EarLy Infusion of Eptinezumab for TreatmEnt of ACute Post-Traumatic Headaches (ELITE-ACT): a Parallel Group, Randomized, Double Blind, Placebo Controlled Trial

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.