A Study to Test if Fremanezumab Reduces Headache in Participants With Posttraumatic Headache (PTH)

A Phase 2, Multicenter, Randomized, Proof-of-Concept, Double-Blind, Placebo-Controlled, Parallel-Group Study, Including an Open-Label Period, Evaluating the Efficacy and Safety of 1 Subcutaneous Dose Regimen of Fremanezumab for the Treatment of Posttraumatic Headache (PTH)

This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the safety and efficacy of fremanezumab in adult participants aged 18 to 70 years, inclusive, for the prevention of PTH. The study will include a double-blind (DB) treatment period (12 weeks) and an open-label (OL) treatment period (12 weeks).

Study Overview

• Status: Completed
• Conditions: Post-Traumatic Headache
• Intervention / Treatment: Drug: Fremanezumab; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 87
• Phase: Phase 2

Expanded Access

No longer available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85018
      • Teva Investigational Site 14065
    • Scottsdale, Arizona, United States, 85259-5452
      • Teva Investigational Site 14069
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Teva Investigational Site 14048
    • Little Rock, Arkansas, United States, 72205
      • Teva Investigational Site 30236
  • California
    • Long Beach, California, United States, 90806
      • Teva Investigational Site 14052
    • Los Angeles, California, United States, 90073
      • Teva Investigational Site 14053
    • San Diego, California, United States, 92161
      • Teva Investigational Site 14060
    • San Francisco, California, United States, 94109
      • Teva Investigational Site 14054
  • Connecticut
    • Fairfield, Connecticut, United States, 06824
      • Teva Investigational Site 14045
  • Florida
    • Miami, Florida, United States, 33136
      • Teva Investigational Site 14063
    • North Miami, Florida, United States, 33161
      • Teva Investigational Site 14041
    • Tampa, Florida, United States, 33609
      • Teva Investigational Site 14056
  • Illinois
    • Riverwoods, Illinois, United States, 60015
      • Teva Investigational Site 14057
  • Indiana
    • Indianapolis, Indiana, United States, 46256
      • Teva Investigational Site 14067
  • Kentucky
    • Louisville, Kentucky, United States, 40207
      • Teva Investigational Site 14058
  • Massachusetts
    • Waltham, Massachusetts, United States, 02451
      • Teva Investigational Site 14061
  • Missouri
    • Kansas City, Missouri, United States, 64128-2226
      • Teva Investigational Site 14051
    • Saint Louis, Missouri, United States, 63141
      • Teva Investigational Site 14046
    • Springfield, Missouri, United States, 65810
      • Teva Investigational Site 14043
  • New York
    • Albany, New York, United States, 12208
      • Teva Investigational Site 14119
    • Amherst, New York, United States, 14226
      • Teva Investigational Site 14229
    • Bronx, New York, United States, 10467
      • Teva Investigational Site 14118
    • New York, New York, United States, 10021
      • Teva Investigational Site 14047
  • North Carolina
    • Durham, North Carolina, United States, 27713
      • Teva Investigational Site 14114
    • Salisbury, North Carolina, United States, 28144
      • Teva Investigational Site 14059
  • Oregon
    • Portland, Oregon, United States, 97225
      • Teva Investigational Site 14049
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Teva Investigational Site 14064
    • Pittsburgh, Pennsylvania, United States, 15236
      • Teva Investigational Site 14040
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Teva Investigational Site 14230
  • Texas
    • Dallas, Texas, United States, 75390-8565
      • Teva Investigational Site 14055
    • Waco, Texas, United States, 76711
      • Teva Investigational Site 14050
  • Washington
    • Spokane, Washington, United States, 99202
      • Teva Investigational Site 14113
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • Teva Investigational Site 14044

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 68 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• The participant has a body weight greater than or equal to (≥) 45 kilograms (kg).
• Traumatic injury to the head has occurred, defined as a structural or functional injury resulting from the action of external forces.
• The participant has a diagnosis of PTH.
• The participant is not using preventive medications for headache.
• Women of childbearing potential whose male partners are potentially fertile (that is, no vasectomy) must use highly effective birth control methods for the duration of the study and for 30 weeks after the last study drug administration. Men must be sterile or, if they are potentially fertile or reproductively competent (that is, not surgically or congenitally sterile) and their female partners are of childbearing potential, must use, together with their female partners, acceptable birth control methods for the duration of the study and for 30 weeks after the last study drug administration.

NOTE- Additional criteria apply, please contact the investigator for more information.

Exclusion Criteria:

• The participant has a previous history of brain imaging showing evidence of intracerebral hemorrhage, subdural or epidural hematomas, or subarachnoid hemorrhage as a consequence of the traumatic head injury. Brain images with structurally insignificant changes, as discussed and approved by the sponsor, will be reviewed by the sponsor on a case-by-case basis.
• The participant has PTH attributed to craniotomy.
• The participant has whiplash and subsequent headache but no history of head injury or concussion.
• The participant is using analgesic medications containing opioids (including codeine) or a barbiturate on average more than 15 days per month.
• The participant has had exposure to a monoclonal antibody (mAb) targeting the calcitonin gene-related peptide (CGRP) pathway (erenumab, eptinezumab, galcanezumab, and fremanezumab) during the 6 months prior to the day of the screening visit.
• The participant is currently being treated with onabotulinumtoxinA (for example, Botox, Dysport, Xeomin) application in the head or neck or received any such injection during the 3 months prior to the screening visit.
• The participant has been implanted with any electronic devices for headache prevention during the 3 months prior to the screening visit or is currently using any implanted or externally applied stimulator or device.
• The participant has been treated with a nerve block for head and/or neck during the 3 months prior to the screening visit.
• The participant is a pregnant or lactating woman or plans to become pregnant during the study.

NOTE- Additional criteria apply, please contact the investigator for more information.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fremanezumab; Participants will receive fremanezumab 675 milligrams (mg) administered as 3 subcutaneous (SC) injections (225 mg/1.5 milliliters [mL] each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who complete the DB treatment period and continue into the OL treatment period will receive fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.	Drug: Fremanezumab; Fremanezumab will be administered per dose and schedule specified in the arm.; Other Names: TEV-48125
Placebo Comparator: Placebo; Participants will receive placebo matching to fremanezumab administered as 3 SC injections (1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who complete the DB treatment period and continue into the OL treatment period will receive fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.	Drug: Placebo; Placebo matching to fremanezumab will be administered per schedule specified in the arm.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DB Period: Mean Change From Baseline in Monthly Average Number of Headache Days of at Least Moderate Severity During the 12-Week Treatment Period After the First Dose of Fremanezumab	A headache day was defined as a day when a participant reported a headache of at least moderate severity. Monthly averages were derived and normalized to 28 days equivalent by the following formula: (number of days of efficacy variable over relevant period/number of days with assessments recorded in the e-diary over the relevant period) * 28. The change was calculated as post-baseline value - baseline value. Least square (LS) mean was calculated using analysis of covariance (ANCOVA) model with the duration of post traumatic headache history (less than 12 month since the brain injury or greater or equal to 12 month since the brain injury) and treatment as fixed effects and the baseline monthly average number of headache days of at least moderate severity as a covariate.	Baseline (Day -28 to Day -1), up to Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DB Period: Number of Participants Reaching at Least 50% Reduction From Baseline in Monthly Average Number of Headache Days of Any Severity During 12-Week Treatment With Fremanezumab	Monthly averages were derived and normalized to 28 days equivalent by the following formula: (number of days of efficacy variable over relevant period/number of days with assessments recorded in the e-diary over the relevant period) * 28.	Baseline (Day -28 to Day-1) up to Week 12
DB Period: Number of Participants Reaching at Least 50% Reduction From Baseline in the Monthly Average Number of Headache Days of at Least Moderate Severity During 12-Week Treatment With Fremanezumab	A headache day was defined as a day when a participant reported a headache of at least moderate severity. Monthly averages were derived and normalized to 28 days equivalent by the following formula: (number of days of efficacy variable over relevant period/number of days with assessments recorded in the e-diary over the relevant period) * 28.	Baseline (Day -28 to Day-1) up to Week 12
DB Period: Number of Participants Reaching at Least 50% Reduction From Baseline in the Monthly Average Number of Headache Days of at Least Moderate Severity During First 4-Week (Month 1), 5- to 8-Week (Month 2), and 9- to 12-Week (Month 3)	A headache day was defined as a day when a participant reported a headache of at least moderate severity. Monthly averages were derived and normalized to 28 days equivalent by the following formula: (number of days of efficacy variable over relevant period/number of days with assessments recorded in the e-diary over the relevant period) * 28.	Baseline (Day -28 to Day-1) up to Months 1, 2, and 3
DB Period: Change From Baseline in the Number of Headache Days of At Least Moderate Severity During the First 4-Week (Month 1), 5- to 8-Week (Month 2), and 9- to 12-Week (Month 3)	A headache day was defined as a day when a participant reported a headache of at least moderate severity. Monthly averages were derived and normalized to 28 days equivalent by the following formula: (number of days of efficacy variable over relevant period/number of days with assessments recorded in the e-diary over the relevant period) * 28. The change was calculated as post-baseline value - baseline value. LS mean was calculated using ANCOVA model with the duration of post traumatic headache history (less than 12 month since the brain injury or greater or equal to 12 month since the brain injury) and treatment as fixed effects and the baseline monthly average number of headache days of at least moderate severity as a covariate. This approach was used in generating the LS mean values only and was not considered to be an additional statistical analysis, no additional statistical analyses are reported for this outcome measure.	Baseline (Day -28 to Day -1), up to Months 1, 2, and 3
DB Period: Change From Baseline in Disability Score, as Measured by the 6-Item Headache Impact Test (HIT-6) Total Score at Week 12 After the First Dose of Fremanezumab	HIT-6 is a tool used to measure the impact headaches have on a participant's normal daily life and ability to function. The HIT-6 consists of 6 items, including pain, social functioning, role functioning, vitality, cognitive functioning, and psychological distress. Each item was answered on a 5-point Likert scale (6=never, 8=rarely, 10=sometimes, 11=very often, or 13=always), which were summed to produce a total score that ranged from 36 to 78, with larger scores reflecting greater impact of headache on the daily life of the participant.	Baseline (Day -28 to Day -1), Week 12
DB Period: Number of Participants (Responder and Non-Responder) With the Patient Global Impression of Change (PGIC) Scale at Weeks 4, 8, and 12 After the First Dose of Fremanezumab	The PGIC scale is a validated generic tool for the assessment of overall change in the severity of illness following treatment. Participants rated how they felt during assigned time points compared with how they felt before receiving study drug on a 7-point scale, where 1 = No change (or it got worse); 2 = Almost the same, hardly any change at all; 3 = A little better, but no noticeable change; 4 = Somewhat better, but the change has not made any real difference; 5 = Moderately better, and a slight but noticeable change; 6 = Better, and a definite improvement that has made a real and worthwhile difference; and 7 = A great deal better, and a considerable improvement that has made all the difference. Responders were those with a scale of 5 to 7 and non-responders were those with a scale of 1 to 4.	Weeks 4, 8, and 12
DB Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	An adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as AEs occurring at or after the first dose of the study drug. Serious AEs were defined as death, a life-threatening AE, 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 participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.	Baseline (Day -28 to -1) up to Week 12
OL Period: Number of Participants With TEAEs	An AE was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs were defined as AEs occurring at or after the first dose of the study drug. Serious AEs were defined as death, a life-threatening AE, 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 participant and required medical intervention to prevent 1 of the outcomes listed in this definition. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section.	Week 12 up to Week 24
DB Period: Number of Participants Who Did Not Complete the Study	Number of participants who did not complete the study due to any reason and due to AEs are reported.	Baseline (Day -28 to Day -1) up to Week 12
OL Period: Number of Participants Who Did Not Complete the Study	Number of participants who did not complete the study due to any reason and due to AEs are reported.	Week 12 up to Week 24
DB Period: Number of Participants Who Received Concomitant Medications	Concomitant medications included: agents acting on renin-angiotensin system, analgesics, anesthetics, anti-parkinson drugs, antianemic preparations, antibacterials for systemic use, antidiarrheals, intestinal antiinflammatory/antiinfective agents, antiemetics and antinauseants, antiepileptics, antifungals for dermatologiocal use, antihistamines for systemic use, antihypertensives, antiinflammatory and antirheumatics, antineoplastic agents, antiobesity preparations, antipruritics, antithrombotics, antivirals for systemic use, beta blocking agents, calcium channel blockers, cardiac therapy, corticosteroids, cough and cold preparations, diuretics, lipid modifying agents, nasal preparations, thyroid therapy, urologicals, vaccines, psycholeptics, psycoanaleptics, ophthalmologicals, general nutrients, mineral supplements, muscle relaxants, vitamins, drugs used in diabetes, sex hormones and modulators of the genital system, immunosuppresants, drugs for acid related disorders etc.	Baseline (Day -28 to Day -1) up to Week 12
OL Period: Number of Participants Who Received Concomitant Medications	Concomitant medications included: agents acting on renin-angiotensin system, analgesics, anti-parkinson drugs, antianemic preparations, antibacterials for systemic use, antiemetics and antinauseants, antihistamines for systemic use, antihypertensives, antiinflammatory and antirheumatics, antineoplastic agents, antithrombotics, beta blocking agents, calcium channel blockers, corticosteroids for systemic use, cough and cold preparations, diuretics, lipid modifying agents, nasal preparations, other gynecologicals, other nervous system drugs, thyroid therapy, unspecified herbal and traditional medicine, urologicals, vaccines, psycholeptics, psycoanaleptics, general nutrients, mineral supplements, muscle relaxants, vitamins, sex hormones and modulators of the genital system, drugs for acid related disorders, drugs for constipation, drugs for obstructive airways disease etc.	Week 12 up to Week 24
Number of Participants With Positive Findings on Electronic Columbia Suicide Severity Rating Scale (eC-SSRS)	eC-SSRS is a questionnaire to assess suicidal ideation (severity and intensity) and behavior. Suicidal ideation: A series of 1 -5 questions (with 'yes' or 'no' response) with 5 types of ideation of increasing severity: 1. wish to be dead, 2. non-specific active suicidal thoughts, 3. active suicidal ideation with any methods (not plan) without intent to act, 4. active suicidal ideation with some intent to act, without specific plan, 5. active suicidal ideation with specific plan and intent. A positive finding was defined as a 'yes' response to question 4 or 5.	Baseline (Day -28 to Day -1) up to Week 24
Number of Participants With Treatment-Emergent Antidrug Antibodies (ADA)	Number of participants with treatment-emergent antidrug antibodies reported.	Baseline (Day -28 to Day -1) up to Week 24

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): December 18, 2017
• Primary Completion (Actual): March 13, 2020
• Study Completion (Actual): June 3, 2020

Study Registration Dates

• First Submitted: November 14, 2017
• First Submitted That Met QC Criteria: November 16, 2017
• First Posted (Actual): November 20, 2017

Study Record Updates

• Last Update Posted (Estimate): December 13, 2022
• Last Update Submitted That Met QC Criteria: December 9, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: posttraumatic headache (PTH)
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Pain; Neurologic Manifestations; Headache Disorders; Headache Disorders, Secondary; Headache; Post-Traumatic Headache
• Other Study ID Numbers: TV48125-CNS-20024

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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