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

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ClinicalTrials.gov Identifier: NCT02945046
Recruitment Status : Terminated (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.)
First Posted : October 26, 2016
Results First Posted : April 13, 2020
Last Update Posted : July 7, 2020
Sponsor:
Information provided by (Responsible Party):
Teva Pharmaceutical Industries ( Teva Branded Pharmaceutical Products R&D, Inc. )

Tracking Information
First Submitted Date  ICMJE October 25, 2016
First Posted Date  ICMJE October 26, 2016
Results First Submitted Date  ICMJE March 27, 2020
Results First Posted Date  ICMJE April 13, 2020
Last Update Posted Date July 7, 2020
Actual Study Start Date  ICMJE January 19, 2017
Actual Primary Completion Date May 13, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 27, 2020)
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 [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: October 25, 2016)
the proportion of patients experiencing reduction from baseline in the weekly average number of cluster headache (CH) attacks during the 4-week period [ Time Frame: Week 0 to 4 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 27, 2020)
  • 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 [ Time Frame: 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.
  • 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 [ Time Frame: 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.
  • 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 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, 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. 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 (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 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 ≥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 Shift From Baseline to Endpoint (Last Assessment) in Electrocardiogram (ECG) Parameters [ Time Frame: 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 Who Received Concomitant Medications [ Time Frame: 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.
  • 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, swelling, and pruritus. 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 [ Time Frame: 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.
  • 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  ICMJE
 (submitted: October 25, 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  ICMJE A Study to Evaluate the Efficacy and Safety of TEV-48125 (Fremanezumab) for the Prevention of Episodic Cluster Headache (ECH)
Official Title  ICMJE 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
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 Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Episodic Cluster Headache
Intervention  ICMJE
  • Drug: Fremanezumab
    Fremanezumab will be administered per dose and schedule specified in the arm.
    Other Name: TEV-48125
  • Drug: Placebo
    Placebo matching to fremanezumab will be administered per schedule specified in the arm.
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Placebo
  • 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.
    Intervention: Drug: Fremanezumab
  • 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.
    Intervention: Drug: Fremanezumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: June 10, 2019)
169
Original Estimated Enrollment  ICMJE
 (submitted: October 25, 2016)
171
Actual Study Completion Date  ICMJE May 13, 2019
Actual Primary Completion Date May 13, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Canada,   Finland,   Germany,   Israel,   Italy,   Netherlands,   Poland,   Spain,   Sweden,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02945046
Other Study ID Numbers  ICMJE TV48125-CNS-30056
2016-003278-42 ( 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  ICMJE Not Provided
Responsible Party Teva Pharmaceutical Industries ( Teva Branded Pharmaceutical Products R&D, Inc. )
Study Sponsor  ICMJE Teva Branded Pharmaceutical Products R&D, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Teva Medical Expert, MD Teva Pharmaceuticals USA
PRS Account Teva Pharmaceutical Industries
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP