Evaluation of Tenofovir Alafenamide as an Adjunct to Anti-CD20 Therapy in Reducing Neuronal Damage in Multiple Sclerosis: A Phase 2b Randomized Controlled Trial

The primary objective of this study is to evaluate the efficacy of **Tenofovir Alafenamide Fumarate (TAF)** as an add-on to anti-CD20 therapy in reducing neuronal damage in patients with **multiple sclerosis** (MS) compared to placebo. This is clinically relevant as neuronal damage is a critical factor in the progression of MS, and effective management could potentially alter the disease course and improve patient outcomes.

Secondary objectives include:

• Assessing whether TSPO binding on PET is reduced after one year of treatment with TAF compared to placebo.
• Evaluating if patient-reported outcomes of fatigue are reduced after one year of treatment with TAF compared to placebo.
• Determining if the number of Paramagnetic Rim Lesions (PRLs) is reduced after one year of treatment with TAF compared to placebo.
• Testing the safety of TAF as an add-on treatment.
• Testing the tolerability of TAF as an add-on treatment.

The clinical trial involves participants diagnosed with **multiple sclerosis** according to the revised McDonald criteria. The study population includes both male and female subjects, aged between 18 to 70 years. Participants are required to have a creatinine clearance greater than 15 ml/min, serum bilirubin less than two times the upper limit of normal, and negative tests for HIV, chronic active hepatitis B, and hepatitis C. They must have been treated with the anti-CD20 monoclonal antibody rituximab for at least 24 months prior to inclusion. The trial does not involve a vulnerable population. Participants are expected to have a previous cerebral MRI with a T2 lesion volume of at least 15.00 cm³ and an EDSS score between 2 and 6.5. The sponsor has not provided information regarding the total number of participants. Key lifestyle considerations include the use of highly effective contraceptives by women and the willingness to participate in all study procedures, including lumbar puncture and travel for imaging. The selection criteria ensure that participants are in a stable health condition suitable for the study's requirements.

The clinical trial is designed as a **randomized**, **double-blind**, **controlled** study to evaluate the efficacy of **Tenofovir Alafenamide** as an add-on treatment to anti-CD20 therapy in reducing neuronal damage in patients with **multiple sclerosis**. The trial will involve a parallel group phase 2b study, comparing the active treatment with a placebo. The trial is expected to last for a total duration of 52 weeks, with the estimated recruitment start date set for October 1, 2025, and the estimated end date on September 30, 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, diagnosis of multiple sclerosis, and previous treatment with anti-CD20 monoclonal antibody rituximab. The inclusion criteria also require participants to have a creatinine clearance greater than 15 ml/min, serum bilirubin less than twice the upper normal limit, and negative tests for HIV, chronic active hepatitis B, and hepatitis C. Following the screening, participants will be randomized to receive either the active treatment or placebo, administered orally.

Throughout the trial, participants will attend follow-up visits to monitor treatment effects and safety. These visits will include assessments such as cerebrospinal fluid analysis to measure changes in Neurofilament light chain levels, PET imaging to evaluate TSPO binding, and patient-reported outcomes of fatigue. The primary endpoint is the change in mean cerebrospinal fluid Neurofilament light chain level from baseline to the end of the study. Secondary endpoints include differences in TSPO binding, changes in fatigue, and the number of new or enlarging lesions.

The expected length of participant involvement is approximately 52 weeks. Conditions that may lead to early termination from the study include significant adverse events, serious adverse events, or suspected unexpected serious adverse reactions. Participants' willingness and ability to comply with all study procedures, including lumbar puncture and travel for imaging, are essential for continued participation. The trial aims to provide valuable insights into the potential benefits of targeting Epstein Barr Virus in the treatment of multiple sclerosis.

The clinical trial involves the use of **Tenofovir Alafenamide** as the experimental medication. Tenofovir Alafenamide is an antiviral agent with the ATC code J05AF13. It is administered in the form of oral tablets, with a pharmaceutical form code of PHF00082MIG. The dosage for this medication is set at 25 mg per day, and it is to be taken orally. The maximum treatment period for Tenofovir Alafenamide is 52 weeks. The medication is provided by Gilead Sciences, Inc, under the scientific product code SCP17542550. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment protocol.

The study also includes the use of a **placebo** as a comparator treatment. The placebo is provided in the form of hard capsules, designed to mimic the appearance and administration route of the experimental medication. The placebo is administered orally, following the same dosing schedule as the Tenofovir Alafenamide, to maintain the double-blind nature of the trial. The placebo serves as a control to evaluate the efficacy of the experimental treatment in reducing neuronal damage in patients with multiple sclerosis. Compliance with the placebo administration will be monitored in a similar manner to ensure the integrity of the study results.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change in mean cerebrospinal fluid (CSF) **Neurofilament light chain** (NfL) levels between the treatment groups from baseline (week 0) to the end of the study (week 52). This biomarker is indicative of neuronal damage and will be measured to evaluate the treatment's impact on multiple sclerosis.

Secondary endpoints include the difference in TSPO binding on PET scans between the treatment groups from baseline to week 52, which will provide insights into neuroinflammation. Additionally, changes in patient-reported outcomes of fatigue will be assessed over the same period to evaluate the treatment's effect on this common symptom of multiple sclerosis. The difference in the number of paramagnetic rim lesions (PRLs) between the treatment groups will also be measured, as these lesions are associated with chronic active inflammation in multiple sclerosis. Furthermore, the total number of adverse events (AEs), serious adverse events (SAEs), and suspected unexpected serious adverse reactions (SUSARs) will be recorded to assess treatment tolerability.