Evaluation of Basimglurant Efficacy and Safety in Trigeminal Neuralgia Patients with Suboptimal Response to Current Analgesic Therapy

The primary objective of this study is to evaluate the **safety**, tolerability, and efficacy of basimglurant in patients with pain associated with **trigeminal neuralgia** (TN). This is clinically relevant as TN is a chronic pain condition that can significantly impact a patient's quality of life, and current treatments may not provide adequate relief. The study aims to assess the effects of basimglurant administered daily at doses of 1.5 to 3.5 mg during an 8-week run-in phase, followed by a 12-week double-blind phase to determine the maintenance of pain relief compared to placebo. Additionally, the long-term safety of basimglurant will be evaluated in an open-label extension phase.

Secondary objectives include:

• Period 1: Run-in - Evaluating the efficacy of basimglurant on various aspects of pain associated with TN, such as impact on facial pain, patient-perceived change in pain, quantitative and qualitative pain assessments, pain freedom, patient medication satisfaction, and functional impairment.
• Period 2: Double Blind - Assessing the effect of basimglurant versus placebo on facial pain, pain frequency and severity, patient-perceived change in pain, medication satisfaction, and safety of dosing.
• Open-Label Extension - Evaluating the continued efficacy of basimglurant on facial pain, pain frequency and severity, and patient-perceived severity of pain.

The clinical trial involves a total of **125 participants** diagnosed with **trigeminal neuralgia**. The study population includes both male and female subjects, aged between **18 to 75 years**. Participants were selected based on their ability and willingness to provide written informed consent, fluency in the language of the investigator and study staff, and a confirmed diagnosis of primary trigeminal neuralgia as per the ICHD3 criteria. The trial includes individuals who experience pain due to trigeminal neuralgia, with a baseline of at least three paroxysms per day, each with an intensity of four or more on a pain intensity numerical rating scale during the last seven days. Female participants are required to be either sterile, menopausal, or, if of childbearing potential, neither pregnant nor lactating, with appropriate contraceptive precautions and prior negative pregnancy tests. The trial population is not limited by specific lifestyle considerations such as diet or physical activity, but it does include a vulnerable population. The selection criteria ensure a comprehensive evaluation of the safety, tolerability, and efficacy of basimglurant in managing pain associated with trigeminal neuralgia.

The clinical trial is designed to evaluate the efficacy and safety of **basimglurant** in patients with pain associated with **trigeminal neuralgia** who have a suboptimal response to their current anti-pain therapy. This study is structured as a Phase II/III, multicenter, 8-week run-in phase followed by a 12-week, prospective, parallel-group, double-blind, randomized withdrawal, placebo-controlled study, with a 52-week open-label extension. The trial aims to assess the maintenance of effect on pain with daily dosing of basimglurant at 1.5 to 3.5 mg compared to placebo. The overall duration of the trial is estimated to conclude by May 2026, with recruitment having started in December 2021.

Participants will undergo a sequence of study visits beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of primary trigeminal neuralgia, and pain intensity. The run-in phase will evaluate the safety, tolerability, and initial efficacy of basimglurant. During the double-blind phase, participants will be randomized to receive either basimglurant or placebo to assess the maintenance of pain relief. The open-label extension will focus on the long-term safety of basimglurant. Follow-up visits will be scheduled to monitor adverse events, laboratory results, vital signs, and psychiatric status. The end-of-study visit will conclude the participant's involvement, which is expected to last up to 72 weeks, depending on the phase of the trial they are participating in.

Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The primary endpoints include changes in pain as measured by a pain diary, incidence and severity of adverse events, and time to loss of efficacy. Secondary endpoints will assess the proportion of pain-free days, severity of attacks, and changes in pain interference with daily activities. The study is not classified as low intervention and adheres to the regulatory requirements for a Category 2 trial under EU regulations.

The clinical trial involves the administration of **Basimglurant**, a chemical compound with the active substance name **BASIMGLURANT**. It is provided in the form of a capsule, with each capsule containing a dosage ranging from 1.5 mg to 3.5 mg. The capsules are intended for **oral use**. The maximum daily dose is 3.5 mg, and the total maximum dose over the treatment period is 1729 mg. The treatment period extends up to 72 weeks. Basimglurant is manufactured by NOEMA PHARMA AG and is identified by the sponsor product code NOE-101. The chemical structure of Basimglurant is also known as 2-Chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridinium sulphate. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.

The study also includes a **placebo** control, which is designed to match the Basimglurant capsules in appearance. The placebo consists of microcrystalline cellulose spheres (Vivapur 1000) encapsulated in a hard gelatin capsule with an opaque white body and cap, size 1. The placebo is administered orally, following the same dosing schedule as the active treatment, to maintain the double-blind nature of the trial. The placebo serves as a comparator to evaluate the efficacy and safety of Basimglurant in patients with pain associated with trigeminal neuralgia. Compliance with the placebo administration is similarly monitored to ensure the integrity of the study results.

The efficacy of **basimglurant** in patients with pain associated with trigeminal neuralgia will be assessed through a series of primary and secondary endpoints across different phases of the clinical trial. During the run-in phase, efficacy will be evaluated by changes in pain as recorded in the pain diary (TnED), alongside the incidence and severity of adverse events (AEs), and changes in psychiatric status measured by the Brief Psychiatric Rating Scale (BPRS). The double-blind phase will focus on the time to loss of efficacy for each participant, as determined by the Independent Adjudication Committee (IAC). The open-label extension will continue to monitor the incidence and severity of AEs, laboratory, vital signs, cardiovascular safety, and psychiatric status changes using the BPRS.

Secondary endpoints include the proportion of pain-free days, the number and severity of attacks (paroxysms), and the severity and duration of continuous pain, all measured by TnED. Additional assessments involve changes in pain interference with daily activities, mean changes in the total patient-rated Pain Effects Numeric Rating Scale (PENN-FPS-R), and patient-reported outcomes such as the Patient Global Impression of Change (PGI-C) and the Migraine-Specific Quality of Life Questionnaire (MSQ). These parameters will be measured at various timepoints, including baseline, week 8, and the end of the double-blind randomized treatment period. The study will also evaluate the overall patient global impression using the PGI-S during the open-label extension phase.