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

• ClinicalTrials.gov Identifier: NCT03347188
• Recruitment Status: Completed
• First Posted: November 20, 2017
• Results First Posted: March 26, 2021
• Last Update Posted: December 13, 2022
• 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 14, 2017
• First Posted Date: November 20, 2017
• Results First Submitted Date: February 22, 2021
• Results First Posted Date: March 26, 2021
• Last Update Posted Date: December 13, 2022
• Actual Study Start Date: December 18, 2017
• Actual Primary Completion Date: March 13, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 22, 2021)

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 [ Time Frame: Baseline (Day -28 to Day -1), up to Week 12 ]

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.

• Original Primary Outcome Measures (submitted: November 16, 2017): mean change in the monthly average number of headache days [ Time Frame: Baseline-Week 12 ]

Current Secondary Outcome Measures (submitted: March 25, 2021)

• 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 [ Time Frame: Baseline (Day -28 to Day-1) up to Week 12 ]
  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.
• 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 [ Time Frame: Baseline (Day -28 to Day-1) up to Week 12 ]
  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.
• 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) [ Time Frame: Baseline (Day -28 to Day-1) up to Months 1, 2, and 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.
• 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) [ Time Frame: Baseline (Day -28 to Day -1), up to Months 1, 2, and 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.
• 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 [ Time Frame: Baseline (Day -28 to Day -1), Week 12 ]
  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.
• 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 [ Time Frame: Weeks 4, 8, and 12 ]
  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.
• DB Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: Baseline (Day -28 to -1) up to Week 12 ]
  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.
• OL Period: Number of Participants With TEAEs [ Time Frame: Week 12 up to Week 24 ]
  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.
• DB Period: Number of Participants Who Did Not Complete the Study [ Time Frame: Baseline (Day -28 to Day -1) up to Week 12 ]
  Number of participants who did not complete the study due to any reason and due to AEs are reported.
• OL Period: Number of Participants Who Did Not Complete the Study [ Time Frame: Week 12 up to Week 24 ]
  Number of participants who did not complete the study due to any reason and due to AEs are reported.
• DB Period: Number of Participants Who Received Concomitant Medications [ Time Frame: Baseline (Day -28 to Day -1) up to Week 12 ]
  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.
• OL Period: Number of Participants Who Received Concomitant Medications [ Time Frame: Week 12 up to Week 24 ]
  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.
• Number of Participants With Positive Findings on Electronic Columbia Suicide Severity Rating Scale (eC-SSRS) [ Time Frame: Baseline (Day -28 to Day -1) up to Week 24 ]
  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.
• Number of Participants With Treatment-Emergent Antidrug Antibodies (ADA) [ Time Frame: Baseline (Day -28 to Day -1) up to Week 24 ]
  Number of participants with treatment-emergent antidrug antibodies reported.

Original Secondary Outcome Measures (submitted: November 16, 2017)

• proportion of patients reaching at least 50% reduction in the monthly average number of headache days of any severity [ Time Frame: Baseline-Week 12 ]
• mean change in the number of headache days of at least moderate severity [ Time Frame: during the first 4-week period, the 5- to 8-week period, and the 9- to 12-week period after the first dose ]
• mean change in disability score, as measured by the 6-item Headache Impact Test (HIT-6) [ Time Frame: Baseline, Week 12 after the first dose ]
  Six questions ask asked about the effect the headache has on normal daily life and ability to function. They can be rated never (6 points), rarely (8 points), sometimes (10 points), very often (11 points), always (13 points). A higher total number represents a worse outcome.
• occurrence of adverse events [ Time Frame: 44 weeks ]
• Number (%) of patients who did not complete the study [ Time Frame: Day 56 ]
• Number (%) of patients who did not complete the study due to adverse events [ Time Frame: Day 56 ]

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

Descriptive Information

• Brief Title: A Study to Test if Fremanezumab Reduces Headache in Participants With Posttraumatic Headache (PTH)
• Official Title: 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)
• Brief Summary: 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).
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Prevention
• Condition: Post-Traumatic Headache

Intervention

• 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

• 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.
  Intervention: Drug: Fremanezumab
• 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.
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 27, 2020): 87
• Original Estimated Enrollment (submitted: November 16, 2017): 172
• Actual Study Completion Date: June 3, 2020
• Actual Primary Completion Date: March 13, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

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: United States

Administrative Information

• NCT Number: NCT03347188
• Other Study ID Numbers: TV48125-CNS-20024
• 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

• Plan to Share IPD: No

• 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: December 2022