Efficacy and Safety of Botulinum Toxin A in Persistent Post-Traumatic Headache: A Double-Blind, Randomized, Placebo-Controlled Trial

The primary objective of this study is to evaluate whether **botulinum toxin type A (BTX-A)** is safe and more effective than placebo in reducing the number of moderate-to-severe headache days in patients with persistent post-traumatic headache during the evaluation period (weeks 5 to 8) compared to the baseline period (weeks -4 to -1). This is clinically relevant as it aims to provide an effective treatment option for individuals suffering from this debilitating condition, potentially improving their quality of life.

Secondary objectives include:

• Investigating the degree of change in inflammatory biomarkers in plasma and tears in responders versus non-responders in the BTX-A and placebo groups.
• Assessing the proportion of subjects achieving a ≥50% or a ≥75% reduction in the number of days with moderate-to-severe headache during the evaluation period compared with baseline.
• Evaluating changes in various patient-reported outcome measures (PROMs) from baseline to the evaluation period in the BTX-A group versus the placebo group.
• Assessing the effectiveness of blinding.
• Evaluating tolerability and safety by examining the proportion of dropouts due to increased intake of post-traumatic headache medication or use of prohibited rescue medication, and the proportion of subjects with side effects in the BTX-A group compared to the placebo group.

The clinical trial focuses on individuals diagnosed with **persistent post-traumatic headache**. The study population includes both male and female participants, aged between 18 and 80 years. Participants are required to have experienced headaches on at least 15 days per month during the last four weeks prior to the baseline phase, with moderate-to-severe headaches occurring on at least 8 days. The trial does not involve a vulnerable population. Participants must be fluent in Danish. The sponsor has not provided information regarding the total number of participants. The selection criteria ensure that the study population is representative of individuals who suffer from persistent post-traumatic headaches, allowing for a comprehensive evaluation of the safety and efficacy of botulinum toxin type A compared to a placebo.

The clinical trial is designed to evaluate the **safety** and efficacy of **botulinum toxin A** in patients with persistent post-traumatic headache. This study is a double-blind, randomized, placebo-controlled, parallel-group trial. The primary objective is to determine if botulinum toxin type A (BTX-A) is more effective than placebo in reducing the number of moderate-to-severe headache days during the evaluation period, which spans weeks 5 to 8, compared to baseline weeks -4 to -1. The trial is expected to commence recruitment on October 1, 2024, and conclude by April 1, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of persistent post-traumatic headache, age between 18 and 80 years, and a history of headaches occurring at least 15 days per month. Following the screening, eligible participants will enter a baseline phase, during which they must experience moderate-to-severe headaches on at least 8 days and headaches on at least 15 days to qualify for randomization into the treatment phase.

The trial will include follow-up visits to monitor the participants' response to treatment and any adverse effects. The primary endpoint is the proportion of responders, defined as participants achieving a reduction of ≥30% in the number of days with moderate or severe headache during the evaluation period compared to baseline. Secondary endpoints include changes in inflammatory biomarkers and various clinical scales, as well as the proportion of subjects achieving ≥50% and ≥75% reduction in headache days.

Participant involvement is expected to last for the duration of the trial, with conditions for early termination including increased intake of prohibited medications or significant adverse effects. The trial will ensure rigorous monitoring to maintain the integrity of the double-blind design and the validity of the results.

The clinical trial involves the administration of **Botulinum Toxin** as the experimental medication. This substance is provided in a pharmaceutical form identified as "PHF00231MIG" and is administered subcutaneously. The maximum daily dose is 155 units, with a total maximum dose of 155 units over the treatment period. The treatment duration is limited to one day. The role of Botulinum Toxin in the trial is as the test substance, and it is not a paediatric formulation. The administration of Botulinum Toxin is monitored to ensure compliance with the dosing schedule.

In addition to the experimental treatment, the trial includes the use of **Sodium Chloride** as a placebo. The product, known as Natriumklorid Fresenius Kabi 9 mg/ml, is a solvent for parenteral use and is also administered subcutaneously. The maximum daily and total dose is 3.1 ml, with the treatment period restricted to one day. Sodium Chloride serves as the comparator treatment in the trial, providing a control for evaluating the efficacy and safety of Botulinum Toxin. Compliance with the administration of Sodium Chloride is similarly monitored to ensure adherence to the study protocol.

Efficacy in this clinical trial will be assessed by evaluating the impact of **botulinum toxin A (BTX-A)** on reducing the number of moderate-to-severe headache days in patients with persistent post-traumatic headache. The primary endpoint is the proportion of responders in the BTX-A and placebo groups during the evaluation period (weeks 5 to 8) compared to baseline (weeks -4 to -1). A responder is defined as a subject who experiences a reduction of ≥30% in the number of days with moderate or severe headache.

Secondary endpoints include the degree of change in inflammatory biomarkers in plasma and tears among responders versus non-responders in both the BTX-A and placebo groups. Additional secondary endpoints involve the proportion of subjects achieving ≥50% and ≥75% reduction in headache days during the evaluation period, as well as changes in scores from baseline to week 5 on the HIT-6, RPQ, HADS, and ISI scales. The proportion of subjects with a PGI-C scale response of "much improved" or "very much improved" at week 8, and the proportion of dropouts due to increased medication intake or side effects, will also be assessed.