A Phase 3 interventional study of Botox 200 UNT Injection in Posttraumatic Headache, sponsored by Danish Headache Center. Recruiting at 1 site in Denmark. Open to participants aged 18 Years to 80 Years. Per ClinicalTrials.gov, last updated 2025-02-21.
Sponsored by Danish Headache Center · Phase 3, Interventional, and Treatment
The study is an investigator-initiated randomized, placebo-controlled, double-blind, parallelgroup trial. Eighty subjects with PTH will be included and randomized 1:1 for treatment with BTX-A or placebo (isotonic saline). The study comprises a 4-week baseline phase before injection of either active drug or placebo followed by a 12-week evaluation period. Treatment will be double-blind, and subjects will only receive one treatment cycle. Endpoints will be assessed in the evaluation period (weeks 5 to 8) compared to baseline (weeks -4 to -1).
Post-traumatic headache (PTH) accounts for 4% of all symptomatic headache disorders and is one of the most common consequences of mild traumatic brain injury, also known as concussion. There is significant overlap between PTH and primary headache disorders, making treatment strategies highly dependent on the specific headache pattern.
Initial treatment typically involves common analgesics, with triptans as an alternative option. For patients experiencing persistent PTH or inadequate response to acute treatment, preventive medication is recommended based on the characteristics of their headache. While PTH is classified as a secondary headache disorder, its symptoms often resemble migraine, suggesting a potential overlap in underlying molecular mechanisms.
One molecule that has drawn attention in this context is calcitonin gene-related peptide (CGRP), which plays a key role in migraine pathogenesis. Studies have shown that intravenous infusion of CGRP can trigger migraine attacks, while CGRP antagonism has been effective for both acute and preventive migraine treatment. Supporting its role in PTH, research has indicated that blocking CGRP may have therapeutic benefits for patients with persistent PTH. Additionally, animal studies have suggested that concussed rodents exhibit hypersensitivity to CGRP, further implicating its involvement in post-traumatic headache.
The relationship between botulinum toxin type A (BTX-A) and CGRP has also been explored in experimental models using capsaicin. Capsaicin activates sensory nerve fibers, causing pain through the release of pain mediators such as CGRP and substance P. Interestingly, BTX-A has been shown to reduce pain, inflammation, and hyperalgesia by blocking CGRP release, which may contribute to its clinical effectiveness.
Botulinum Toxin A (BTX-A) BTX-A is a neurotoxin produced by Clostridium botulinum that inhibits the release of acetylcholine at the neuromuscular junction, leading to muscle relaxation. When administered subcutaneously to the face and scalp, BTX-A has been approved as a preventive treatment for chronic migraine, as well as several other conditions.
In the treatment of trigeminal neuralgia, BTX-A is used off-label, with injections of 50-150 units in affected areas supplied by branches of the trigeminal nerve. The treatment is generally well-tolerated, with minimal side effects, such as mild muscle weakness at the injection site. Importantly for PTH, BTX-A does not cause cognitive side effects. However, scientific evidence supporting its effectiveness in PTH remains weak, and well-powered randomized controlled trials are needed.
Research suggests that BTX-A can reduce inflammation in the periosteum and inhibit the release of signaling molecules such as CGRP. It also prevents the insertion of pain-related ion channels in the synaptic membrane, which are involved in pain processing. Additionally, CGRP and vasoactive intestinal peptide (VIP) have been identified as potential biomarkers predicting the effectiveness of BTX-A in other pain conditions. BTX-A has also been shown to decrease inflammatory biomarkers, including interleukin-1 at the trigeminal ganglion and tumor necrosis factor alpha in experimental pain models. These findings suggest that BTX-A may act as a modulator of neuronal signaling and neuroinflammation, providing a potential mechanism for its effect in treating PTH.
Clinical Efficacy and Safety of BTX-A The effectiveness of BTX-A was evaluated in a study involving 40 PTH patients who were randomly assigned to receive either BTX-A or a saline placebo. The study assessed changes in headache frequency, severity, and the number of headache days per week. Patients treated with BTX-A experienced a significant reduction in weekly headaches, with a decrease of 2.24 headaches per week (43.3%). In contrast, those receiving placebo experienced an increase of 1.28 headaches per week (35.1%). The difference between the two groups was statistically significant, supporting the potential benefit of BTX-A for PTH treatment.
Rationale for Study Endpoints During the evaluation period, the primary measure of efficacy in this study is the change in the number of moderate-to-severe headache days compared to baseline. A moderate-to-severe headache day is defined as a day with headache pain of moderate or severe intensity lasting at least 30 minutes without medication or a headache that responds to acute treatment. A clinically meaningful treatment response is considered to be a reduction of at least 30% in moderate-to-severe headache days.
Rationale for Injection Site and Dosage Patients will receive 155 units of BTX-A through 31 injections of 5 units each, following the PREEMPT protocol. The placebo will consist of isotonic saline administered through 31 injections of 0.1 ml each.
Investigating Neuroinflammatory Biomarkers There is limited research on neuroinflammatory biomarkers and their role in PTH. This study could provide valuable insights into the underlying mechanisms of PTH and determine whether biomarkers can predict treatment response. Since the trigeminal nerve innervates the cornea, measuring CGRP levels in tear fluid may be a more sensitive method for detecting concentration changes compared to blood plasma, given the tear fluid's proximity to trigeminal nerve endings.
Clinical Hypothesis BTX-A reduces the number of moderate-to-severe headache days in PTH patients with minimal side effects, making it an effective and safe treatment.
In PTH patients, changes in neuroinflammatory biomarker concentrations are significantly greater in those who respond to BTX-A compared to non-responders or those receiving placebo.
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 →Danish Headache Center is the lead sponsor of 129 studies on the registry; 15 are open to participants now.
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Exclusion Criteria:
Female subject of who is unwilling to use an acceptable method of effective during the study. Acceptable methods of effective birth control include not having intercourse (true abstinence, when this is in line with the preferred and usual lifestyle of the subject), hormonal birth control methods (pills, shots/injections, implants, or patches), intrauterine devices, surgical contraceptive methods (vasectomy with medical assessment of the surgical success of this procedure or bilateral tubal ligation). Female subjects not of childbearing potential are defined as any female who: is by history, defined as:
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.
A “mini-stroke”: temporary stroke-like symptoms caused by reduced blood flow to part of the brain, spinal cord or eye, without signs of a new stroke on a scan.
Stroke symptoms need emergency care at once, even if they go away.
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.
Periods have stopped for good: usually no period for 12 months in a row without another medical reason, sometimes confirmed by a blood test (FSH).
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
TIA (transient ischaemic attack)
A “mini-stroke”: temporary stroke-like symptoms caused by reduced blood flow to part of the brain, spinal cord or eye, without signs of a new stroke on a scan.
Stroke symptoms need emergency care at once, even if they go away.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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.
Postmenopausal
Periods have stopped for good: usually no period for 12 months in a row without another medical reason, sometimes confirmed by a blood test (FSH).
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Investigational drug or device
A drug or device being studied in a clinical trial.
It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
BTX-A used in this study will be Botox® and delivered in vials. A concentration of 50U/mL BTX-A is prepared using saline in four syringes: one with 1 mL, one with 0.8 mL, one with 0.7 mL, one with 0.6 mL. This equals a total administration dose of 155U.
Drug: Botox 200 UNT Injection
Placebo syringes are prepared exclusively with similar amounts of fluid as in the BTX-A arm.
Drug: Botox 200 UNT Injection
A concentration of 50U/mL BTX-A is prepared using saline in four syringes: one with 1 mL, one with 0.8 mL, one with 0.7 mL, one with 0.6 mL. This equals a total administration dose of 155U. A total of 155U BTX-A will be injected at day 1 (first day in week 1) by subcutaneous injections according to the PREEMPT protocol.
Also known as: Botulinumtoxin-A
Primary aim
To investigate if botulinum toxin type A (BTX-A) is safe and more effective than placebo to lower the number of moderate-to-severe headache days in the evaluation period (weeks 5 to 8) compared to baseline (weeks -4 to -1). Headache days will defined as mild, moderate or severe in intensity based on the International Headache Society guideline for conduction studies on preventive medication in post-traumatic headache
Time frame: 3 months
First secondary aim
To investigate the degree of change in inflammatory biomarkers concentration in plasma and tears in responders versus non-responders in the BTX-A and placebo groups at week 0 and week 8.
Time frame: 2 months
Second secondary aim
To investigate the proportion of subjects reaching a ≥50% or a ≥75% reduction in the number of days with moderate-to-severe headache during the evaluation period (weeks 5 to 8) compared with baseline (weeks -4 to -1), respectively.
Time frame: 3 months
Third secondary aim
To evaluate the change from baseline period (weeks -4 to -1) to evaluation period (weeks 5 to 8) in Headache Impact Test (HIT-6) at week 8 in the BTX-A group versus the placebo group.
Time frame: 3 months
Fourth secondary aim
To evaluate the change from baseline period (weeks -4 to -1) to evaluation period (weeks 5 to 8) in Headache Impact Test (HIT-6) at week 8 in the BTX-A group versus the placebo group.
Time frame: 3 months
Fifth secondary aim
To evaluate the effectiveness of blinding. Participants will be asked to guess which study drug was administered to make sure that blinding was not broken because of visible discrete facial paralysis.
Time frame: 3 months
Sixth secondary aim
To evaluate tolerability and safety by A. Evaluating the proportion of dropouts caused by increased intake of posttraumatic headache (PTH) medication or use of prohibited rescue medication in the BTX-A group compared to the placebo group. B: Evaluating the proportion of subjects with side effects registered in the evaluation period (weeks 5 to 8) in the BTX-A group compared to the placebo group.
Time frame: 3 months
Seventh secondary aim
To evaluate the change from baseline period (weeks -4 to -1) to evaluation period (weeks 5 to 8) in Rivermead Post-Concussion Symptoms Questionnaire at week 8 in the BTX-A group versus the placebo group.
Time frame: 3 months
Eight secondary aim
To evaluate the change from baseline period (weeks -4 to -1) to evaluation period (weeks 5 to 8) in Hospital Anxiety and Depression Scale (HADS) at week 8 in the BTX-A group versus the placebo group.
Time frame: 3 months
Ninth secondary aim
To evaluate the change from baseline period (weeks -4 to -1) to evaluation period (weeks 5 to 8) in The Insomnia Severity Index (ISI) at week 8 in the BTX-A group versus the placebo group.
Time frame: 3 months
Plan to share: No
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Started Jan 2025 (actual). Primary completion is estimated for Mar 2026, 13 months after the start.
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Studies of the drug tested here: BOTOX 200