo/Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	113/294 (38.4%)		132/289 (45.7%)		133/291 (45.7%)
General disorders
Injection site erythema	41/294 (13.9%)	88	52/289 (18%)	102	55/291 (18.9%)	110
Injection site induration	45/294 (15.3%)	93	71/289 (24.6%)	134	57/291 (19.6%)	126
Injection site pain	76/294 (25.9%)	191	87/289 (30.1%)	245	86/291 (29.6%)	234
Infections and infestations
Upper respiratory tract infection	15/294 (5.1%)	15	16/289 (5.5%)	17	11/291 (3.8%)	11

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.