Evaluation of Botulinum Toxin Type A Efficacy and Safety in Trigeminal Neuralgia: A Double-Blind, Randomized, Placebo-Controlled Trial

The primary objective of this study is to evaluate the efficacy of **botulinum toxin A** compared to placebo in the treatment of **trigeminal neuralgia**. This is clinically relevant as trigeminal neuralgia is a chronic pain condition that can significantly impact a patient's quality of life, and effective treatment options are limited. The study aims to determine whether botulinum toxin A can provide superior pain relief, which could offer a new therapeutic avenue for patients suffering from this debilitating condition.

Secondary objectives include investigating whether neuroinflammatory biomarkers can predict the treatment response to botulinum toxin A in patients with trigeminal neuralgia. Identifying predictive biomarkers could enhance personalized treatment strategies, allowing for more targeted and effective management of the condition.

The clinical trial focuses on evaluating the efficacy of **botulinum toxin A** compared to placebo in the treatment of **trigeminal neuralgia**. The study population comprises both male and female participants, aged between 18 and 85 years, who have been diagnosed with either classical or idiopathic trigeminal neuralgia as per the criteria of The International Classification of Headache Disorders 3rd edition. Participants are required to experience at least one trigeminal neuralgia-related pain paroxysm per day, with an average intensity ranging from 3 to 10 on the 11-point Numerical Rating Scale, both prior to and during the baseline phase. The trial does not involve a vulnerable population, and fluency in Danish is necessary for inclusion. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed to evaluate the **safety** and **efficacy** of **botulinum toxin A** in patients diagnosed with **trigeminal neuralgia**. This study is structured as a randomized, double-blind, placebo-controlled, parallel-group trial. The primary objective is to determine if botulinum toxin A is more effective than a placebo in alleviating the symptoms of trigeminal neuralgia. The trial is expected to commence on October 1, 2023, and conclude by September 30, 2025, with the total duration of participant involvement being approximately 12 weeks.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18-85 years), diagnosis of classical or idiopathic trigeminal neuralgia, and pain intensity. Following successful screening, participants will enter a baseline phase where pain intensity and frequency are monitored. Randomization occurs after the baseline phase, provided the participant continues to meet the inclusion criteria.

Subsequent visits will include regular follow-up assessments to monitor the primary endpoint, which is the proportion of responders in the botulinum toxin A and placebo groups during the evaluation period (weeks 2 to 5) compared to baseline. Secondary endpoints will assess changes in inflammatory biomarkers, pain reduction, and side effects. The end-of-study visit will evaluate the overall outcomes and any adverse events experienced by the participants.

Participants are expected to remain in the study for the full duration unless specific conditions necessitate early termination. These conditions include significant adverse reactions, increased intake of trigeminal neuralgia medication, or use of prohibited rescue medication. The trial will ensure that all procedures adhere to ethical standards and regulatory requirements, maintaining the integrity and scientific validity of the study.

The clinical trial involves the administration of **botulinum toxin type A** as the experimental medication. The product, marketed under the name "BOTOX, pulver til injektionsvæske, opløsning 100 Allergan-enheder," is provided in the form of a powder for solution for injection. The active substance, **botulinum toxin type A**, is a protein derived from the bacterium Clostridium botulinum. The medication is administered subcutaneously with a maximum daily dose of 85 U units, and the total dose should not exceed 85 U units over the treatment period. The maximum treatment period is set at one day. The administration of the drug is monitored to ensure compliance with the dosing schedule.

In addition to the experimental treatment, the study utilizes **sodium chloride** as a non-experimental treatment. The product, "Natriumklorid Fresenius Kabi 9 mg/ml, spädningsvätska för parenteral användning," serves as a solvent for parenteral use. The active substance, **sodium chloride**, is a chemical compound commonly used in clinical settings. It is administered subcutaneously with a maximum daily dose of 1.7 ml millilitres, and the total dose should not exceed 1.7 ml millilitres over the treatment period. The maximum treatment period is also set at one day. This non-experimental treatment is used as a placebo in the trial to compare the efficacy of the experimental medication.

Efficacy in this clinical trial will be assessed by evaluating the effectiveness of **botulinum toxin A** in treating patients with trigeminal neuralgia. The primary endpoint is the proportion of responders in the botulinum toxin A (BTX-A) and placebo groups during the evaluation period, which spans from week 2 to week 5, compared with baseline measurements taken from week -4 to week -1. Responders are defined according to specific criteria outlined in the trial protocol.

Secondary endpoints include several measures: the degree of change in inflammatory biomarkers in responders versus non-responders in both the BTX-A and placebo groups, the difference in inflammatory biomarkers between the symptomatic and asymptomatic sides, and the proportion of subjects achieving various levels of reduction in mean average daily pain (ADP) during specified evaluation periods. Additionally, changes in the mean number of daily pain paroxysms and the proportion of subjects with a Patient Global Impression of Change (PGI-C) scale response of "much improved" or "very much improved" at week 5 will be assessed. Other secondary measures include changes in the PENN-FPS-R score from baseline to week 5, the proportion of subjects correctly guessing their treatment group, dropout rates due to increased medication intake, and the incidence of side effects during weeks 2 to 5.