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

• ClinicalTrials.gov Identifier: NCT02964338
• Recruitment Status: Terminated
• First Posted: November 16, 2016
• Results First Posted: September 18, 2019
• Last Update Posted: November 9, 2021
• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
• Information provided by (Responsible Party): Teva Branded Pharmaceutical Products R&D, Inc.

Tracking Information

• First Submitted Date: November 11, 2016
• First Posted Date: November 16, 2016
• Results First Submitted Date: July 16, 2019
• Results First Posted Date: September 18, 2019
• Last Update Posted Date: November 9, 2021
• Actual Study Start Date: January 17, 2017
• Actual Primary Completion Date: July 18, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 28, 2019)

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

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

• Original Primary Outcome Measures (submitted: November 11, 2016): the proportion of patients experiencing reduction from baseline in the weekly average number of cluster headache (CH) attacks during the 12-week period [ Time Frame: Week 0 to 12 ]

Current Secondary Outcome Measures (submitted: August 28, 2019)

• Percentage of Participants With a ≥50% Reduction From Baseline in the Monthly Average Number of CH Attacks Up to Week 12 [ Time Frame: Baseline Period (from at least Week -4 to Week 0) up to Week 12 ]
  A CH attack was defined as a severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15 to 180 minutes with either or both of the following 2 categories: 1) at least 1 of the following symptoms or signs, ipsilateral to the headache: -conjunctival injection and/or lacrimation; -nasal congestion and/or rhinorrhea; -eyelid edema; -forehead and facial sweating; -forehead and facial flushing; -sensation of fullness in the ear; -miosis and/or ptosis. 2) a sense of restlessness or agitation.
• Mean Change From Baseline in the Monthly Average Number of CH Attacks at Week 4 and Week 12 [ Time Frame: Baseline Period (from at least Week -4 to Week 0), Week 4 and Week 12 ]
  A CH attack was defined as a severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15 to 180 minutes with either or both of the following 2 categories: 1) ≥1 of the following symptoms or signs, ipsilateral to the headache: -conjunctival injection and/or lacrimation; -nasal congestion and/or rhinorrhea; -eyelid edema; -forehead and facial sweating; -forehead and facial flushing; -sensation of fullness in the ear; -miosis and/or ptosis. 2) a sense of restlessness or agitation. Mean change from baseline in monthly average number of CH attacks during 4-week period after administration of first dose of study drug (based on Week 0 to 4 data) and during 4-week period after administration of third dose of study drug (based on Week 8 to 12 data) is reported.
• 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 [ Time Frame: Baseline Period (from at least Week -4 to Week 0), Up to Week 12 ]
  A maximum of 2 concomitant preventive medications for CH were allowed during the study. Participants must have been on a stable dose and regimen of the concomitant medication for at least 2 weeks before screening and throughout the study. Baseline data and the mean change from baseline in the overall weekly average number of days with the use of cluster-specific acute headache medications (triptans and ergot compounds) during the 12-week period after administration of the first dose of study drug (based on Week 0 to 12 data) is reported.
• Mean Change From Baseline in the Weekly Average Number of Days Oxygen Was Used to Treat CCH Up to Week 12 [ Time Frame: Baseline Period (from at least Week -4 to Week 0), Up to Week 12 ]
  Baseline data and the mean change from baseline in the overall weekly average number of days oxygen was used to treat CCH during the 12-week period after administration of the first dose of study drug (based on Week 0 to 12 data) is reported.
• 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 [ Time Frame: Baseline and Weeks 1, 4, 8, and 12 ]
  The PPSI assessment was developed to measure pain intensity and was adjusted for CH symptoms improvement. Participants marked the level of CH-associated pain and indicated if pain is "1=much worse," "2=moderately worse," "3=slightly worse," "4=unchanged," "5=slightly improved," "6=moderately improved," or "7=much improved" compared with 4 weeks prior. PPSI was defined as the change in pain that corresponds with a minimal rating of "5=slightly improved." Data at Week 1 was recorded on Day 7 in the electronic diary device at home. Week 12 data also included assessment at the early withdrawal visit for participants who discontinued the study early.
• Number of Participants With Adverse Events (AEs) [ Time Frame: Baseline up to Week 12 ]
  An AE was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the Investigator on a scale of mild, moderate and severe, with severe as an AE that prevents usual activities. Relationship of AE to treatment was determined by the Investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent the previously listed serious outcomes. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
• Number of Participants With Potentially Clinically Significant Laboratory (Serum Chemistry, Hematology, and Urinalysis) Abnormal Results [ Time Frame: Baseline up to Week 12 ]
  Serum chemistry, hematology, urinalysis laboratory tests with potentially clinically significant abnormal findings included: Alanine Aminotransferase (units/liter [U/L]) ≥3*upper limit of normal (ULN); Aspartate Aminotransferase (U/L) ≥3*ULN; Bilirubin (Total) ≥34.2 micromole/liter (umol/L); Blood Urea Nitrogen ≥10.71 millimole (mmol)/L; Creatinine ≥177 umol/L; Gamma Glutamyl Transferase (U/L) ≥3*ULN; hemoglobin less than (<)115 grams (g)/L (males) or less than or equal to (≤)95 g/L (females); leukocytes ≥20*10^9/L or ≤3*10^9/L; Eosinophils/Leukocytes ≥10%; Hematocrit <0.37 L/L (males) and <0.32 L/L (females); platelets ≥700*10^9/L or ≤75*10^9/L; blood ≥2 unit increase from baseline; urine glucose (milligrams/decilitre [mg/dL]) ≥2 U increase from baseline; ketones (mg/dL) ≥2 U increase from baseline; urine protein (mg/dL) ≥2 U increase from baseline. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
• Number of Participants With Shift From Baseline to Endpoint in Coagulation Laboratory Test Results [ Time Frame: 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 [ Time Frame: Baseline up to Week 12 ]
  Potentially clinically significant abnormal vital signs findings included: pulse rate ≤50 beats/minute (bpm) and decrease of ≥15 bpm, or ≥120 bpm and increase of ≥15 bpm; systolic blood pressure ≤90 millimeters of mercury (mmHg) and decrease of ≥20 mmHg, or ≥180 mmHg and increase of ≥20 mmHg; diastolic blood pressure ≤50 mmHg and decrease of ≥15 mmHg, or ≥105 mmHg and increase of ≥15 mmHg; respiratory rate <10 breaths/minute; and body temperature ≥38.3 degrees centigrade and change of ≥1.1 degrees centigrade. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
• Number of Participants With Shift From Baseline to Endpoint (Last Assessment) in Electrocardiogram (ECG) Parameters [ Time Frame: Baseline to Week 12 ]
  ECG parameters included: heart rate, PR interval, QRS interval, QT interval corrected using the Fridericia formula (QTcF), QT interval corrected using the Bazett's formula (QTcB) and RR interval. Shifts represented as Baseline - endpoint value (last observed post-baseline value). Abnormal NCS indicated an abnormal but not clinically significant finding. Abnormal CS indicated an abnormal and clinically significant finding. Missing ECG shift data are also presented. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
• Number of Participants With Injection Site Reactions [ Time Frame: Baseline up to Week 12 ]
  Number of participants who reported treatment-emergent injection site reactions are summarized. Preferred terms from Medical Dictionary for Regulatory Activities (MedDRA) version 18.1 were offered without a threshold applied. Injection site reactions included injection site erythema, induration, pain, haemorrhage, bruising, hypersensitivity, swelling, rash, and flushing. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.
• Number of Participants With Suicidal Ideation and Suicidal Behavior as Assessed by the Electronic Columbia Suicide Severity Rating Scale (eC-SSRS) [ Time Frame: 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.

Original Secondary Outcome Measures (submitted: November 11, 2016)

• the mean change from baseline in the number of CH attacks during the 4-week period after administration of the first dose [ Time Frame: Week 0 to 4 ]
• the mean change from baseline in the number of CH attacks during the 12-week period after administration of the first dose [ Time Frame: Week 0 to 12 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study Comparing the Efficacy and Safety of Fremanezumab (TEV-48125) for the Prevention of Chronic Cluster Headache (CCH)
• Official Title: A Multicenter, Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, Parallel-Group Study Comparing the Efficacy and Safety of 2 Dose Regimens (Intravenous/Subcutaneous and Subcutaneous) of TEV-48125 Versus Placebo for the Prevention of Chronic Cluster Headache
• Brief Summary: The purpose of the current study is to evaluate the efficacy and safety of Fremanezumab (TEV-48125), in the prevention of CCH in adult participants.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Chronic Cluster Headache

Intervention

• Drug: Fremanezumab
  Fremanezumab will be administered as per the dose and schedule specified in the respective arms.
  Other Name: TEV-48125
• Drug: Placebo
  Placebo matching to fremanezumab will be administered as per the schedule specified in the respective arms.

Study Arms

• Placebo Comparator: Placebo
  Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8.
  Intervention: Drug: Placebo
• Experimental: Fremanezumab 675/225/225 mg
  Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 milligrams (mg) as 3 subcutaneous injections (225 mg/1.5 milliliters [mL]) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.
  Interventions:

  • Drug: Fremanezumab
  • Drug: Placebo
• Experimental: Fremanezumab 900/225/225 mg
  Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.
  Interventions:

  • Drug: Fremanezumab
  • Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: August 21, 2018): 259
• Original Estimated Enrollment (submitted: November 11, 2016): 171
• Actual Study Completion Date: July 18, 2018
• Actual Primary Completion Date: July 18, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 70 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, Finland, Germany, Israel, Italy, Netherlands, Poland, Spain, Sweden, United Kingdom, United States

Administrative Information

• NCT Number: NCT02964338
• Other Study ID Numbers: TV48125-CNS-30057; 2016-003171-21 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Teva Branded Pharmaceutical Products R&D, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: Teva Branded Pharmaceutical Products R&D, Inc.
• Verification Date: November 2021