Evaluation of Perampanel Efficacy in Pre-Surgical Treatment of Patients with Progressive Glioblastoma: A Controlled Study

The primary objective of this clinical trial is to evaluate the **efficacy** of pre-surgical **perampanel** treatment compared to placebo in patients with recurrent or progressive **glioblastoma**. This will be assessed by examining the shift in mRNA expression patterns to a lower connectivity score in tumor tissue and the presurgical tumor growth rate, as determined by tumor volume using AI-quantified MRI parameters (T2/FLAIR-weighted images) reviewed by a central blinded independent review committee. This objective is clinically relevant as it aims to determine the potential of perampanel to modify tumor biology and growth, which could lead to improved surgical outcomes and overall management of glioblastoma.

The secondary objectives include: - Assessing the kinetics in contrast-enhancing tumor volume (T1CE images) and tumor volume (T2/FLAIR) using central AI-based MRI assessment. - Evaluating health-related quality of life and symptoms through EORTC QLQ-C30 and QLQ-BN20 questionnaires. - Measuring the severity of cognitive impairment using the mini-mental state examination. - Determining overall survival and progression-free survival from randomization until progression according to RANO criteria. - Monitoring epileptic seizure activity. - Checking for the occurrence of adverse effects as reported in the summary of the medical product characteristics and comparing between treatments.

The clinical trial involves participants diagnosed with **progressive glioblastoma**, a condition characterized by aggressive brain tumor growth. The study population includes both male and female subjects, aged 18 years and older, with a **Karnofsky Performance Status** score of at least 60%, indicating a requirement for participants to have a relatively stable general health status. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants were selected based on their histologically confirmed diagnosis of glioblastoma that is progressive or recurrent after one or two lines of prior treatment, including radiotherapy and drug treatments. Key lifestyle considerations include the ability to comply with regular neurocognitive and health-related quality of life assessments. The trial population includes individuals who are willing to undergo surgery and adhere to the randomized treatment protocol. The study also involves a vulnerable population, as indicated by the inclusion of individuals with cognitive capacity to understand the study's rationale and procedures. Participants must have a life expectancy of more than three months and provide written informed consent to participate in the trial.

The clinical trial is designed to evaluate the efficacy of **perampanel** treatment in patients with **progressive glioblastoma**. This is a randomized, double-blind, controlled trial, with a primary objective to assess the impact of pre-surgical perampanel compared to placebo on mRNA expression patterns and presurgical tumor growth rate. The trial is expected to commence on December 1, 2023, and conclude by December 1, 2025. Participants will be randomly assigned to receive either perampanel or a placebo, with both treatments encapsulated and administered orally. The trial will span a maximum treatment period of 60 days.

Study visits are structured to ensure comprehensive data collection and participant safety. The inclusion visit, or screening, will confirm eligibility based on criteria such as histologically confirmed glioblastoma, cognitive ability to understand the study, and a negative pregnancy test for females of reproductive potential. Follow-up visits will occur regularly to monitor tumor progression, neurocognitive function, and quality of life. The end-of-study visit will evaluate the primary and secondary endpoints, including changes in tumor volume and connectivity scores.

Participants are expected to be involved in the study for the duration of the treatment period, with additional time allocated for follow-up assessments. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with study procedures. The trial's endpoints will be assessed using AI-quantified MRI parameters and other validated measures to ensure robust and reliable data collection.

The clinical trial involves the administration of **Perampanel**, an antiepileptic agent, in the form of **film-coated tablets**. Each tablet contains 2 mg of the active substance, perampanel. The tablets are administered **orally**. The maximum daily dose is 10 mg, with a total maximum dose of 600 mg over the course of the treatment period. The treatment duration is set for a maximum of 60 days. The tablets, along with the placebo, are encapsulated and packaged to ensure blinding in the study. Participant compliance with the dosing schedule is monitored throughout the trial.

The study also utilizes a **placebo** control, which is composed of Füllstoff DAC in hard gelatine capsules. The placebo consists of 99.5% mannitol and 0.5% colloidal silicon dioxide. The placebo is administered in the same manner as the experimental medication, ensuring that the study remains double-blind. The placebo capsules are also encapsulated and packaged similarly to the perampanel tablets to maintain the integrity of the blinding process. Compliance with the placebo administration is monitored in the same manner as the active treatment.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the evaluation of the **connectivity score** determined from RNA sequencing of tumor tissue and the kinetics of T2/FLAIR signal abnormality volume, assessed by a central blinded independent review committee (BIRC) using AI-based MRI parameters. These assessments will focus on the shift in mRNA expression patterns and the presurgical tumor growth rate in patients with recurrent or progressive glioblastoma.

Secondary endpoints will further evaluate efficacy through various measures, including pre-surgical and post-surgical log-transformed tumor volume based on AI-quantified MRI parameters, changes in health-related quality of life scores using EORTC QLQ-C30 and QLQ-BN20, and cognitive function assessed by the Mini-Mental State Examination (MMSE). Additionally, overall survival (OS) and progression-free survival (PFS) will be monitored, with PFS defined as the time from randomization to the first documented radiographic progression or death. The total number of epileptic seizures and the occurrence of side effects will also be recorded. These efficacy parameters will be collected and analyzed at specified timepoints, including baseline, pre-surgical, and post-surgical intervals, to provide a comprehensive evaluation of the treatment's impact.