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

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02964338
• Collaborator: (none)
• Enrollment: 259
• Locations: 83
• Arms: 3
• Actual Duration (Months): 18
• Patients Per Site: 3.1
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of the current study is to evaluate the efficacy and safety of Fremanezumab (TEV-48125), in the prevention of CCH in adult participants.

Condition or Disease	Intervention/Treatment	Phase
Chronic Cluster Headache	Drug: Fremanezumab; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 259 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, Double-Dummy, Placebo-Controlled, Parallel-Group Study Comparing the Efficacy and Safety of 2 Dose Regimens (Intravenous/Subcutaneous and Subcutaneous) of TEV-48125 Versus Placebo for the Prevention of Chronic Cluster Headache
• Actual Study Start Date: Jan 17, 2017
• Actual Primary Completion Date: Jul 18, 2018
• Actual Study Completion Date: Jul 18, 2018

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8.	Drug: Placebo; Placebo matching to fremanezumab will be administered as per the schedule specified in the respective arms.
Experimental: Fremanezumab 675/225/225 mg Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 milligrams (mg) as 3 subcutaneous injections (225 mg/1.5 milliliters [mL]) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.	Drug: Fremanezumab; Fremanezumab will be administered as per the dose and schedule specified in the respective arms.; Other Names: TEV-48125 ; Drug: Placebo; Placebo matching to fremanezumab will be administered as per the schedule specified in the respective arms.
Experimental: Fremanezumab 900/225/225 mg Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.	Drug: Fremanezumab; Fremanezumab will be administered as per the dose and schedule specified in the respective arms.; Other Names: TEV-48125 ; Drug: Placebo; Placebo matching to fremanezumab will be administered as per the schedule specified in the respective arms.

Outcome Measures

Primary Outcome Measures

1. Mean Change From Baseline in the Overall Monthly Average Number of CH Attacks Up to Week 12 [Baseline Period (from at least Week -4 to Week 0), Up to Week 12]

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

Secondary Outcome Measures

1. Percentage of Participants With a ≥50% Reduction From Baseline in the Monthly Average Number of CH Attacks Up to Week 12 [Baseline Period (from at least Week -4 to Week 0) up to Week 12]

   A CH attack was defined as a severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15 to 180 minutes with either or both of the following 2 categories: 1) at least 1 of the following symptoms or signs, ipsilateral to the headache: -conjunctival injection and/or lacrimation; -nasal congestion and/or rhinorrhea; -eyelid edema; -forehead and facial sweating; -forehead and facial flushing; -sensation of fullness in the ear; -miosis and/or ptosis. 2) a sense of restlessness or agitation.

2. Mean Change From Baseline in the Monthly Average Number of CH Attacks at Week 4 and Week 12 [Baseline Period (from at least Week -4 to Week 0), Week 4 and Week 12]

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

3. Mean Change From Baseline in the Overall Weekly Average Number of Days With Use of Cluster-Specific Acute Headache Medications (Triptans and Ergot Compounds) Up to Week 12 [Baseline Period (from at least Week -4 to Week 0), Up to Week 12]

   A maximum of 2 concomitant preventive medications for CH were allowed during the study. Participants must have been on a stable dose and regimen of the concomitant medication for at least 2 weeks before screening and throughout the study. Baseline data and the mean change from baseline in the overall weekly average number of days with the use of cluster-specific acute headache medications (triptans and ergot compounds) during the 12-week period after administration of the first dose of study drug (based on Week 0 to 12 data) is reported.

4. Mean Change From Baseline in the Weekly Average Number of Days Oxygen Was Used to Treat CCH Up to Week 12 [Baseline Period (from at least Week -4 to Week 0), Up to Week 12]

   Baseline data and the mean change from baseline in the overall weekly average number of days oxygen was used to treat CCH during the 12-week period after administration of the first dose of study drug (based on Week 0 to 12 data) is reported.

5. Number of Participants Who Perceived Improvement of CH-Associated Pain From Baseline as Measured by the Patient-Perceived Satisfactory Improvement (PPSI) Scale at Weeks 1, 4, 8, and 12 [Baseline and Weeks 1, 4, 8, and 12]

   The PPSI assessment was developed to measure pain intensity and was adjusted for CH symptoms improvement. Participants marked the level of CH-associated pain and indicated if pain is "1=much worse," "2=moderately worse," "3=slightly worse," "4=unchanged," "5=slightly improved," "6=moderately improved," or "7=much improved" compared with 4 weeks prior. PPSI was defined as the change in pain that corresponds with a minimal rating of "5=slightly improved." Data at Week 1 was recorded on Day 7 in the electronic diary device at home. Week 12 data also included assessment at the early withdrawal visit for participants who discontinued the study early.

6. Number of Participants With Adverse Events (AEs) [Baseline up to Week 12]

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

7. Number of Participants With Potentially Clinically Significant Laboratory (Serum Chemistry, Hematology, and Urinalysis) Abnormal Results [Baseline up to Week 12]

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

8. Number of Participants With Shift From Baseline to Endpoint in Coagulation Laboratory Test Results [Baseline up to Week 12]

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

9. Number of Participants With Potentially Clinically Significant Abnormal Vital Signs Values [Baseline up to Week 12]

   Potentially clinically significant abnormal vital signs findings included: pulse rate ≤50 beats/minute (bpm) and decrease of ≥15 bpm, or ≥120 bpm and increase of ≥15 bpm; systolic blood pressure ≤90 millimeters of mercury (mmHg) and decrease of ≥20 mmHg, or ≥180 mmHg and increase of ≥20 mmHg; diastolic blood pressure ≤50 mmHg and decrease of ≥15 mmHg, or ≥105 mmHg and increase of ≥15 mmHg; respiratory rate <10 breaths/minute; and body temperature ≥38.3 degrees centigrade and change of ≥1.1 degrees centigrade. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.

10. Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Electrocardiogram (ECG) Parameters [Baseline to Week 12]

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

11. Number of Participants With Injection Site Reactions [Baseline up to Week 12]

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

12. Number of Participants With Suicidal Ideation and Suicidal Behavior as Assessed by the Electronic Columbia Suicide Severity Rating Scale (eC-SSRS) [Baseline up to Week 12]

    eC-SSRS is a questionnaire to assess suicidal ideation and suicidal behavior. Suicidal behavior was defined as a "yes" answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide. Suicidal ideation was defined as a "yes" answer to any one of 5 suicidal ideation questions: wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent, any self-injurious behavior with no suicidal intent.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• The participant has a history of CCH according to the International Classification of Headache Disorders - 3 beta criteria (Headache Classification Committee of the International Headache Society [IHS] 2013) for greater than or equal to (≥)12 months prior to screening.

• The participant has a total body weight of ≥45 kilograms (kg) (99 pounds [lbs]).

• The participant is in good health in the opinion of the Investigator.

• Women of childbearing potential (WOCBP) whose male partners are potentially fertile (that is, no vasectomy) must use highly effective birth control methods for the duration of the study.

• Men must be sterile, or if they are potentially fertile/reproductively competent (not surgically [for example, vasectomy] or congenitally sterile) and their female partners are of childbearing potential, must agree to use, together with their female partners, acceptable birth control.

• If a participant is receiving Botox, it should be in a stable dose regimen, which is considered as having ≥2 cycles of Botox prior to screening. The participant should not receive Botox during the run-in period up to the evaluation period (12 weeks) where the primary endpoint is evaluated.

• Additional criteria apply, please contact the Investigator for more information.

Exclusion Criteria:

• The participant has used systemic steroids for any medical reason (including treatment of the current cluster headache (CH) cycle within less than or equal to (≤)7 days prior to screening. The participant has used an intervention/device (for example, scheduled nerve blocks) for headache during the 4 weeks prior to screening.

• The participant has clinically significant hematological, renal, endocrine, immunologic, pulmonary, gastrointestinal, genitourinary, cardiovascular, neurologic, hepatic, or ocular disease at the discretion of the Investigator.

• The participant has evidence or medical history of clinically significant psychiatric issues determined at the discretion of the Investigator.

• The participant has a past or current history of cancer or malignant tumor in the past 5 years, except for appropriately treated non-melanoma skin carcinoma.

• The participant is pregnant or lactating.

• The participant has a history of hypersensitivity reactions to injected proteins, including monoclonal antibodies.

• The participant has participated in a clinical study of a monoclonal antibody within 3 months or 5 half-lives before administration of the first dose of the investigational medicinal product (IMP), whichever is longer, unless it is known that the participant received placebo during the study.

• The participant has a history of prior exposure to a monoclonal antibody targeting the calcitonin gene-related peptide (CGRP) pathway (AMG 334, ALD304, LY2951742, or fremanezumab). If participant has participated in a clinical study with any of these monoclonal antibodies, it has to be confirmed that the participant received placebo in order to be eligible for this study.

• The participant is an employee of the sponsor/participating study center who is directly involved in the study or is the relative of such an employee.

• The participant has an active implant for neurostimulation used in the treatment of CH.

• The participant is a member of a vulnerable population (for example, people kept in detention).

• The participant has a history of alcohol abuse prior to screening and/or drug abuse that in the Investigator's opinion could interfere with the study evaluations or the participant's safety.

• Additional criteria apply, please contact the Investigator for more information.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Teva Investigational Site 13834	Phoenix	Arizona	United States	85018
2	Teva Investigational Site 13819	Canoga Park	California	United States	91303
3	Teva Investigational Site 13811	Santa Monica	California	United States	90404
4	Teva Investigational Site 13823	Stanford	California	United States	94305
5	Teva Investigational Site 13837	Aurora	Colorado	United States	80045
6	Teva Investigational Site 13814	Colorado Springs	Colorado	United States	80918
7	Teva Investigational Site 13836	Denver	Colorado	United States	80218
8	Teva Investigational Site 13813	Englewood	Colorado	United States	80113
9	Teva Investigational Site 13821	New Haven	Connecticut	United States	06510-2483
10	Teva Investigational Site 13812	Stamford	Connecticut	United States	06905
11	Teva Investigational Site 13810	Gainesville	Florida	United States	32607
12	Teva Investigational Site 13815	Orlando	Florida	United States	32806
13	Teva Investigational Site 13829	Ormond Beach	Florida	United States	32174
14	Teva Investigational Site 13830	Saint Petersburg	Florida	United States	33709
15	Teva Investigational Site 13840	Tampa	Florida	United States	33634
16	Teva Investigational Site 34222	Augusta	Georgia	United States	30901
17	Teva Investigational Site 13833	Columbus	Georgia	United States	31904
18	Teva Investigational Site 13826	Chicago	Illinois	United States	60614
19	Teva Investigational Site 13818	Ann Arbor	Michigan	United States	48104
20	Teva Investigational Site 13835	Las Vegas	Nevada	United States	89106
21	Teva Investigational Site 13832	Las Vegas	Nevada	United States	89113
22	Teva Investigational Site 13831	Lebanon	New Hampshire	United States	03756
23	Teva Investigational Site 13820	Princeton	New Jersey	United States	08540
24	Teva Investigational Site 13827	Albuquerque	New Mexico	United States	87102
25	Teva Investigational Site 13816	Amherst	New York	United States	14226
26	Teva Investigational Site 13817	New York	New York	United States	10019
27	Teva Investigational Site 13809	Raleigh	North Carolina	United States	27607
28	Teva Investigational Site 13839	Salisbury	North Carolina	United States	28144
29	Teva Investigational Site 13825	Cleveland	Ohio	United States	44195
30	Teva Investigational Site 13824	Philadelphia	Pennsylvania	United States	19107
31	Teva Investigational Site 13841	Richmond	Texas	United States	77307
32	Teva Investigational Site 13822	Virginia Beach	Virginia	United States	23454
33	Teva Investigational Site 78120	Auchenflower		Australia	4066
34	Teva Investigational Site 78118	Clayton		Australia	3168
35	Teva Investigational Site 78123	Melbourne		Australia	3004
36	Teva Investigational Site 78122	Parkville		Australia	3050
37	Teva Investigational Site 78121	Randwick		Australia	2031
38	Teva Investigational Site 11132	Newmarket	Ontario	Canada	L3Y5G8
39	Teva Investigational Site 11130	Calgary		Canada	T3M 1M4
40	Teva Investigational Site 11131	Toronto		Canada	H3A 2B4
41	Teva Investigational Site 40030	Helsinki		Finland	00180
42	Teva Investigational Site 40031	Oulu		Finland	90100
43	Teva Investigational Site 40029	Turku		Finland	20100
44	Teva Investigational Site 32666	Berlin		Germany	10117
45	Teva Investigational Site 32667	Bochum		Germany	44787
46	Teva Investigational Site 32660	Essen		Germany	45147
47	Teva Investigational Site 32665	Hamburg		Germany	20246
48	Teva Investigational Site 32662	Kiel		Germany	24149
49	Teva Investigational Site 32661	Konigstein im Taunus		Germany	61462
50	Teva Investigational Site 32663	Rostock		Germany	18147
51	Teva Investigational Site 80124	Ashkelon		Israel	7830604
52	Teva Investigational Site 80122	Hadera		Israel	3810101
53	Teva Investigational Site 80125	Holon		Israel	58100
54	Teva Investigational Site 80121	Jerusalem		Israel	9112001
55	Teva Investigational Site 80123	Netanya		Israel	4244916
56	Teva Investigational Site 80120	Ramat Gan		Israel	5265601
57	Teva Investigational Site 80127	Tel Aviv		Israel	64239
58	Teva Investigational Site 80126	Tel-Aviv		Israel	6812509
59	Teva Investigational Site 30190	Milan		Italy	20133
60	Teva Investigational Site 30192	Modena		Italy	41124
61	Teva Investigational Site 30194	Napoli		Italy	80131
62	Teva Investigational Site 30193	Pavia		Italy	27100
63	Teva Investigational Site 30191	Rome		Italy	00161
64	Teva Investigational Site 30189	Rome		Italy	163
65	Teva Investigational Site 38118	Leiden		Netherlands	2333 ZA
66	Teva Investigational Site 38119	Nijmegen		Netherlands	6532 SZ
67	Teva Investigational Site 38117	Zwolle		Netherlands	8025 AB
68	Teva Investigational Site 53380	Bialystok		Poland	15-402
69	Teva Investigational Site 53383	Krakow		Poland	31-505
70	Teva Investigational Site 53379	Krakow		Poland	33-332
71	Teva Investigational Site 53382	Lodz		Poland	90-338
72	Teva Investigational Site 53381	Szczecin		Poland	70-111
73	Teva Investigational Site 31211	Galdakao.		Spain	48960
74	Teva Investigational Site 31214	Madrid		Spain	28034
75	Teva Investigational Site 31213	Sevilla		Spain	41013
76	Teva Investigational Site 31212	Valladolid		Spain	47003
77	Teva Investigational Site 31215	Zaragoza		Spain	50009
78	Teva Investigational Site 42047	Huddinge		Sweden	141 86
79	Teva Investigational Site 42045	Vallingby		Sweden	162 68
80	Teva Investigational Site 34224	Glasgow		United Kingdom	G51 4TF
81	Teva Investigational Site 34220	London		United Kingdom	W6 8RF
82	Teva Investigational Site 34223	London		United Kingdom	WC1N 3BG
83	Teva Investigational Site 34221	Oxford		United Kingdom	OX2 6HE

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 - May 1, 2017
• Statistical Analysis Plan - Sep 19, 2018

More Information

Publications

None provided.

• Responsible Party: Teva Branded Pharmaceutical Products R&D, Inc.
• ClinicalTrials.gov Identifier: NCT02964338
• Other Study ID Numbers: TV48125-CNS-30057; 2016-003171-21
• First Posted: Nov 16, 2016
• 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: Cluster Headache; Headache

Study Results

Participant Flow

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

Arm/Group Title	Placebo	Fremanezumab 675/225/225 mg	Fremanezumab 900/225/225 mg
Arm/Group Description	Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8.	Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 milliliters [mL]) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.	Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.
Period Title: Overall Study
STARTED	84	88	87
Safety Analysis Set	83	88	87
Full Analysis Set	81	86	87
COMPLETED	67	64	68
NOT COMPLETED	17	24	19

Baseline Characteristics

Arm/Group Title	Placebo	Fremanezumab 675/225/225 mg	Fremanezumab 900/225/225 mg	Total
Arm/Group Description	Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8.	Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.	Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.	Total of all reporting groups
Overall Participants	84	88	87	259
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	46.3 (11.29)	45.3 (11.40)	43.8 (12.92)	45.1 (11.90)
Sex: Female, Male (Count of Participants)
Female	35 41.7%	36 40.9%	36 41.4%	107 41.3%
Male	49 58.3%	52 59.1%	51 58.6%	152 58.7%
Race/Ethnicity, Customized (participants) [Number]
White	79 94%	83 94.3%	79 90.8%	241 93.1%
Black or African American	4 4.8%	4 4.5%	8 9.2%	16 6.2%
Asian	0 0%	1 1.1%	0 0%	1 0.4%
American Indian or Alaska native	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Middle Eastern	1 1.2%	0 0%	0 0%	1 0.4%
Not Hispanic or Latino	77 91.7%	78 88.6%	83 95.4%	238 91.9%
Hispanic or Latino	5 6%	9 10.2%	4 4.6%	18 6.9%
Missing Ethnicity	2 2.4%	1 1.1%	0 0%	3 1.2%
Number of CH Attacks During the Baseline Period (CH attacks) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [CH attacks]	38.0 (33.88)	33.9 (27.37)	44.0 (43.78)	38.6 (35.75)

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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

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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Fremanezumab 675/225/225 mg
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2741
	Comments	Threshold for significance at 0.05 level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least square (LS) mean difference
	Estimated Value	3.5
	Confidence Interval	(2-Sided) 95%; -2.80 to 9.82
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Fremanezumab 900/225/225 mg
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3047
	Comments	Threshold for significance at 0.05 level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-3.3
	Confidence Interval	(2-Sided) 95%; -9.59 to 3.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo	Fremanezumab 675/225/225 mg	Fremanezumab 900/225/225 mg
Arm/Group Description	Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8.	Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.	Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.
Measure Participants	81	86	87
Number [percentage of participants]	40 47.6%	40 45.5%	45 51.7%

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo	Fremanezumab 675/225/225 mg	Fremanezumab 900/225/225 mg
Arm/Group Description	Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8.	Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.	Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.
Measure Participants	81	86	87
Change at Week 4	-10.4 (17.22)	-7.7 (19.53)	-15.0 (24.17)
Change at Week 12	-12.6 (25.72)	-3.1 (34.42)	-17.9 (25.98)

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

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

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

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

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo	Fremanezumab 675/225/225 mg	Fremanezumab 900/225/225 mg
Arm/Group Description	Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8.	Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.	Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.
Measure Participants	81	86	87
Much worse, Baseline	3 3.6%	1 1.1%	1 1.1%
Moderately worse, Baseline	1 1.2%	4 4.5%	4 4.6%
Slightly worse, Baseline	1 1.2%	5 5.7%	4 4.6%
Unchanged, Baseline	69 82.1%	72 81.8%	75 86.2%
Slightly improved, Baseline	5 6%	3 3.4%	3 3.4%
Moderately improved, Baseline	1 1.2%	1 1.1%	0 0%
Much improved, Baseline	1 1.2%	0 0%	0 0%
Missing, Baseline	0 0%	0 0%	0 0%
Much worse, Week 1	0 0%	3 3.4%	3 3.4%
Moderately worse, Week 1	0 0%	2 2.3%	1 1.1%
Slightly worse, Week 1	0 0%	2 2.3%	5 5.7%
Unchanged, Week 1	35 41.7%	31 35.2%	26 29.9%
Slightly improved, Week 1	23 27.4%	20 22.7%	32 36.8%
Moderately improved, Week 1	5 6%	4 4.5%	8 9.2%
Much improved, Week 1	6 7.1%	13 14.8%	8 9.2%
Missing, Week 1	12 14.3%	11 12.5%	4 4.6%
Much worse, Week 4	0 0%	1 1.1%	0 0%
Moderately worse, Week 4	1 1.2%	2 2.3%	3 3.4%
Slightly worse, Week 4	1 1.2%	2 2.3%	2 2.3%
Unchanged, Week 4	24 28.6%	24 27.3%	25 28.7%
Slightly improved, Week 4	30 35.7%	17 19.3%	25 28.7%
Moderately improved, Week 4	5 6%	9 10.2%	12 13.8%
Much improved, Week 4	12 14.3%	18 20.5%	11 12.6%
Missing, Week 4	8 9.5%	13 14.8%	9 10.3%
Much worse, Week 8	3 3.6%	2 2.3%	0 0%
Moderately worse, Week 8	1 1.2%	3 3.4%	3 3.4%
Slightly worse, Week 8	3 3.6%	4 4.5%	5 5.7%
Unchanged, Week 8	27 32.1%	18 20.5%	24 27.6%
Slightly improved, Week 8	18 21.4%	12 13.6%	13 14.9%
Moderately improved, Week 8	10 11.9%	13 14.8%	14 16.1%
Much improved, Week 8	4 4.8%	12 13.6%	15 17.2%
Missing, Week 8	15 17.9%	22 25%	13 14.9%
Much worse, Week 12	0 0%	2 2.3%	1 1.1%
Moderately worse, Week 12	3 3.6%	5 5.7%	3 3.4%
Slightly worse, Week 12	4 4.8%	6 6.8%	6 6.9%
Unchanged, Week 12	29 34.5%	27 30.7%	31 35.6%
Slightly improved, Week 12	21 25%	18 20.5%	15 17.2%
Moderately improved, Week 12	8 9.5%	11 12.5%	11 12.6%
Much improved, Week 12	13 15.5%	14 15.9%	12 13.8%
Missing, Week 12	3 3.6%	3 3.4%	8 9.2%

7. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs)
Description	An AE was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the Investigator on a scale of mild, moderate and severe, with severe as an AE that prevents usual activities. Relationship of AE to treatment was determined by the Investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent the previously listed serious outcomes. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
Time Frame	Baseline up to Week 12

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo	Fremanezumab 675/225/225 mg	Fremanezumab 900/225/225 mg
Arm/Group Description	Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8.	Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.	Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.
Measure Participants	83	88	87
Any AE	43 51.2%	51 58%	49 56.3%
Severe AE	3 3.6%	1 1.1%	3 3.4%
Treatment-related AE	17 20.2%	23 26.1%	28 32.2%
Serious AE	2 2.4%	2 2.3%	3 3.4%
AE leading to discontinuation	2 2.4%	1 1.1%	2 2.3%

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

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

9. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo	Fremanezumab 675/225/225 mg	Fremanezumab 900/225/225 mg
Arm/Group Description	Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8.	Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.	Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.
Measure Participants	83	88	87
PT: Low-Low	0 0%	0 0%	0 0%
PT: Low-Normal	0 0%	0 0%	0 0%
PT: Low-High	0 0%	0 0%	0 0%
PT: Normal-Low	0 0%	0 0%	0 0%
PT: Normal-Normal	68 81%	69 78.4%	62 71.3%
PT: Normal-High	3 3.6%	2 2.3%	5 5.7%
PT: High-Low	0 0%	0 0%	0 0%
PT: High-Normal	5 6%	8 9.1%	11 12.6%
PT: High-High	5 6%	4 4.5%	3 3.4%
PT: Missing	2 2.4%	5 5.7%	6 6.9%
Prothrombin INR: Low-Low	0 0%	0 0%	0 0%
Prothrombin INR: Low-Normal	0 0%	0 0%	0 0%
Prothrombin INR: Low-High	0 0%	0 0%	0 0%
Prothrombin INR: Normal-Low	0 0%	0 0%	0 0%
Prothrombin INR: Normal-Normal	70 83.3%	71 80.7%	69 79.3%
Prothrombin INR: Normal-High	4 4.8%	2 2.3%	5 5.7%
Prothrombin INR: High-Low	0 0%	0 0%	0 0%
Prothrombin INR: High-Normal	5 6%	7 8%	6 6.9%
Prothrombin INR: High-High	2 2.4%	3 3.4%	1 1.1%
Prothrombin INR: Missing	2 2.4%	5 5.7%	6 6.9%

10. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

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

11. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo	Fremanezumab 675/225/225 mg	Fremanezumab 900/225/225 mg
Arm/Group Description	Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8.	Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.	Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.
Measure Participants	83	88	87
Normal / Normal	47 56%	46 52.3%	45 51.7%
Normal / NCS	8 9.5%	11 12.5%	14 16.1%
Normal / CS	0 0%	0 0%	0 0%
NCS / Normal	10 11.9%	7 8%	8 9.2%
NCS / NCS	15 17.9%	20 22.7%	12 13.8%
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%
Missing	3 3.6%	4 4.5%	8 9.2%

12. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Placebo	Fremanezumab 675/225/225 mg	Fremanezumab 900/225/225 mg
Arm/Group Description	Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8.	Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.	Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.
Measure Participants	83	88	87
Injection site erythema	3 3.6%	7 8%	5 5.7%
Injection site induration	3 3.6%	6 6.8%	6 6.9%
Injection site pain	6 7.1%	5 5.7%	2 2.3%
Injection site haemorrhage	0 0%	0 0%	2 2.3%
Injection site bruising	0 0%	0 0%	1 1.1%
Injection site hypersensitivity	0 0%	1 1.1%	0 0%
Injection site swelling	2 2.4%	0 0%	0 0%
Injection site rash	1 1.2%	0 0%	0 0%
Injection site flushing	0 0%	1 1.1%	0 0%

13. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

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

Adverse Events

Time Frame	Baseline up to Week 12
Adverse Event Reporting Description	Safety population included all randomized participants who received at least 1 dose of study drug.
Arm/Group Title	Placebo		Fremanezumab 675/225/225 mg		Fremanezumab 900/225/225 mg
Arm/Group Description	Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8.		Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 mg as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.		Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.
All Cause Mortality
	Placebo		Fremanezumab 675/225/225 mg		Fremanezumab 900/225/225 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/83 (0%)		0/88 (0%)		0/87 (0%)
Serious Adverse Events
	Placebo		Fremanezumab 675/225/225 mg		Fremanezumab 900/225/225 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/83 (2.4%)		2/88 (2.3%)		3/87 (3.4%)
Gastrointestinal disorders
Gastric haemorrhage	0/83 (0%)	0	1/88 (1.1%)	1	0/87 (0%)	0
Pancreatitis acute	1/83 (1.2%)	1	0/88 (0%)	0	0/87 (0%)	0
General disorders
Infusion site necrosis	0/83 (0%)	0	0/88 (0%)	0	1/87 (1.1%)	1
Hepatobiliary disorders
Cholecystitis	0/83 (0%)	0	0/88 (0%)	0	1/87 (1.1%)	1
Immune system disorders
Anaphylactic reaction	0/83 (0%)	0	1/88 (1.1%)	1	0/87 (0%)	0
Infections and infestations
Cellulitis	0/83 (0%)	0	0/88 (0%)	0	1/87 (1.1%)	1
Pelvic abscess	0/83 (0%)	0	0/88 (0%)	0	1/87 (1.1%)	1
Psychiatric disorders
Conversion disorder	1/83 (1.2%)	1	0/88 (0%)	0	0/87 (0%)	0
Surgical and medical procedures
Hospitalisation	0/83 (0%)	0	0/88 (0%)	0	1/87 (1.1%)	1
Other (Not Including Serious) Adverse Events
	Placebo		Fremanezumab 675/225/225 mg		Fremanezumab 900/225/225 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/83 (21.7%)		22/88 (25%)		19/87 (21.8%)
Gastrointestinal disorders
Nausea	4/83 (4.8%)	4	5/88 (5.7%)	5	3/87 (3.4%)	4
General disorders
Injection site erythema	3/83 (3.6%)	4	7/88 (8%)	15	5/87 (5.7%)	6
Injection site induration	3/83 (3.6%)	8	6/88 (6.8%)	12	6/87 (6.9%)	12
Injection site pain	6/83 (7.2%)	11	5/88 (5.7%)	9	2/87 (2.3%)	2
Infections and infestations
Nasopharyngitis	6/83 (7.2%)	7	6/88 (6.8%)	7	8/87 (9.2%)	9

Limitations/Caveats

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

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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.