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
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 80
- 试验地点
- 1
- 主要终点
- Primary aim
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •A diagnosis of persistent PTH according to criteria 5.2.2 Persistent headache attributed to mild traumatic injury to the head according to The International Classification of Headache Disorders 3rd edition.
- •Age between 18 and 80 years.
- •Subjects must have headache at least 15 days per month during the last 4 weeks to enter the baseline phase.
- •During baseline phase subjects must experience moderate-to-severe headache at least 8 days and headache at least 15 days to enter the treatment phase (to be randomized).
- •Fluency in Danish
排除标准
- •More than 2 TBI's.
- •Severe cardiovascular and cerebrovascular disease such as ischemic heart disease, myocardial infarction or previous stroke or transient ischemic attack, major CVD interventions during the last three months.
- •Expected poor compliance, i.e., considered unlikely to be able to complete all protocol required study visits or procedures, and/or to comply with all required study procedures to the best of the subject's and investigator's knowledge.
- •Ongoing and unstable severe psychiatric disease.
- •Anamnestic or clinical symptoms of any kind that are deemed relevant for study participation by the physician who examines the patient.
- •A history of migraine or tension-type headache more than 5 days per month before the TBI.
- •Medication-overuse headache according to the according to The International Classification of Headache Disorders 3rd edition.
- •A history of moderate-to-severe TBI, whiplash injury, or craniotomy.
- •Change of preventive PTH treatment or treatment dose within two months prior to the baseline visit (see Section 6.4 for a full list of these medications).
- •Previous treatment with injections of BTX-A in the head or face.
- •Female subjects either pregnant, breastfeeding or with planned conception within the study period.
- •Female subject of childbearing potential who is unwilling to use an acceptable method of effective contraception 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 post-menopausal by history, defined as:
- •Age ≥ 55 years with cessation of menses for 12 or more months, OR
- •Age < 55 years but no spontaneous menses for at least 2 years, OR
- •Age < 55 years and spontaneous menses within the past 1 year, but currently amenorrheic (e.g., spontaneous, or secondary to hysterectomy), AND with postmenopausal gonadotropin levels (luteinizing hormone and follicle-stimulating hormone levels > 40 IU/L) or postmenopausal estradiol levels (< 5 ng/dL) or according to the definition of "postmenopausal range" for the laboratory involved OR underwent bilateral oophorectomy OR underwent hysterectomy OR underwent bilateral salpingectomy.
- •Known allergy to any component of BTX-A.
- •Infection at the proposed injection site.
- •Known severe neuromuscular disorders or any degree of disorder affecting the neuromuscular transmission.
- •Known comprised respiratory function.
- •Member of investigational site staff or relative of the investigator.
研究组 & 干预措施
BTX-A
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.
干预措施: Botox 200 UNT Injection (Drug)
Isotonic saline
Placebo syringes are prepared exclusively with similar amounts of fluid as in the BTX-A arm.
干预措施: Botox 200 UNT Injection (Drug)
结局指标
主要结局
Primary aim
时间窗: 3 months
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
次要结局
- Second secondary aim(3 months)
- Third secondary aim(3 months)
- Sixth secondary aim(3 months)
- First secondary aim(2 months)
- Eight secondary aim(3 months)
- Fourth secondary aim(3 months)
- Fifth secondary aim(3 months)
- Seventh secondary aim(3 months)
- Ninth secondary aim(3 months)
研究者
Henrik Schytz
Associate Professor
Danish Headache Center