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

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

Official Title
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A Multicenter, Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, Parallel-Group Study Comparing the Efficacy and Safety of 2 Dose Regimens (Intravenous/Subcutaneous and Subcutaneous) of TEV-48125 Versus Placebo for the Prevention of Chronic Cluster Headache

Conditions
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Chronic Cluster Headache

Intervention / Treatment
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* Drug: Fremanezumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The participant has a history of CCH according to the International Classification of Headache Disorders - 3 beta criteria (Headache Classification Committee of the International Headache Society [IHS] 2013) for greater than or equal to (≥)12 months prior to screening. The participant has a total body weight of ≥45 kilograms (kg) (99 pounds [lbs]). The participant is in good health in the opinion of the Investigator. Women of childbearing potential (WOCBP) whose male partners are potentially fertile (that is, no vasectomy) must use highly effective birth control methods for the duration of the study. Men must be sterile, or if they are potentially fertile/reproductively competent (not surgically [for example, vasectomy] or congenitally sterile) and their female partners are of childbearing potential, must agree to use, together with their female partners, acceptable birth control. If a participant is receiving Botox, it should be in a stable dose regimen, which is considered as having ≥2 cycles of Botox prior to screening. The participant should not receive Botox during the run-in period up to the evaluation period (12 weeks) where the primary endpoint is evaluated. Additional criteria apply, please contact the Investigator for more information. Exclusion Criteria: The participant has used systemic steroids for any medical reason (including treatment of the current cluster headache (CH) cycle within less than or equal to (≤)7 days prior to screening. The participant has used an intervention/device (for example, scheduled nerve blocks) for headache during the 4 weeks prior to screening. The participant has clinically significant hematological, renal, endocrine, immunologic, pulmonary, gastrointestinal, genitourinary, cardiovascular, neurologic, hepatic, or ocular disease at the discretion of the Investigator. The participant has evidence or medical history of clinically significant psychiatric issues determined at the discretion of the Investigator. The participant has a past or current history of cancer or malignant tumor in the past 5 years, except for appropriately treated non-melanoma skin carcinoma. The participant is pregnant or lactating. The participant has a history of hypersensitivity reactions to injected proteins, including monoclonal antibodies. The participant has participated in a clinical study of a monoclonal antibody within 3 months or 5 half-lives before administration of the first dose of the investigational medicinal product (IMP), whichever is longer, unless it is known that the participant received placebo during the study. The participant has a history of prior exposure to a monoclonal antibody targeting the calcitonin gene-related peptide (CGRP) pathway (AMG 334, ALD304, LY2951742, or fremanezumab). If participant has participated in a clinical study with any of these monoclonal antibodies, it has to be confirmed that the participant received placebo in order to be eligible for this study. The participant is an employee of the sponsor/participating study center who is directly involved in the study or is the relative of such an employee. The participant has an active implant for neurostimulation used in the treatment of CH. The participant is a member of a vulnerable population (for example, people kept in detention). The participant has a history of alcohol abuse prior to screening and/or drug abuse that in the Investigator's opinion could interfere with the study evaluations or the participant's safety. Additional criteria apply, please contact the Investigator for more information.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a ≥50% Reduction From Baseline in the Monthly Average Number of CH Attacks 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. | Baseline Period (from at least Week -4 to Week 0) up to Week 12 | 
| Mean Change From Baseline in the Monthly Average Number of CH Attacks at Week 4 and Week 12 | A CH attack was defined as a severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15 to 180 minutes with either or both of the following 2 categories: 1) ≥1 of the following symptoms or signs, ipsilateral to the headache: -conjunctival injection and/or lacrimation; -nasal congestion and/or rhinorrhea; -eyelid edema; -forehead and facial sweating; -forehead and facial flushing; -sensation of fullness in the ear; -miosis and/or ptosis. 2) a sense of restlessness or agitation. Mean change from baseline in monthly average number of CH attacks during 4-week period after administration of first dose of study drug (based on Week 0 to 4 data) and during 4-week period after administration of third dose of study drug (based on Week 8 to 12 data) is reported. | Baseline Period (from at least Week -4 to Week 0), Week 4 and Week 12 | 
| Mean Change From Baseline in the Overall Weekly Average Number of Days With Use of Cluster-Specific Acute Headache Medications (Triptans and Ergot Compounds) Up to Week 12 | A maximum of 2 concomitant preventive medications for CH were allowed during the study. Participants must have been on a stable dose and regimen of the concomitant medication for at least 2 weeks before screening and throughout the study. Baseline data and the mean change from baseline in the overall weekly average number of days with the use of cluster-specific acute headache medications (triptans and ergot compounds) during the 12-week period after administration of the first dose of study drug (based on Week 0 to 12 data) is reported. | Baseline Period (from at least Week -4 to Week 0), Up to Week 12 | 
| Mean Change From Baseline in the Weekly Average Number of Days Oxygen Was Used to Treat CCH Up to Week 12 | Baseline data and the mean change from baseline in the overall weekly average number of days oxygen was used to treat CCH during the 12-week period after administration of the first dose of study drug (based on Week 0 to 12 data) is reported. | Baseline Period (from at least Week -4 to Week 0), Up to Week 12 | 
| 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 | 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. | Baseline and Weeks 1, 4, 8, and 12 | 
| Number of Participants With Adverse Events (AEs) | An AE was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the Investigator on a scale of mild, moderate and severe, with severe as an AE that prevents usual activities. Relationship of AE to treatment was determined by the Investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent the previously listed serious outcomes. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Baseline up to Week 12 | 
| Number of Participants With Potentially Clinically Significant Laboratory (Serum Chemistry, Hematology, and Urinalysis) Abnormal Results | Serum chemistry, hematology, urinalysis laboratory tests with potentially clinically significant abnormal findings included: Alanine Aminotransferase (units/liter [U/L]) ≥3*upper limit of normal (ULN); Aspartate Aminotransferase (U/L) ≥3*ULN; Bilirubin (Total) ≥34.2 micromole/liter (umol/L); Blood Urea Nitrogen ≥10.71 millimole (mmol)/L; Creatinine ≥177 umol/L; Gamma Glutamyl Transferase (U/L) ≥3*ULN; hemoglobin less than (<)115 grams (g)/L (males) or less than or equal to (≤)95 g/L (females); leukocytes ≥20*10^9/L or ≤3*10^9/L; Eosinophils/Leukocytes ≥10%; Hematocrit <0.37 L/L (males) and <0.32 L/L (females); platelets ≥700*10^9/L or ≤75*10^9/L; blood ≥2 unit increase from baseline; urine glucose (milligrams/decilitre [mg/dL]) ≥2 U increase from baseline; ketones (mg/dL) ≥2 U increase from baseline; urine protein (mg/dL) ≥2 U increase from baseline. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Baseline up to Week 12 | 
| Number of Participants With Shift From Baseline to Endpoint in Coagulation Laboratory Test Results | 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. | Baseline up to Week 12 | 
| Number of Participants With Potentially Clinically Significant Abnormal Vital Signs Values | Potentially clinically significant abnormal vital signs findings included: pulse rate ≤50 beats/minute (bpm) and decrease of ≥15 bpm, or ≥120 bpm and increase of ≥15 bpm; systolic blood pressure ≤90 millimeters of mercury (mmHg) and decrease of ≥20 mmHg, or ≥180 mmHg and increase of ≥20 mmHg; diastolic blood pressure ≤50 mmHg and decrease of ≥15 mmHg, or ≥105 mmHg and increase of ≥15 mmHg; respiratory rate <10 breaths/minute; and body temperature ≥38.3 degrees centigrade and change of ≥1.1 degrees centigrade. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Baseline up to Week 12 | 
| Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Electrocardiogram (ECG) Parameters | 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. | Baseline to Week 12 | 
| Number of Participants With Injection Site Reactions | Number of participants who reported treatment-emergent injection site reactions are summarized. Preferred terms from Medical Dictionary for Regulatory Activities (MedDRA) version 18.1 were offered without a threshold applied. Injection site reactions included injection site erythema, induration, pain, haemorrhage, bruising, hypersensitivity, swelling, rash, and flushing. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. | Baseline up to Week 12 | 
| Number of Participants With Suicidal Ideation and Suicidal Behavior as Assessed by the Electronic Columbia Suicide Severity Rating Scale (eC-SSRS) | 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. | Baseline up to Week 12 |