Study protocol: double-blind, randomized, prospective, placebo controlled parallel group phase II study to investigate the effect of glycerol phenylbutyrate (GPB) on neurofilament light chain (NfL) levels in patients with corticobasal syndrome (CBS)

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INTRODUCTION: Corticobasal syndrome (CBS) is a rare progressive neurodegenerative disorder, with no disease-modifying treatments currently available. The most common underlying pathology is a 4-repeat tauopathy. Neurofilament light chain (NfL) is a biomarker of neuronal damage and has shown potential as a measure of disease progression. Glycerol phenylbutyrate (GPB), a prodrug of phenylbutyric acid, has demonstrated potential neuroprotective properties in preclinical studies on tauopathies. This phase II clinical trial will investigate the effects of GPB on NfL levels in CBS patients. The primary objective is to assess the efficacy of GPB in reducing NfL levels over 26 weeks compared to placebo as well as safety and tolerability of GPB. Secondary objectives include evaluating changes in clinical scales. METHODS AND ANALYSIS: This is an investigator-initiated double-blind, randomized, placebo-controlled, parallel-group phase II clinical trial, performed in two German university hospitals. A total of 32 patients with CBS will be enrolled and randomized to receive either GPB or placebo. The primary outcome is the change in NfL levels between baseline and 26 weeks as well as safety and tolerability of GPB. Secondary outcomes are changes in clinical scores. Exploratory analyses involve pharmacokinetics, changes in the metabolomic, proteomic and lipidomic profiles and imaging outcomes, such as MRI and microglia-PET. ETHICS AND DISSEMINATION: The study protocol has been approved by the lead ethics committee at LMU Munich and conforms to the ethical principles outlined in the Declaration of Helsinki and Good Clinical Practice (GCP) guidelines. PERSPECTIVES: If successful, this clinical trial could identify a novel therapeutic approach for slowing disease progression in CBS, contributing to a broader understanding of GPB's therapeutic potential. CLINICAL TRIAL REGISTRATION: The clinical trial has been registered in ClinicalTrials.gov (NCT05983588) and due to Transition in the Clinical Trials Information System (CTIS; EUCT No. 2024-516897-31-00, date of transition: 2024-09-26).

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