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

Phase 3

Terminated

Conditions: Episodic Cluster Headache

Interventions: Drug: Placebo
Drug: Fremanezumab

Registration Number: NCT02945046

Lead Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 169

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	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.
Fremanezumab 675 mg/Placebo/Placebo	Fremanezumab	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.
Fremanezumab 900/225/225 mg	Fremanezumab	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.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.

Trial Locations

Locations (82): Teva Investigational Site 13834
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Phoenix, Arizona, United States
Teva Investigational Site 13819
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Canoga Park, California, United States
Teva Investigational Site 13811
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Santa Monica, California, United States
Teva Investigational Site 13823
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Stanford, California, United States
Teva Investigational Site 13837
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Aurora, Colorado, United States
Teva Investigational Site 13814
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Colorado Springs, Colorado, United States
Teva Investigational Site 13813
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Englewood, Colorado, United States
Teva Investigational Site 13821
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New Haven, Connecticut, United States
Teva Investigational Site 13810
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Gainesville, Florida, United States
Teva Investigational Site 13812
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Stamford, Connecticut, United States
Teva Investigational Site 13815
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Orlando, Florida, United States
Teva Investigational Site 13829
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Ormond Beach, Florida, United States
Teva Investigational Site 13830
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Saint Petersburg, Florida, United States
Teva Investigational Site 13840
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Tampa, Florida, United States
Teva Investigational Site 13833
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Columbus, Georgia, United States
Teva Investigational Site 13826
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Chicago, Illinois, United States
Teva Investigational Site 13818
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Ann Arbor, Michigan, United States
Teva Investigational Site 13835
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Las Vegas, Nevada, United States
Teva Investigational Site 13832
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Las Vegas, Nevada, United States
Teva Investigational Site 13831
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Lebanon, New Hampshire, United States
Teva Investigational Site 13820
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Princeton, New Jersey, United States
Teva Investigational Site 13827
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Albuquerque, New Mexico, United States
Teva Investigational Site 13816
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Amherst, New York, United States
Teva Investigational Site 13817
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New York, New York, United States
Teva Investigational Site 13809
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Raleigh, North Carolina, United States
Teva Investigational Site 13839
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Salisbury, North Carolina, United States
Teva Investigational Site 13825
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Cleveland, Ohio, United States
Teva Investigational Site 13824
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Philadelphia, Pennsylvania, United States
Teva Investigational Site 13841
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Richmond, Texas, United States
Teva Investigational Site 13822
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Virginia Beach, Virginia, United States
Teva Investigational Site 78120
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Auchenflower, Australia
Teva Investigational Site 78118
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Clayton, Australia
Teva Investigational Site 78123
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Melbourne, Australia
Teva Investigational Site 78121
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Randwick, Australia
Teva Investigational Site 78122
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Parkville, Australia
Teva Investigational Site 11131
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Toronto, Canada
Teva Investigational Site 40030
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Helsinki, Finland
Teva Investigational Site 40031
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Oulu, Finland
Teva Investigational Site 40029
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Turku, Finland
Teva Investigational Site 32666
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Berlin, Germany
Teva Investigational Site 32660
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Essen, Germany
Teva Investigational Site 32665
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Hamburg, Germany
Teva Investigational Site 32662
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Kiel, Germany
Teva Investigational Site 32661
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Konigstein im Taunus, Germany
Teva Investigational Site 80124
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Ashkelon, Israel
Teva Investigational Site 32663
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Rostock, Germany
Teva Investigational Site 80122
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Hadera, Israel
Teva Investigational Site 80125
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Holon, Israel
Teva Investigational Site 80121
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Jerusalem, Israel
Teva Investigational Site 80123
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Netanya, Israel
Teva Investigational Site 80127
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Tel Aviv, Israel
Teva Investigational Site 80120
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Ramat Gan, Israel
Teva Investigational Site 30190
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Milan, Italy
Teva Investigational Site 80126
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Tel-Aviv, Israel
Teva Investigational Site 30194
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Napoli, Italy
Teva Investigational Site 30193
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Pavia, Italy
Teva Investigational Site 30189
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Rome, Italy
Teva Investigational Site 30191
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Rome, Italy
Teva Investigational Site 38118
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Leiden, Netherlands
Teva Investigational Site 38119
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Nijmegen, Netherlands
Teva Investigational Site 38117
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Zwolle, Netherlands
Teva Investigational Site 53380
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Bialystok, Poland
Teva Investigational Site 53383
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Krakow, Poland
Teva Investigational Site 53379
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Krakow, Poland
Teva Investigational Site 53382
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Lodz, Poland
Teva Investigational Site 53381
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Szczecin, Poland
Teva Investigational Site 31211
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Galdakao., Spain
Teva Investigational Site 31213
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Sevilla, Spain
Teva Investigational Site 31215
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Zaragoza, Spain
Teva Investigational Site 42047
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Huddinge, Sweden
Teva Investigational Site 42045
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Vallingby, Sweden
Teva Investigational Site 34223
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London, United Kingdom
Teva Investigational Site 30192
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Modena, Italy
Teva Investigational Site 34221
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Oxford, United Kingdom
Teva Investigational Site 34224
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Glasgow, United Kingdom
Teva Investigational Site 34222
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Liverpool, United Kingdom
Teva Investigational Site 11130
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Calgary, Canada
Teva Investigational Site 32667
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Bochum, Germany
Teva Investigational Site 31214
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Madrid, Spain
Teva Investigational Site 31212
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Valladolid, Spain
Teva Investigational Site 34220
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London, United Kingdom
Teva Investigational Site 13836
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Denver, Colorado, United States