A Study to Evaluate the Efficacy and Safety of TEV-48125 (Fremanezumab) for the Prevention of Episodic Cluster Headache (ECH)

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02945046
• Collaborator: (none)
• Enrollment: 169
• Locations: 82
• Arms: 3
• Actual Duration (Months): 27.7
• Patients Per Site: 2.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a 13-week, multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel-group study to compare the efficacy and safety of 2 dose regimens of TEV-48125 (Fremanezumab) versus placebo in adult participants for the prevention of ECH.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 169 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 Epidosic Cluster Headache
• Actual Study Start Date: Jan 19, 2017
• Actual Primary Completion Date: May 13, 2019
• Actual Study Completion Date: May 13, 2019

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Mean Change From Baseline in the Weekly Average Number of Cluster Headache (CH) Attacks During the 4-Week Period After Administration of the First Dose of the IMP [Baseline (Week 0), up to Week 4]

   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 weekly average number of CH attacks during the 4-week period after administration of the first dose of study drug (based on Week 0 to 4 data) is reported.

Secondary Outcome Measures

1. Percentage of Participants With a ≥50% Reduction From Baseline in the Weekly Average Number of CH Attacks During the 4-Week Period After the First Dose of the IMP [Baseline (Week 0), up to Week 4]

   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 Weekly Average Number of CH Attacks During the 12-Week Period After Administration of the First Dose of the IMP [Baseline (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. LS mean calculated using mixed model for repeated measures (MMRM) with baseline preventive medication use (yes or no), gender, region (US/Canada or other), treatment, month, and month-by-treatment interaction as fixed effects and baseline number of CH attacks as a covariate. Change from baseline in the overall weekly 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.

3. Mean Change From Baseline in Weekly Average Number of CH Attacks During the 4-Week Period After Administration of the Third Dose of the IMP [Baseline (Week 0), Week 8 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. LS mean calculated using MMRM with baseline preventive medication use (yes or no), gender, region (US/Canada or other), treatment, month, and month-by-treatment interaction as fixed effects and baseline number of CH attacks as a covariate. Change from baseline in the overall weekly average number of CH attacks during the 4-week period after administration of the first dose of study drug (based on Week 8 to 12 data) is reported.

4. Mean Change From Baseline in the Weekly Average Number of Days With Use of Cluster-Specific Acute Headache Medications (Triptans and Ergot Compounds) During the 12-Week Period After the First Dose of the IMP [Baseline (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. LS mean calculated using ANCOVA model with baseline preventive medication use (yes or no), gender, region (US/Canada or other), and treatment as fixed effects and the baseline number of cluster headache attacks as a covariate. 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.

5. Mean Change From Baseline in the Weekly Average Number of Days Oxygen Was Used to Treat Episodic Cluster Headache (ECH) During the 12-Week Period After the First Dose of the IMP [Baseline (Week 0), up to Week 12]

   LS mean calculated using ANCOVA model with baseline preventive medication use (yes or no), gender, region (US/Canada or other), and treatment as fixed effects and the baseline number of cluster headache attacks as a covariate. Baseline data and the mean change from baseline in the overall weekly average number of days oxygen was used to treat ECH during the 12-week period after administration of the first dose of IMP (based on Week 0 to 12 data) is reported.

6. 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, 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.

7. 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. 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.

8. 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 (ALP), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), lactate dehydrogenase (LDH) each ≥3*upper limit of normal (ULN); blood urea nitrogen (BUN) ≥10.71 millimole (mmol)/L; Bilirubin (Total) ≥34.2 micromole/liter (umol/L); Blood Urea Nitrogen ≥10.71 millimoles (mmol)/L; creatinine ≥177 umol/L; hemoglobin less than or equal to (≤)115 grams (g)/L (males) or ≤95 g/L (females); leukocytes ≥20*10^9/L or ≤3*10^9/L; eosinophils ≥10%; hematocrit <0.37 L/L (males) and <0.32 L/L (females); platelets ≥700*10^9/L or ≤75*10^9/L; haemoglobin, urine glucose, ketones, urine total protein each ≥2 unit (U) increase from baseline. 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 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.

10. 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 ≥120 beats per minute (bpm) and increase of 15 bpm; systolic blood pressure ≤90 millimeters of mercury (mmHg) and decrease of 20 mmHg; diastolic blood pressure ≤50 mmHg and decrease of 15 mmHg, or ≥105 mmHg and increase of 15 mmHg. 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 Shift From Baseline to Endpoint (Last Assessment) in Electrocardiogram (ECG) Parameters [Baseline up 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.

12. Number of Participants Who Received Concomitant Medications [Baseline up to Week 12]

    Concomitant medications included: agents acting on the renin-angiotensin system, all other therapeutic products (for example: homeopathic preparation), allergens, analgesics, anesthetics, anti-parkinson drugs, antianemic preparations, antibacterials for systemic use, antibiotics and chemotherapeutics for dermatological use, antidiarrheals, intestinal antiinflammatory/antiinfective agents, antiemetic, antiepileptics, antifungals for dermatologiocal use, antigout preparations, antihemorrhagics, antihistamines for systemic use, antihypertensives, antiinflammatory and antirheumatic products, antimycotics for systemic use, antipruritics, antipsoriatics, antivirals for systemic use, beta blocking agents, blood substitutes and perfusion solutions, cardiac therapy, corticosteroids, cough and cold preparations, diagnostic radiopharmaceuticals, diuretics, thyroid therapy, urologicals, vaccines, psycoleptics, psycoanaleptics, ophthalmologicals, muscle relaxants, drugs used in diabetes etc.

13. 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, swelling, and pruritus. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.

14. Number of Participants With Hypersensitivity/Anaphylaxis Reactions [Baseline up to Week 12]

    A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.

15. 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 ECH according to the International Classification of Headache Disorders - 3 beta criteria (Headache Classification Committee of the International Headache Society [IHS] 2013) for ≥12 months prior to screening.

• The participant has a total body weight of ≥45 kg (99 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 for the duration of the study.

• If a participant is receiving Botox, it should be in a stable dose regimen, 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 (4 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 CH cycle within ≤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 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 13833	Columbus	Georgia	United States	31904
17	Teva Investigational Site 13826	Chicago	Illinois	United States	60614
18	Teva Investigational Site 13818	Ann Arbor	Michigan	United States	48104
19	Teva Investigational Site 13835	Las Vegas	Nevada	United States	89106
20	Teva Investigational Site 13832	Las Vegas	Nevada	United States	89113
21	Teva Investigational Site 13831	Lebanon	New Hampshire	United States	03756
22	Teva Investigational Site 13820	Princeton	New Jersey	United States	08540
23	Teva Investigational Site 13827	Albuquerque	New Mexico	United States	87102
24	Teva Investigational Site 13816	Amherst	New York	United States	14226
25	Teva Investigational Site 13817	New York	New York	United States	10019
26	Teva Investigational Site 13809	Raleigh	North Carolina	United States	27607
27	Teva Investigational Site 13839	Salisbury	North Carolina	United States	28144
28	Teva Investigational Site 13825	Cleveland	Ohio	United States	44195
29	Teva Investigational Site 13824	Philadelphia	Pennsylvania	United States	19107
30	Teva Investigational Site 13841	Richmond	Texas	United States	77307
31	Teva Investigational Site 13822	Virginia Beach	Virginia	United States	23454
32	Teva Investigational Site 78120	Auchenflower		Australia	4066
33	Teva Investigational Site 78118	Clayton		Australia	3168
34	Teva Investigational Site 78123	Melbourne		Australia	3004
35	Teva Investigational Site 78122	Parkville		Australia	3050
36	Teva Investigational Site 78121	Randwick		Australia	2031
37	Teva Investigational Site 11130	Calgary		Canada	T3M 1M4
38	Teva Investigational Site 11131	Toronto		Canada	H3A 2B4
39	Teva Investigational Site 40030	Helsinki		Finland	00180
40	Teva Investigational Site 40031	Oulu		Finland	90100
41	Teva Investigational Site 40029	Turku		Finland	20100
42	Teva Investigational Site 32666	Berlin		Germany	10177
43	Teva Investigational Site 32667	Bochum		Germany	44787
44	Teva Investigational Site 32660	Essen		Germany	45147
45	Teva Investigational Site 32665	Hamburg		Germany	20246
46	Teva Investigational Site 32662	Kiel		Germany	24149
47	Teva Investigational Site 32661	Konigstein im Taunus		Germany	61462
48	Teva Investigational Site 32663	Rostock		Germany	18147
49	Teva Investigational Site 80124	Ashkelon		Israel	7830604
50	Teva Investigational Site 80122	Hadera		Israel	3810101
51	Teva Investigational Site 80125	Holon		Israel	58100
52	Teva Investigational Site 80121	Jerusalem		Israel	9112001
53	Teva Investigational Site 80123	Netanya		Israel	4244916
54	Teva Investigational Site 80120	Ramat Gan		Israel	5265601
55	Teva Investigational Site 80127	Tel Aviv		Israel	64239
56	Teva Investigational Site 80126	Tel-Aviv		Israel	6812509
57	Teva Investigational Site 30190	Milan		Italy	20133
58	Teva Investigational Site 30192	Modena		Italy	41124
59	Teva Investigational Site 30194	Napoli		Italy	80131
60	Teva Investigational Site 30193	Pavia		Italy	27100
61	Teva Investigational Site 30191	Rome		Italy	00161
62	Teva Investigational Site 30189	Rome		Italy	00163
63	Teva Investigational Site 38118	Leiden		Netherlands	2333 ZA
64	Teva Investigational Site 38119	Nijmegen		Netherlands	6532 SZ
65	Teva Investigational Site 38117	Zwolle		Netherlands	8025 AB
66	Teva Investigational Site 53380	Bialystok		Poland	15-402
67	Teva Investigational Site 53383	Krakow		Poland	31-505
68	Teva Investigational Site 53379	Krakow		Poland	33-332
69	Teva Investigational Site 53382	Lodz		Poland	90-338
70	Teva Investigational Site 53381	Szczecin		Poland	70-111
71	Teva Investigational Site 31211	Galdakao.		Spain	48960
72	Teva Investigational Site 31214	Madrid		Spain	28034
73	Teva Investigational Site 31213	Sevilla		Spain	41013
74	Teva Investigational Site 31212	Valladolid		Spain	47003
75	Teva Investigational Site 31215	Zaragoza		Spain	50009
76	Teva Investigational Site 42047	Huddinge		Sweden	141 86
77	Teva Investigational Site 42045	Vallingby		Sweden	162 68
78	Teva Investigational Site 34224	Glasgow		United Kingdom	G51 4TF
79	Teva Investigational Site 34222	Liverpool		United Kingdom	L9 7LJ
80	Teva Investigational Site 34223	London		United Kingdom	SE1 9RT
81	Teva Investigational Site 34220	London		United Kingdom	W6 8RF
82	Teva Investigational Site 34221	Oxford		United Kingdom	OX3 9DU

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 - Jun 19, 2019

More Information

Publications

None provided.

• Responsible Party: Teva Branded Pharmaceutical Products R&D, Inc.
• ClinicalTrials.gov Identifier: NCT02945046
• Other Study ID Numbers: TV48125-CNS-30056; 2016-003278-42
• First Posted: Oct 26, 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

Pre-assignment Detail	A total of 169 participants were randomized in a 1:1:1 ratio to placebo, fremanezumab 675 milligrams (mg)/placebo/placebo, or fremanezumab 900/225/225 mg groups.

Arm/Group Title	Placebo	Fremanezumab 675 mg/Placebo/Placebo	Fremanezumab 900/225/225 mg
Arm/Group Description	Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 milligrams (mg) administered as 3 subcutaneous injections (225 mg/1.5 milliliters [mL]) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Period Title: Overall Study
STARTED	59	55	55
Safety Analysis Set	59	55	55
Full Analysis Set	57	53	55
COMPLETED	46	42	40
NOT COMPLETED	13	13	15

Baseline Characteristics

Arm/Group Title	Placebo	Fremanezumab 675 mg/Placebo/Placebo	Fremanezumab 900/225/225 mg	Total
Arm/Group Description	Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Total of all reporting groups
Overall Participants	59	55	55	169
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43.1 (10.39)	45.4 (11.23)	43.5 (11.48)	43.9 (11.01)
Sex: Female, Male (Count of Participants)
Female	16 27.1%	17 30.9%	17 30.9%	50 29.6%
Male	43 72.9%	38 69.1%	38 69.1%	119 70.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 3.4%	3 5.5%	5 9.1%	10 5.9%
Not Hispanic or Latino	56 94.9%	52 94.5%	49 89.1%	157 92.9%
Unknown or Not Reported	1 1.7%	0 0%	1 1.8%	2 1.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	1 1.7%	0 0%	1 1.8%	2 1.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	3 5.1%	0 0%	2 3.6%	5 3%
White	54 91.5%	55 100%	51 92.7%	160 94.7%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	1 1.7%	0 0%	1 1.8%	2 1.2%
Number of CH Attacks (CH attacks) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [CH attacks]	14.8 (10.50)	15.9 (9.18)	14.5 (7.55)	15.1 (9.15)

Outcome Measures

1. Primary Outcome

Title	Mean Change From Baseline in the Weekly Average Number of Cluster Headache (CH) Attacks During the 4-Week Period After Administration of the First Dose of the IMP
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 weekly average number of CH attacks during the 4-week period after administration of the first dose of study drug (based on Week 0 to 4 data) is reported.
Time Frame	Baseline (Week 0), up to Week 4

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants who received at least 1 dose of IMP and had at least 10 days of postbaseline efficacy assessment in the first 4 weeks on the primary endpoint.

Arm/Group Title	Placebo	Fremanezumab 675 mg/Placebo/Placebo	Fremanezumab 900/225/225 mg
Arm/Group Description	Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Measure Participants	57	53	55
Least Squares Mean (Standard Error) [CH attacks/week]	-5.7 (1.00)	-5.8 (1.02)	-7.6 (1.01)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fremanezumab 675 mg/Placebo/Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9093
	Comments	Threshold for significance at 0.05 level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -2.72 to 2.42
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.30
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Fremanezumab 900/225/225 mg
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1345
	Comments	Threshold for significance at 0.05 level.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.9
	Confidence Interval	(2-Sided) 95%; -4.49 to 0.61
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.29
	Estimation Comments

2. Secondary Outcome

Title	Percentage of Participants With a ≥50% Reduction From Baseline in the Weekly Average Number of CH Attacks During the 4-Week Period After the First Dose of the IMP
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 (Week 0), up to Week 4

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants who received at least 1 dose of IMP and had at least 10 days of postbaseline efficacy assessment in the first 4 weeks on the primary endpoint.

Arm/Group Title	Placebo	Fremanezumab 675 mg/Placebo/Placebo	Fremanezumab 900/225/225 mg
Arm/Group Description	Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Measure Participants	57	53	55
Number [percentage of participants]	60 101.7%	55 100%	75 136.4%

3. Secondary Outcome

Title	Mean Change From Baseline in Weekly Average Number of CH Attacks During the 12-Week Period After Administration of the First Dose of the IMP
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. LS mean calculated using mixed model for repeated measures (MMRM) with baseline preventive medication use (yes or no), gender, region (US/Canada or other), treatment, month, and month-by-treatment interaction as fixed effects and baseline number of CH attacks as a covariate. Change from baseline in the overall weekly 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 (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 IMP and had at least 10 days of postbaseline efficacy assessment in the first 4 weeks on the primary endpoint.

Arm/Group Title	Placebo	Fremanezumab 675 mg/Placebo/Placebo	Fremanezumab 900/225/225 mg
Arm/Group Description	Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Measure Participants	57	53	55
Least Squares Mean (Standard Error) [CH attacks/week]	-8.4 (0.66)	-8.9 (0.68)	-9.6 (0.67)

4. Secondary Outcome

Title	Mean Change From Baseline in Weekly Average Number of CH Attacks During the 4-Week Period After Administration of the Third Dose of the IMP
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. LS mean calculated using MMRM with baseline preventive medication use (yes or no), gender, region (US/Canada or other), treatment, month, and month-by-treatment interaction as fixed effects and baseline number of CH attacks as a covariate. Change from baseline in the overall weekly average number of CH attacks during the 4-week period after administration of the first dose of study drug (based on Week 8 to 12 data) is reported.
Time Frame	Baseline (Week 0), Week 8 up to Week 12

Outcome Measure Data

Analysis Population Description

Full analysis set included all randomized participants who received at least 1 dose of IMP and had at least 10 days of postbaseline efficacy assessment in the first 4 weeks on the primary endpoint. Here, 'overall number of participants analyzed'=participants evaluable for this outcome measure.

Arm/Group Title	Placebo	Fremanezumab 675 mg/Placebo/Placebo	Fremanezumab 900/225/225 mg
Arm/Group Description	Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Measure Participants	46	42	40
Least Squares Mean (Standard Error) [CH attacks/week]	-10.8 (0.75)	-10.8 (0.78)	-10.9 (0.78)

5. Secondary Outcome

Title	Mean Change From Baseline in the Weekly Average Number of Days With Use of Cluster-Specific Acute Headache Medications (Triptans and Ergot Compounds) During the 12-Week Period After the First Dose of the IMP
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. LS mean calculated using ANCOVA model with baseline preventive medication use (yes or no), gender, region (US/Canada or other), and treatment as fixed effects and the baseline number of cluster headache attacks as a covariate. 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 (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 IMP and had at least 10 days of postbaseline efficacy assessment in the first 4 weeks on the primary endpoint.

Arm/Group Title	Placebo	Fremanezumab 675 mg/Placebo/Placebo	Fremanezumab 900/225/225 mg
Arm/Group Description	Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Measure Participants	57	53	55
Least Squares Mean (Standard Error) [days of use/week]	-1.6 (0.36)	-2.4 (0.36)	-2.8 (0.36)

6. Secondary Outcome

Title	Mean Change From Baseline in the Weekly Average Number of Days Oxygen Was Used to Treat Episodic Cluster Headache (ECH) During the 12-Week Period After the First Dose of the IMP
Description	LS mean calculated using ANCOVA model with baseline preventive medication use (yes or no), gender, region (US/Canada or other), and treatment as fixed effects and the baseline number of cluster headache attacks as a covariate. Baseline data and the mean change from baseline in the overall weekly average number of days oxygen was used to treat ECH during the 12-week period after administration of the first dose of IMP (based on Week 0 to 12 data) is reported.
Time Frame	Baseline (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 IMP and had at least 10 days of postbaseline efficacy assessment in the first 4 weeks on the primary endpoint.

Arm/Group Title	Placebo	Fremanezumab 675 mg/Placebo/Placebo	Fremanezumab 900/225/225 mg
Arm/Group Description	Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Measure Participants	57	53	55
Least Squares Mean (Standard Error) [days of use/week]	-1.1 (0.30)	-1.5 (0.31)	-1.0 (0.30)

7. 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, 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 IMP and had at least 10 days of postbaseline efficacy assessment in the first 4 weeks on the primary endpoint.

Arm/Group Title	Placebo	Fremanezumab 675 mg/Placebo/Placebo	Fremanezumab 900/225/225 mg
Arm/Group Description	Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Measure Participants	57	53	55
Much worse	10 16.9%	14 25.5%	7 12.7%
Moderately worse	3 5.1%	5 9.1%	8 14.5%
Slightly worse	3 5.1%	3 5.5%	3 5.5%
Unchanged	37 62.7%	31 56.4%	28 50.9%
Slightly improved	3 5.1%	0 0%	6 10.9%
Moderately improved	1 1.7%	0 0%	1 1.8%
Much improved	0 0%	0 0%	2 3.6%
Missing	0 0%	0 0%	0 0%
Much worse	2 3.4%	4 7.3%	1 1.8%
Moderately worse	2 3.4%	2 3.6%	1 1.8%
Slightly worse	5 8.5%	3 5.5%	2 3.6%
Unchanged	19 32.2%	11 20%	9 16.4%
Slightly improved	11 18.6%	8 14.5%	14 25.5%
Moderately improved	5 8.5%	3 5.5%	6 10.9%
Much improved	6 10.2%	12 21.8%	12 21.8%
Missing	7 11.9%	10 18.2%	10 18.2%
Much worse	1 1.7%	1 1.8%	2 3.6%
Moderately worse	3 5.1%	0 0%	1 1.8%
Slightly worse	4 6.8%	2 3.6%	0 0%
Unchanged	8 13.6%	11 20%	5 9.1%
Slightly improved	9 15.3%	9 16.4%	8 14.5%
Moderately improved	5 8.5%	7 12.7%	8 14.5%
Much improved	23 39%	19 34.5%	27 49.1%
Missing	4 6.8%	4 7.3%	4 7.3%
Much worse	1 1.7%	1 1.8%	0 0%
Moderately worse	3 5.1%	0 0%	1 1.8%
Slightly worse	0 0%	1 1.8%	1 1.8%
Unchanged	13 22%	8 14.5%	12 21.8%
Slightly improved	1 1.7%	6 10.9%	5 9.1%
Moderately improved	7 11.9%	6 10.9%	7 12.7%
Much improved	20 33.9%	20 36.4%	17 30.9%
Missing	12 20.3%	11 20%	12 21.8%
Much worse	3 5.1%	2 3.6%	2 3.6%
Moderately worse	0 0%	0 0%	1 1.8%
Slightly worse	2 3.4%	1 1.8%	0 0%
Unchanged	16 27.1%	16 29.1%	16 29.1%
Slightly improved	5 8.5%	5 9.1%	4 7.3%
Moderately improved	8 13.6%	7 12.7%	5 9.1%
Much improved	17 28.8%	19 34.5%	24 43.6%
Missing	6 10.2%	3 5.5%	3 5.5%

8. 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. 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 analysis set included all randomized participants who received at least 1 dose of the IMP.

Arm/Group Title	Placebo	Fremanezumab 675 mg/Placebo/Placebo	Fremanezumab 900/225/225 mg
Arm/Group Description	Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Measure Participants	59	55	55
Any AEs	28 47.5%	26 47.3%	28 50.9%
Treatment-related AEs	8 13.6%	11 20%	13 23.6%
Serious AEs	5 8.5%	0 0%	1 1.8%
AEs leading to discontinuation	1 1.7%	0 0%	2 3.6%

9. 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 (ALP), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), lactate dehydrogenase (LDH) each ≥3*upper limit of normal (ULN); blood urea nitrogen (BUN) ≥10.71 millimole (mmol)/L; Bilirubin (Total) ≥34.2 micromole/liter (umol/L); Blood Urea Nitrogen ≥10.71 millimoles (mmol)/L; creatinine ≥177 umol/L; hemoglobin less than or equal to (≤)115 grams (g)/L (males) or ≤95 g/L (females); leukocytes ≥20*10^9/L or ≤3*10^9/L; eosinophils ≥10%; hematocrit <0.37 L/L (males) and <0.32 L/L (females); platelets ≥700*10^9/L or ≤75*10^9/L; haemoglobin, urine glucose, ketones, urine total protein each ≥2 unit (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 analysis set included all randomized participants who received at least 1 dose of the IMP. Here, 'overall number of participants analyzed'=participants evaluable for this outcome measure.

Arm/Group Title	Placebo	Fremanezumab 675 mg/Placebo/Placebo	Fremanezumab 900/225/225 mg
Arm/Group Description	Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Measure Participants	56	54	54
With at least 1 serum chemistry abnormality	1 1.7%	1 1.8%	0 0%
With at least 1 hematology abnormality	4 6.8%	1 1.8%	4 7.3%
With at least 1 urinalysis abnormality	0 0%	0 0%	0 0%

10. 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 analysis set included all randomized participants who received at least 1 dose of the IMP.

Arm/Group Title	Placebo	Fremanezumab 675 mg/Placebo/Placebo	Fremanezumab 900/225/225 mg
Arm/Group Description	Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Measure Participants	59	55	55
Low-Low	0 0%	0 0%	0 0%
Low-Normal	0 0%	0 0%	0 0%
Low-High	0 0%	0 0%	0 0%
Normal-Low	0 0%	0 0%	0 0%
Normal-Normal	47 79.7%	46 83.6%	44 80%
Normal-High	2 3.4%	2 3.6%	3 5.5%
High-Low	0 0%	0 0%	0 0%
High-Normal	4 6.8%	4 7.3%	4 7.3%
High-High	1 1.7%	1 1.8%	2 3.6%
Missing	5 8.5%	2 3.6%	2 3.6%
Low-Low	0 0%	0 0%	0 0%
Low-Normal	0 0%	0 0%	0 0%
Low-High	0 0%	0 0%	0 0%
Normal-Low	0 0%	0 0%	0 0%
Normal-Normal	48 81.4%	48 87.3%	47 85.5%
Normal-High	2 3.4%	2 3.6%	1 1.8%
High-Low	0 0%	0 0%	0 0%
High-Normal	3 5.1%	3 5.5%	3 5.5%
High-High	1 1.7%	0 0%	2 3.6%
Missing	5 8.5%	2 3.6%	2 3.6%

11. 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 ≥120 beats per minute (bpm) and increase of 15 bpm; systolic blood pressure ≤90 millimeters of mercury (mmHg) and decrease of 20 mmHg; diastolic blood pressure ≤50 mmHg and decrease of 15 mmHg, or ≥105 mmHg and increase of 15 mmHg. 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 analysis set included all randomized participants who received at least 1 dose of the IMP. Here, 'overall number of participants analyzed'=participants evaluable for this outcome measure.

Arm/Group Title	Placebo	Fremanezumab 675 mg/Placebo/Placebo	Fremanezumab 900/225/225 mg
Arm/Group Description	Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Measure Participants	56	54	54
Count of Participants [Participants]	3 5.1%	0 0%	1 1.8%

12. 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 up to Week 12

Outcome Measure Data

Analysis Population Description

Safety analysis set included all randomized participants who received at least 1 dose of the IMP.

Arm/Group Title	Placebo	Fremanezumab 675 mg/Placebo/Placebo	Fremanezumab 900/225/225 mg
Arm/Group Description	Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Measure Participants	59	55	55
Normal / Normal	35 59.3%	33 60%	23 41.8%
Normal / Abnormal NCS	6 10.2%	1 1.8%	5 9.1%
Normal / Abnormal CS	0 0%	0 0%	0 0%
Abnormal NCS / Normal	4 6.8%	9 16.4%	4 7.3%
Abnormal NCS / Abnormal NCS	7 11.9%	9 16.4%	18 32.7%
Abnormal NCS / Abnormal CS	0 0%	0 0%	0 0%
Abnormal CS / Normal	0 0%	0 0%	0 0%
Abnormal CS / Abnormal NCS	0 0%	0 0%	0 0%
Abnormal CS / Abnormal CS	0 0%	0 0%	0 0%
Missing	7 11.9%	3 5.5%	5 9.1%

13. Secondary Outcome

Title	Number of Participants Who Received Concomitant Medications
Description	Concomitant medications included: agents acting on the renin-angiotensin system, all other therapeutic products (for example: homeopathic preparation), allergens, analgesics, anesthetics, anti-parkinson drugs, antianemic preparations, antibacterials for systemic use, antibiotics and chemotherapeutics for dermatological use, antidiarrheals, intestinal antiinflammatory/antiinfective agents, antiemetic, antiepileptics, antifungals for dermatologiocal use, antigout preparations, antihemorrhagics, antihistamines for systemic use, antihypertensives, antiinflammatory and antirheumatic products, antimycotics for systemic use, antipruritics, antipsoriatics, antivirals for systemic use, beta blocking agents, blood substitutes and perfusion solutions, cardiac therapy, corticosteroids, cough and cold preparations, diagnostic radiopharmaceuticals, diuretics, thyroid therapy, urologicals, vaccines, psycoleptics, psycoanaleptics, ophthalmologicals, muscle relaxants, drugs used in diabetes etc.
Time Frame	Baseline up to Week 12

Outcome Measure Data

Analysis Population Description

Safety analysis set included all randomized participants who received at least 1 dose of the IMP.

Arm/Group Title	Placebo	Fremanezumab 675 mg/Placebo/Placebo	Fremanezumab 900/225/225 mg
Arm/Group Description	Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Measure Participants	59	55	55
Count of Participants [Participants]	57 96.6%	52 94.5%	52 94.5%

14. 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, swelling, and pruritus. 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 analysis set included all randomized participants who received at least 1 dose of the IMP.

Arm/Group Title	Placebo	Fremanezumab 675 mg/Placebo/Placebo	Fremanezumab 900/225/225 mg
Arm/Group Description	Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Measure Participants	59	55	55
Injection site induration	1 1.7%	3 5.5%	6 10.9%
Injection site pain	4 6.8%	2 3.6%	6 10.9%
Injection site erythema	2 3.4%	0 0%	2 3.6%
Injection site haemorrhage	0 0%	0 0%	1 1.8%
Injection site pruritus	1 1.7%	0 0%	1 1.8%
Injection site swelling	0 0%	1 1.8%	0 0%

15. Secondary Outcome

Title	Number of Participants With Hypersensitivity/Anaphylaxis Reactions
Description	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 analysis set included all randomized participants who received at least 1 dose of the IMP.

Arm/Group Title	Placebo	Fremanezumab 675 mg/Placebo/Placebo	Fremanezumab 900/225/225 mg
Arm/Group Description	Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Measure Participants	59	55	55
Count of Participants [Participants]	0 0%	0 0%	0 0%

16. 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 analysis set included all randomized participants who received at least 1 dose of the IMP.

Arm/Group Title	Placebo	Fremanezumab 675 mg/Placebo/Placebo	Fremanezumab 900/225/225 mg
Arm/Group Description	Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.	Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.	Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Measure Participants	59	55	55
Count of Participants [Participants]	0 0%	1 1.8%	4 7.3%

Adverse Events

Time Frame	Baseline up to Week 12
Adverse Event Reporting Description	Safety analysis set included all randomized participants who received at least 1 dose of the IMP.
Arm/Group Title	Placebo		Fremanezumab 675 mg/Placebo/Placebo		Fremanezumab 900/225/225 mg
Arm/Group Description	Participants received placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively.		Participants received placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 mg administered as 3 subcutaneous injections (225 mg/1.5 mL) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.		Participants received fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
All Cause Mortality
	Placebo		Fremanezumab 675 mg/Placebo/Placebo		Fremanezumab 900/225/225 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/59 (0%)		0/55 (0%)		0/55 (0%)
Serious Adverse Events
	Placebo		Fremanezumab 675 mg/Placebo/Placebo		Fremanezumab 900/225/225 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/59 (8.5%)		0/55 (0%)		1/55 (1.8%)
Ear and labyrinth disorders
Vertigo	1/59 (1.7%)	1	0/55 (0%)	0	0/55 (0%)	0
Gastrointestinal disorders
Duodenitis	1/59 (1.7%)	1	0/55 (0%)	0	0/55 (0%)	0
General disorders
Chest pain	1/59 (1.7%)	2	0/55 (0%)	0	0/55 (0%)	0
Injury, poisoning and procedural complications
Lumbar vertebral fracture	1/59 (1.7%)	1	0/55 (0%)	0	0/55 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	0/59 (0%)	0	0/55 (0%)	0	1/55 (1.8%)	1
Nervous system disorders
Cluster headache	2/59 (3.4%)	3	0/55 (0%)	0	0/55 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Fremanezumab 675 mg/Placebo/Placebo		Fremanezumab 900/225/225 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/59 (11.9%)		9/55 (16.4%)		16/55 (29.1%)
General disorders
Injection site induration	1/59 (1.7%)	1	3/55 (5.5%)	7	6/55 (10.9%)	10
Injection site pain	4/59 (6.8%)	6	2/55 (3.6%)	5	6/55 (10.9%)	17
Infections and infestations
Influenza	2/59 (3.4%)	2	0/55 (0%)	0	3/55 (5.5%)	3
Nasopharyngitis	1/59 (1.7%)	1	4/55 (7.3%)	5	4/55 (7.3%)	4

Limitations/Caveats

Study was terminated as a result of a pre-specified futility analysis at the interim of 150 participants completing the efficacy analysis of the study.

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.