A Phase 3 interventional study of Eptinezumab and Placebo in Post Traumatic Headache, sponsored by Sunnybrook Health Sciences Centre. Recruiting at 1 site in Canada. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2026-10-29.
Sponsored by Sunnybrook Health Sciences Centre · Phase 3, Interventional, and Treatment
Most individuals with mild traumatic brain injury (mTBI) experience post-traumatic headaches (PTH). Of PTH, 50% present with a migraine phenotype which is the most disabling type of PTH. Patients with migraine-PTH are at greater risk of persistent symptoms whereby the acute PTH (aPTH) becomes persistent PTH (pPTH) (ie. lasting > 3 months) with a conversion rate of 47-95%. As migraine symptoms become chronic, it becomes treatment resistant. Despite these implications, early preventive medication management of PTH is marred by lengthy trials of multiple medications (2-3 months for each) and adverse effects that aggravate mTBI symptoms (fatigue, nausea, and presyncope). There is a compelling need to establish an effective treatment to prevent this debilitating outcome. Eptinezumab is a calcitonin gene-related peptide (CGRP)-blocking monoclonal antibody that reduces migraine burden in patients with migraines after a single infusion. Patients with PTH have higher serum levels of CGRP and experimental infusion of CGRP to patients with mTBI reproduces migraine PTH symptoms. Given the similarly in CGRP expression between chronic migraines and PTH, an infusion of eptinezumab within 8 weeks of PTH is hypothesized to reduce headache burden 3 months after treatment and prevent pPTH.
Approximately 500,000 Canadians aged >12 experienced a mild traumatic brain injury (mTBI) in the preceding year based on a 2020 report. Patients with mTBIs have a cumulative incidence of headaches, termed post-traumatic headaches (PTH), of 91% over one year following injury. Post-traumatic headache (PTH), according to the International Classification of Headache Disorders (ICHD) by definition, is a headache caused by a traumatic injury to the head. This condition is further classified into acute PTH (aPTH) which is a headache of less than 3 months duration following injury to the head, and persistent PTH (pPTH) which refers to the transition of aPTH to longer than 3 months duration.
PTH is the most common symptom after mTBI. The impact of PTH is significant as the majority of patients with aPTH (up to 95%) transition to pPTH. In patients who experience PTH, the frequency of headache burden may vary with one study reporting a mean monthly headache frequency of 25 days. Individuals with PTH have decreased cognitive function with impaired memory tests, slower reaction, and struggle in returning to their previous physical and social functions. Therefore, PTH has a profound emotional, social, and economic impact. Treatment for PTH is currently guided by its phenotype - migraine, tension, or trigeminal autonomic cephalgias. PTH with migraine phenotype occurs in 49% of cases and tension phenotype in 40%, whereas 11% are undefined. Patients with tension-PTH are by definition headaches with mild to moderate intensity, whereas patients with migraine-PTH are categorized as severe. Patients with migraine-PTH are more likely to have near daily headaches and have a higher probability of progressing to pPTH.
The pathophysiology of migraine-PTH results from activation of the trigeminovascular system (TVS). Release of CGRP from the TVS has been identified as the primary mechanism where increased sensitivity of trigeminal nociceptors that innervate the dura mater is responsible for intracranial pain. As migraine progresses, frequent and sustained activation of the TVS and its central connections may lead to neuroplastic changes and a reduced threshold for initiating migraine attacks. Patients with PTH are known to have higher serum levels of CGRP and infusion of CGRP to patients with mTBI reproduces migraine PTH symptoms. Current evidence on treatment of PTH is limited to two placebo-controlled trials involving botulinum toxin and fremanezumab. Both trials involved patients that had established and pPTH and neither specifically selected for patients with migraine-PTH to the best of our knowledge (fremanezumab study is unpublished). The fremanezumab study also did not demonstrate a significant improvement compared to placebo in the pPTH population. A third open label study on pPTH and erenumab demonstrated a reduction of 2.8 days per month in a 12 week trial and was well-tolerated.
There is pre-clinical evidence demonstrating early administration of CGRP-blocking monoclonal antibodies (MAb) is important to prevent establishment of central sensitization after mTBI. Once central sensitization is established, additional CGRP-independent mechanisms promote or maintain central sensitization and CGRP-blocking MAbs are less effective. Therefore, there has been a focus to target aPTH prior to progression to pPTH. The American Headache Society's recent position statement endorsed the use of CGRP-targeting therapies, including MAbs, as first-line options due to their efficacy across multiple patient-important outcomes and favourable safety profile. CGRP-targeting therapies have excellent tolerability and efficacy evidenced by low drop out rates. There are currently two trials registered on www.ClinicalTrials.gov assessing erenumab, a subcutaneously administered CGRP-blocking monoclonal antibody, for treatment of aPTH that are in progress. Notably, both trials have pursued all phenotypes of PTH rather than migraine-PTH to which CGRP MAb is specific for treating.
Eptinezumab is a CGRP-blocking MAb approved by Health Canada for prevention of migraines in patients with greater than 4 migraine days per month. It is unique as the only intravenously administered CGRP MAb. It has superior bioavailability (100% after 30 min infusion achieving maximum plasma concentration with the first dose) and as a single dose, versus monthly subcutaneous injection of erenumab, has higher medication compliance. The Health Canada recommended doses are 100mg or 300mg. Large scale randomized controlled trials have been conducted comparing eptinezumab to placebo in patients with episodic and chronic migraine. These trials showed that monthly migraine days (MMD) were reduced 0.7 to 2.7 days at 12 weeks for the 100 mg dose and 1.0 to 3.2 days for the 300 mg dose compared to placebo. Eptinezumab has been shown to have greater proportions of reductions of 50% in MMD in the first 12 weeks compared to placebo and also a greater proportion of patients who experienced 100% reduction in MMD at 12 weeks than placebo. A recent meta-analysis demonstrated that compared to eptinezumab 100mg, the 300mg dose was associated with substantially reduced MMD with no significant differences in adverse events or serious adverse events.
The most common adverse effects reported with eptinezumab use included upper respiratory tract infections, hypersensitivity or infusion site reactions, nasopharyngitis, nausea, and sinusitis. In post-marketing surveillance, 10.4% of patients reported mild adverse effects including vertigo, constipation, rhinitis, myalgia, weight gain, hoarseness, and hypotension. Hypersensitivity reactions include angioedema, urticaria, flushing, rash, and pruritus (reported in 3-4% of patients). The only absolute contraindication to eptinezumab is hypersensitivity to the active substance or any of the excipients. Eptinezumab contains sorbitol and therefore patients with Hereditary Fructose Intolerance should not receive it.
In the PTH population where memory impairment can be an issue, eptinezumab has the added benefit of prolonged duration of therapeutic benefit (3 vs 1 month compared to other subcutaneous injectable CGRP MAbs) thereby resulting in decreased dosing frequency and increased compliance. Eptinezumab also has the added advantage of rapid onset which has been observed on day 1 post-treatment whereas other MAbs may take 1 month or more to establish benefit. The rapid onset of effect may prove to be advantageous to prevent progress from aPTH to pPTH. Given its ease of use as a rapid-acting single-administration medication, evidence in reduction in MMD, good tolerability and safety profiles, and adherence to treatment (single IV versus multiple doses), eptinezumab is an ideal candidate for study in patients with migraine-PTH.
192 studies on the registry are indexed under Post-Traumatic Headache; 54 are open to participants now.
This study's planned enrollment of 80 is above the median of 44 across 169 interventional studies indexed under Post-Traumatic Headache.
Browse Post-Traumatic Headache studies →Sunnybrook Health Sciences Centre is the lead sponsor of 584 studies on the registry; 135 are open to participants now.
Of its 6 completed or terminated interventional studies of FDA-regulated products, 2 (33%) have results posted.
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Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Within 8 weeks after onset of PTH
* Imaging is not required for inclusion
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
Childbearing potential
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Clinically significant
Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Eptinezumab 300mg IV once within 8 weeks of post-traumatic headache onset
Drug: Eptinezumab
Placebo IV once within 8 weeks of post-traumatic headache onset
Other: Placebo
Eptinezumab 300mg IV
Control - placebo IV
Headache frequency
Number of moderate to severe headache days between 9-12 weeks (inclusive) after intervention
Time frame: 9-12 weeks (inclusive) after intervention
Responder rate
Percentage change from baseline in the number of moderate to severe headache days, as captured by the participant's headache diary and at weekly follow-ups. At 9-12 weeks (inclusive) after treatment, those reporting a 50% reduction from baseline are considered responders.
Time frame: At 9-12 weeks (inclusive) after treatment, those reporting a 50% reduction from baseline are considered responders.
Acute treatment utilization
The number of days in which an acute headache treatment was used, as captured daily in the participant headache diary, at baseline, and at weekly follow-ups until week 12.
Time frame: Daily until 12 weeks
Preventive treatment utilization
The utilization of preventive analgesics, as a categorical yes/no variable, will be recorded daily in the participant headache diary, at baseline and at weekly follow-ups until week 12
Time frame: Daily until 12 weeks
Headache disability
Patient-reported disability due to their headache, assessed using the Headache Impact Test (HIT-6) at baseline and during follow-ups at 4/8/12/24 weeks. Minimum score 36, maximum score 78; higher score indicates worse outcome.
Time frame: Baseline until 24 weeks
Concussion severity
Patient-reported disability due to their headache, assessed using the Rivermead Post-Concussion Symptoms Questionnaire (RPQ), at baseline and during follow-ups at 4/8/12 weeks. Minimum score 0, maximum score 52; higher score indicates worse outcome.
Time frame: Baseline until 12 weeks
Emotional Function
Patient-reported anxiety using General Anxiety Disorder scale (GAD-7) at baseline and during follow-ups at 4/8/12 weeks. Minimum score 0, maximum score 21; higher score indicates worse outcome.
Time frame: Baseline until 12 weeks
Emotional Function
Patient-reported mood using the Patient Health Questionnaire (PHQ-9) at baseline and during follow-ups at 4/8/12 weeks. Minimum score 0, maximum score 27; higher score indicates worse outcome.
Time frame: Baseline until 12 weeks
Emotional Function
Patient-reported post-traumatic stress using the PTSD checklist for DSM-5 (PCL-5) at baseline and during follow-ups at 4/8/12 weeks. Minimum score 0, maximum score 80; higher score indicates worse outcome.
Time frame: Baseline until 12 weeks
Patient satisfaction
Patient-reported satisfaction with their treatment, assessed using the patient global impression of change (PGIC), at baseline and during follow-ups at 4/8/12 weeks. Minimum score 0, maximum score 10; higher score indicates worse outcome.
Time frame: Baseline until 12 weeks
Sleep quality
Patient-reported sleep quality, assessed using the PROMIS 6a sleep questionnaire at baseline and during follow-ups at 4/8/12 weeks. Minimum score 6, maximum score 30; higher score indicates worse outcome.
Time frame: Baseline until 12 weeks
Adverse events
Adverse events related to study medication
Time frame: Baseline until 24 weeks after treatment
Plan to share: Yes — De-identified data will be available upon request
Supporting information: Study protocol, Statistical analysis plan, Informed consent form
Time frame: Upon publication, no limit on time
Access criteria: Contact study investigators
No publications or documents are linked to this record.
Start is estimated for Nov 2026; primary completion for Jun 2027, 7 months later.
Start moved once since we started tracking on Sep 25, 2026: Sep 2026 → Nov 2026, on Oct 23, 2026.
Earlier changes are on the record history on ClinicalTrials.gov ↗
How these figures are worked out, and which studies are left out of them.
From the registry record's own update history. This site started tracking changes on Sep 25, 2026; for anything earlier, see the record history on ClinicalTrials.gov ↗
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