Evaluation of Tenofovir Alafenamide and Natalizumab Combination Therapy on Epstein-Barr Virus Activity in Multiple Sclerosis Patients

The primary objective of the study is to evaluate the **safety** of Tenofovir Alafenamide Fumarate (TAF) when used as an add-on therapy to **natalizumab** in patients with **Multiple Sclerosis** (MS). This is clinically relevant as it aims to assess the potential of TAF to enhance the therapeutic regimen for MS, potentially improving patient outcomes while monitoring for adverse effects.

Secondary objectives include determining the effect of TAF on **Epstein-Barr virus** activity in patients with Relapsing-Remitting Multiple Sclerosis (RRMS). This is significant as Epstein-Barr virus has been implicated in the pathogenesis of MS, and understanding the impact of TAF on this virus could provide insights into additional therapeutic benefits or mechanisms of action.

The clinical trial involves participants diagnosed with **multiple sclerosis**, specifically relapsing-remitting multiple sclerosis (RRMS), as defined by the revised McDonald criteria. The study population includes both male and female patients aged between 18 and 70 years. Participants are currently undergoing treatment with natalizumab and have demonstrated shedding of the Epstein-Barr virus in saliva. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity. The primary objective of the study is to assess the safety of TAF as an add-on therapy to natalizumab.

The clinical trial is designed to evaluate the **safety** of Tenofovir Alafenamide Fumarate (TAF) as an add-on therapy to **natalizumab** in patients with **multiple sclerosis** (MS). This is a Phase 4, randomized, double-blind, controlled study. The trial is expected to last approximately 24 weeks, with participant involvement spanning from the initial screening visit to the end-of-study visit. The study will include several key visits: an inclusion (screening) visit, follow-up visits at 2, 8, and 24 weeks, and an end-of-study visit. The primary endpoint is the total number of serious adverse events (SAEs) from baseline to 24 weeks after the start of the study treatment. Secondary endpoints include changes in IgG antibodies to EBNA1 and other EBV antigens, as well as changes in EBV viral load and shedding in saliva at specified intervals.

Participants eligible for the study must be aged between 18 and 70 years, have a diagnosis of relapsing-remitting multiple sclerosis (RRMS) according to the revised McDonald criteria, currently be treated with natalizumab, and demonstrate shedding of Epstein-Barr virus (EBV) in saliva. The study will involve the administration of TAF in the form of film-coated tablets, with a maximum daily dose of 25 mg, and natalizumab as a concentrate for solution for infusion, with a maximum daily dose of 300 mg. The trial will be conducted over a maximum treatment period of 180 days for TAF and 6 months for natalizumab. Conditions that may lead to early termination from the study include the occurrence of significant adverse events or non-compliance with the study protocol. The trial is set to commence recruitment in September 2023, with an estimated end date in June 2024.

The clinical trial involves the administration of **Vemlidy 25 mg film-coated tablets**, which contain the active substance **tenofovir alafenamide**. This medication is administered orally at a dosage of 25 mg once daily. The maximum treatment period for this medication is 180 days. The pharmaceutical form is a film-coated tablet, and it is classified as an antiviral treatment. Participant compliance with the dosing schedule will be monitored throughout the study.

Another treatment used in the trial is **Tysabri 300 mg concentrate for solution for infusion**, which contains the active substance **natalizumab**. This medication is administered via infusion at a dosage of 300 mg every four weeks, with a maximum total dose of 1200 mg over a six-month period. The pharmaceutical form is a concentrate for solution for infusion, and it is produced by Biogen Netherlands B.V. The administration of this medication will be closely monitored to ensure adherence to the dosing schedule.

The trial also includes the use of **capsule coated tablets** as a comparator treatment. These tablets are administered orally, but specific details regarding the active substance, dosage, and frequency of administration are not provided. The maximum treatment period for this comparator is six months. Compliance with the administration of this treatment will be monitored to ensure consistency with the study protocol.

Efficacy in the clinical trial titled "Tenofovir Alafenamide Fumarate and Epstein-Barr virus activity in people with MS – The TAF-MS study" will be assessed using both primary and secondary endpoints. The primary endpoint focuses on the total number of serious adverse events (SAEs) from baseline to 24 weeks after the initiation of the study treatment. This will provide a measure of the safety profile of the treatment regimen.

Secondary endpoints include changes in **IgG antibodies** to EBNA1 and other Epstein-Barr virus (EBV) antigens, as well as changes in EBV viral load in saliva. These parameters will be measured at baseline and at 2, 8, and 24 weeks after the start of the study treatment. Additionally, a key secondary endpoint is the change in EBV shedding in saliva over the same time periods. These assessments will help determine the impact of the treatment on EBV activity in patients with multiple sclerosis (MS).