A Study to Explore the Long-Term Safety and Efficacy of Fremanezumab (TEV-48125) for the Prevention of Cluster Headache (ENFORCE)

A Multicenter, Double-Blind, Double-Dummy Study to Explore the Long-Term Safety and Efficacy of TEV-48125 for the Prevention of Cluster Headache

This is a 68-week study to evaluate the long-term safety and efficacy of fremanezumab in participants with cluster headache (CH). Participants who complete the pivotal studies TV48125-CNS-30056 (NCT02945046) and TV48125-CNS-30057 (NCT02964338) and enroll into the current study will visit the investigational center for investigational medicinal product (IMP) administration, safety and efficacy assessments, and blood and urine collections for pharmacokinetics, immunogenicity (anti-drug antibodies [ADAs]), and biomarker analyses. Participants will return to the investigational center for a follow-up visit to evaluate ADAs, fremanezumab concentrations, biomarkers, and safety (adverse events and concomitant medications) approximately 7.5 months after the last dose of IMP.

Study Overview

• Status: Terminated
• Conditions: Cluster Headache
• Intervention / Treatment: Drug: Fremanezumab

• Study Type: Interventional
• Enrollment (Actual): 275
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Auchenflower, Australia, 4066
    • Teva Investigational Site 78120
  • Clayton, Australia, 3168
    • Teva Investigational Site 78118
  • Melbourne, Australia, 3004
    • Teva Investigational Site 78123
  • Parkville, Australia, 3050
    • Teva Investigational Site 78122
  • Randwick, Australia, 2031
    • Teva Investigational Site 78121
• Canada
  • Calgary, Canada
    • Teva Investigational Site 11130
  • Ontario
    • Newmarket, Ontario, Canada, L3Y5G8
      • Teva Investigational Site 11132
• Finland
  • Helsinki, Finland, 00180
    • Teva Investigational Site 40030
  • Oulu, Finland, 90100
    • Teva Investigational Site 40031
  • Turku, Finland, 20100
    • Teva Investigational Site 40029
• Germany
  • Berlin, Germany, 10117
    • Teva Investigational Site 32666
  • Bochum, Germany, 44787
    • Teva Investigational Site 32667
  • Essen, Germany, 45147
    • Teva Investigational Site 32660
  • Hamburg, Germany, 20246
    • Teva Investigational Site 32665
  • Kiel, Germany, 24149
    • Teva Investigational Site 32662
  • Konigstein im Taunus, Germany, 61462
    • Teva Investigational Site 32661
  • Rostock, Germany, 18147
    • Teva Investigational Site 32663
• Israel
  • Ashkelon, Israel, 7830604
    • Teva Investigational Site 80124
  • Hadera, Israel, 3810101
    • Teva Investigational Site 80122
  • Holon, Israel, 58100
    • Teva Investigational Site 80125
  • Jerusalem, Israel, 9112001
    • Teva Investigational Site 80121
  • Netanya, Israel, 4244916
    • Teva Investigational Site 80123
  • Ramat Gan, Israel, 5265601
    • Teva Investigational Site 80120
  • Tel Aviv, Israel, 64239
    • Teva Investigational Site 80127
  • Tel-Aviv, Israel, 6812509
    • Teva Investigational Site 80126
• Italy
  • Milan, Italy, 20133
    • Teva Investigational Site 30190
  • Modena, Italy, 41124
    • Teva Investigational Site 30192
  • Napoli, Italy, 80131
    • Teva Investigational Site 30194
  • Pavia, Italy, 27100
    • Teva Investigational Site 30193
  • Rome, Italy, 00161
    • Teva Investigational Site 30191
  • Rome, Italy, 00163
    • Teva Investigational Site 30189
• Netherlands
  • Leiden, Netherlands, 2333 ZA
    • Teva Investigational Site 38118
  • Nijmegen, Netherlands, 6532 SZ
    • Teva Investigational Site 38119
  • Zwolle, Netherlands, 8025 AB
    • Teva Investigational Site 38117
• Poland
  • Bialystok, Poland, 15-402
    • Teva Investigational Site 53380
  • Krakow, Poland, 31-505
    • Teva Investigational Site 53383
  • Krakow, Poland, 33-332
    • Teva Investigational Site 53379
  • Lodz, Poland, 90-338
    • Teva Investigational Site 53382
  • Szczecin, Poland, 70-111
    • Teva Investigational Site 53381
• Spain
  • Galdakao., Spain, 48960
    • Teva Investigational Site 31211
  • Madrid, Spain, 28034
    • Teva Investigational Site 31214
  • Sevilla, Spain, 41013
    • Teva Investigational Site 31213
  • Valladolid, Spain, 47003
    • Teva Investigational Site 31212
  • Zaragoza, Spain, 50009
    • Teva Investigational Site 31215
• Sweden
  • Huddinge, Sweden, 141 86
    • Teva Investigational Site 42047
  • Vallingby, Sweden, 162 68
    • Teva Investigational Site 42045
• United Kingdom
  • Glasgow, United Kingdom, G51 4TF
    • Teva Investigational Site 34224
  • Liverpool, United Kingdom, L9 7LJ
    • Teva Investigational Site 34222
  • London, United Kingdom, SE1 9RT
    • Teva Investigational Site 34223
  • London, United Kingdom, W6 8RF
    • Teva Investigational Site 34220
  • Oxford, United Kingdom, OX3 9DU
    • Teva Investigational Site 34221
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85018
      • Teva Investigational Site 13834
  • California
    • Canoga Park, California, United States, 91303
      • Teva Investigational Site 13819
    • Santa Monica, California, United States, 90404
      • Teva Investigational Site 13811
    • Stanford, California, United States, 94305
      • Teva Investigational Site 13823
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Teva Investigational Site 13837
    • Colorado Springs, Colorado, United States, 80918
      • Teva Investigational Site 13814
    • Denver, Colorado, United States, 80218
      • Teva Investigational Site 13836
    • Englewood, Colorado, United States, 80113
      • Teva Investigational Site 13813
  • Connecticut
    • New Haven, Connecticut, United States, 06510-2483
      • Teva Investigational Site 13821
    • Stamford, Connecticut, United States, 06905
      • Teva Investigational Site 13812
  • Florida
    • Gainesville, Florida, United States, 32607
      • Teva Investigational Site 13810
    • Orlando, Florida, United States, 32806
      • Teva Investigational Site 13815
    • Ormond Beach, Florida, United States, 32174
      • Teva Investigational Site 13829
    • Saint Petersburg, Florida, United States, 33709
      • Teva Investigational Site 13830
    • Tampa, Florida, United States, 33612
      • Teva Investigational Site 13842
    • Tampa, Florida, United States, 33634
      • Teva Investigational Site 13840
  • Georgia
    • Columbus, Georgia, United States, 31904
      • Teva Investigational Site 13833
  • Illinois
    • Chicago, Illinois, United States, 60614
      • Teva Investigational Site 13826
  • Michigan
    • Ann Arbor, Michigan, United States, 48104
      • Teva Investigational Site 13818
  • Nevada
    • Las Vegas, Nevada, United States, 89106
      • Teva Investigational Site 13835
    • Las Vegas, Nevada, United States, 89113
      • Teva Investigational Site 13832
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Teva Investigational Site 13831
  • New Jersey
    • Princeton, New Jersey, United States, 08540
      • Teva Investigational Site 13820
  • New Mexico
    • Albuquerque, New Mexico, United States, 87102
      • Teva Investigational Site 13827
  • New York
    • Amherst, New York, United States, 14226
      • Teva Investigational Site 13816
    • New York, New York, United States, 10019
      • Teva Investigational Site 13817
  • North Carolina
    • Raleigh, North Carolina, United States, 27607
      • Teva Investigational Site 13809
    • Salisbury, North Carolina, United States, 28144
      • Teva Investigational Site 13839
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Teva Investigational Site 13825
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Teva Investigational Site 13824
  • Texas
    • Richmond, Texas, United States, 77307
      • Teva Investigational Site 13841
  • Virginia
    • Virginia Beach, Virginia, United States, 23454
      • Teva Investigational Site 13822

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• The participant completes either the Phase 3 pivotal study for ECH (Study TV48125-CNS-30056) or the Phase 3 pivotal study for CCH (Study TV48125-CNS-30057) without important protocol deviations related to participant safety and participant compliance.
• Prior to 15 June 2018, participants from the ECH study and the CCH study were enrolled. After 15 June 2018, only participants who participated in the ECH study (Study TV48125-CNS-30056) will be enrolled for active treatment.

• In addition, participants who do not complete the pivotal efficacy studies, and participants who complete the pivotal efficacy studies but will not continue treatment during this long-term safety study, will be offered to enroll in this study for the purpose of evaluating ADAs, and safety (adverse events and concomitant medications) approximately 7.5 months after administration of the last dose of the IMP.

  • Additional criteria apply, please contact the investigator for more information

Exclusion Criteria:

• Any finding that, in the judgment of the investigator, is a clinically significant abnormality, including serum chemistry, hematology, coagulation, and urinalysis test values (abnormal tests may be repeated for confirmation)

  • Additional criteria apply, please contact the investigator for more information

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fremanezumab 225 mg Monthly; Participants with ECH or CCH who received fremanezumab at 900 mg intravenous (IV) infusion at Week 0 and fremanezumab at 225 mg subcutaneous (SC) injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056 or TV48125-CNS-30057, and participants with CCH who received fremanezumab at 675 mg SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; will receive fremanezumab at 225 mg SC injection monthly (approximately every 4 weeks, administered as single SC injection of fremanezumab at 225 mg [225 mg/1.5 milliliter {mL}] at Week 0 and 36; and 2 placebo SC injections at Weeks 0, 12, 24, and 36 for blinding in participants rolled over from Study TV48125-CNS-30056; fremanezumab at 225 mg as a single SC injection (225 mg/1.5 mL) at Week 0, 12, 24, and 36; 2 SC injections of placebo at Week 0 for blinding in participants rolled over from Study TV48125-CNS-30057) through Week 36 in this study.	Drug: Fremanezumab; Fremanezumab; Other Names: TEV-48125
Experimental: Fremanezumab 675/225 mg Monthly; Participants with CCH who received placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; will receive fremanezumab 675 mg SC injection as loading dose (administered as 3 SC injections of fremanezumab at 225 mg [225 mg/1.5 mL] at Week 0) followed by monthly (approximately every 4 weeks) fremanezumab at 225 mg SC injection (administered as single SC injection of fremanezumab at 225 mg [225 mg/1.5 mL] at Weeks 12, 24, and 36) through Week 36.	Drug: Fremanezumab; Fremanezumab; Other Names: TEV-48125
Experimental: Fremanezumab 675 mg Quarterly; Participants with ECH who received fremanezumab at 675 mg SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study; or placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056; will receive fremanezumab at 675 mg SC injection quarterly (approximately every 12 weeks, administered as 3 SC injections of fremanezumab at 225 mg [225 mg/1.5 mL] at Weeks 0 an 36; and single placebo SC injections at Weeks 4, 8, 16, 20, 28, and 32 for blinding) through Week 36.	Drug: Fremanezumab; Fremanezumab; Other Names: TEV-48125

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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. 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 refers to the baseline values from the pivotal studies.	Baseline up to follow-up (Week 68)
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Results: Serum Chemistry	Serum chemistry tests with potentially clinically significant abnormal findings included: alanine aminotransferase (ALT), 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); and Creatinine ≥177 umol/L. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Baseline refers to the baseline values from the pivotal studies.	Baseline up to end of treatment (Week 40)
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Results: Hematology	Hematology tests with potentially clinically significant abnormal findings included: hemoglobin less than or equal to (≤)115 grams (g)/L (males) or ≤95 g/L (females), leukocytes count ≥20*10^9/L or ≤3*10^9/L, eosinophils ≥10%, hematocrit <0.37 L/L (males) and <0.32 L/L (females), platelets count ≥700*10^9/L or ≤75*10^9/L, absolute neutrophil count (ANC) ≤1*10^9/L. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Baseline refers to the baseline values from the pivotal studies.	Baseline up to end of treatment (Week 40)
Number of Participants With Potentially Clinically Significant Abnormal Laboratory Results: Urinalysis	Urinalysis laboratory tests with potentially clinically significant abnormal findings included: 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. Baseline refers to the baseline values from the pivotal studies.	Baseline up to end of treatment (Week 40)
Number of Participants With Shift From Baseline to Endpoint (Last Assessment) 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 refers to the baseline values from the pivotal studies.	Baseline up to end of treatment (Week 40)
Number of Participants With Potentially Clinically Significant Abnormal Vital Signs Values	Potentially clinically significant abnormal vital signs findings included: Pulse rate ≥120 beats per minute (bpm) and increase from baseline of ≥15 bpm, or ≤50 bpm and decrease from baseline of ≥15 bpm; Systolic blood pressure ≤90 millimeters of mercury (mmHg) and decrease from baseline of ≥20 mmHg, or ≥180 mmHg and increase from baseline of ≥20 mmHg; Diastolic blood pressure ≤50 mmHg and decrease from baseline of ≥15 mmHg, or ≥105 mmHg and increase from baseline of ≥15 mmHg; Temperature >38.3 degrees celsius (°C). A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Baseline refers to the baseline values from the pivotal studies.	Baseline up to follow-up (Week 68)
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 refers to the baseline values from the pivotal studies.	Baseline up to follow-up (Week 68)
Number of Participants With Abnormal Physical Examination Findings	A complete physical examination included the following organ systems: general appearance; head, eyes, ears, nose, and throat; chest and lungs; heart; abdomen; musculoskeletal; skin; lymph nodes; and neurological. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Baseline refers to the baseline values from the pivotal studies.	Baseline up to follow-up (Week 68)
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, rash, warmth, and pruritus. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Baseline refers to the baseline values from the pivotal studies.	Baseline up to Week 36
Number of Participants With Hypersensitivity/Anaphylaxis Reactions	A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. Baseline refers to the baseline values from the pivotal studies.	Baseline up to Week 36
Number of Participants Who Received Concomitant Medications	Concomitant medications included: agents acting on the renin-angiotensin system, all other therapeutic products (homeopathic), allergens, analgesics, anesthetics, anti-parkinson drugs, antianemic preparations, antibacterials, 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. Baseline refers to values from the pivotal studies.	Baseline up to follow-up (Week 68)
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 refers to the baseline values from the pivotal studies.	Baseline up to follow-up (Week 68)

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): April 27, 2017
• Primary Completion (Actual): June 11, 2019
• Study Completion (Actual): June 11, 2019

Study Registration Dates

• First Submitted: March 23, 2017
• First Submitted That Met QC Criteria: April 4, 2017
• First Posted (Actual): April 11, 2017

Study Record Updates

• Last Update Posted (Actual): November 9, 2021
• Last Update Submitted That Met QC Criteria: November 6, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pain; Neurologic Manifestations; Headache Disorders, Primary; Headache Disorders; Trigeminal Autonomic Cephalalgias; Headache; Cluster Headache
• Other Study ID Numbers: TV48125-CNS-30058; 2016-003172-43 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No