Ignite Creation Date:
2025-12-25 @ 5:04 AM
Ignite Modification Date:
2025-12-26 @ 4:07 AM
Study NCT ID:
NCT06839118
Status:
RECRUITING
Last Update Posted:
2025-02-21
First Post:
2025-02-03
Is NOT Gene Therapy:
False
Has Adverse Events:
False
Brief Title:
Safety and Efficacy of Botulinum Toxin A in Patients With Posttraumatic Headache
Sponsor:
Danish Headache Center
Organization:
Study Overview
Official Title:
Safety and Efficacy of Botulinum Toxin A in Patients With Posttraumatic Headache: a Double-blind, Randomized, Placebo-controlled, Parallel-group Trial and Investigation of Neuroinflammatory Biomarkers as Predictors of Efficacy
Status:
RECRUITING
Status Verified Date:
2025-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
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).
Detailed Description:
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.
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.
Study Oversight
Has Oversight DMC:
True
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?: