Efficacy of Efgartigimod Alfa in Cognitive Impairment of Autoimmune Dementia: A Double-Blind, Randomized, Placebo-Controlled, Multi-Center Trial

The primary objective of this study is to evaluate the **efficacy** of a 52-week treatment with the FcRn inhibitor Efgartigimod compared to placebo in addressing cognitive impairment in patients diagnosed with autoimmune dementia. This objective is clinically relevant as it aims to determine the potential of Efgartigimod to improve cognitive function, which is a significant concern in the management of autoimmune dementia.

Secondary objectives include a comprehensive assessment of cognitive impairment using a neuropsychological test battery, a quality of life questionnaire, and evaluation of independent activities of daily living, as well as neuropsychiatric evaluation from baseline to 53 weeks post-administration of the first dose of Efgartigimod. Additional secondary objectives involve monitoring laboratory parameters, including serum and CSF immune cells, and potential changes in the autoantibody repertoire. All adverse events and serious adverse events are tracked throughout the trial duration.

The clinical trial focuses on patients diagnosed with **autoimmune dementia**, aiming to assess the efficacy of a 52-week treatment with the FcRn inhibitor Efgartigimod compared to a placebo. The study population includes both male and female subjects aged 40 years and older, with a confirmed diagnosis of progressive cognitive impairment or dementia persisting for more than three months. Participants are required to have a Montreal Cognitive Assessment (MoCA) score between 10 and 25 and must exhibit the presence of anti-brain autoantibodies in serum and/or cerebrospinal fluid. The trial includes individuals who can communicate in German sufficiently to comprehend study information and perform neuropsychological assessments reliably. Participants must have received vaccinations according to STIKO recommendations, including the COVID-19 vaccine. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy of the **FcRn inhibitor Efgartigimod** in patients with **autoimmune dementia**. The trial will span a duration of 52 weeks, with the primary objective being to assess the impact of Efgartigimod on cognitive impairment compared to a placebo. Participants will be randomly assigned to receive either the active treatment, Vyvgart 1,000 mg solution for injection, or a placebo, administered via **subcutaneous injection**. The trial will include male and female subjects aged 40 years and older, who have been diagnosed with progressive cognitive impairment or dementia for more than three months and have the presence of anti-brain autoantibodies in serum and/or cerebrospinal fluid.

The study will commence with an inclusion (screening) visit to confirm eligibility based on the inclusion criteria, such as a **Montreal Cognitive Assessment (MoCA)** score between 10 and 25, and the ability to understand German for reliable neuropsychological assessments. Following the screening, participants will undergo baseline assessments before the initiation of treatment. Study visits will be scheduled at weeks 13, 27, and 53 to evaluate changes in cognitive function, quality of life, activities of daily living, and laboratory parameters. The primary endpoint will be the change in MoCA score from baseline to week 53, with secondary endpoints including evaluations at weeks 13 and 27, as well as assessments of neuropsychological tests and reduction of autoantibodies.

The expected length of participant involvement is approximately 53 weeks, including the screening period. Conditions that may lead to early termination from the study include withdrawal of consent, non-compliance with study procedures, or adverse events that, in the opinion of the investigator, warrant discontinuation. The trial is categorized as a Phase 4 study, and it is not considered a low-intervention trial. The estimated recruitment start date is July 14, 2025, with an anticipated end date of March 15, 2027. Participants will be required to provide written consent and adhere to vaccination recommendations, including COVID-19 vaccination, as part of the eligibility criteria.

The clinical trial involves the administration of **Efgartigimod alfa**, marketed under the name Vyvgart, as the experimental medication. Vyvgart is a **solution for injection** containing 1,000 mg of the active substance Efgartigimod alfa, a human monoclonal antibody fragment targeting the FcRn receptor. The pharmaceutical form is a solution intended for **subcutaneous injection**. The maximum total dose administered is 1,000 mg, with a maximum daily dose of 142.86 mg. The treatment period extends up to 52 weeks. The administration schedule and participant compliance are monitored throughout the trial to ensure adherence to the dosing regimen.

The study also includes a **placebo** group, which receives an injection solution formulated to match Vyvgart 1,000 mg s.c. but without the active substance Efgartigimod alfa. This placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo is administered via the same route and frequency as the experimental medication to provide a valid comparison of efficacy and safety outcomes.

The efficacy of the clinical trial investigating the FcRn inhibitor **Efgartigimod** in patients with autoimmune dementia will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on cognitive impairment, specifically evaluating the change in the Montreal Cognitive Assessment (MoCA) score from baseline to 53 weeks. This change will be dichotomized as either ≥0 or <0.

Secondary endpoints include a comprehensive evaluation of the MoCA score as a continuous measure, with assessments conducted at baseline, week 13, week 27, and week 53. Additional neuropsychological tests will be administered to assess changes from baseline to week 13 and week 53. Quality of life and activities of daily living will also be evaluated at these time points. The trial will monitor the reduction of autoantibodies and partial normalization of laboratory parameters from baseline to week 53. Serum and cerebrospinal fluid analyses will be conducted to measure cell count, cytology, protein, glucose, lactate, and infection markers.