Tenofovir Alafenamide for Treatment of Symptoms and Neuroprotection in Relapsing Remitting Multiple Sclerosis

As the in vivo reservoir of the Epstein-Barr virus, B cells play an important role in the perpetuation of MS disease activity. B cell depletion therapy with medications like ocrelizumab or rituximab have proved very successful in preventing clinical relapses and MRI activity in MS, but incomplete in terms of neuroprotection and symptomatic outcomes. Ocrelizumab and rituximab only target naïve and memory B cells expressing the CD20 marker but do not deplete the wide spectrum of B cell lineages including plasmablasts and plasma cells, which are also key reservoirs for EBV. This is particularly relevant to the mechanism of action of TAF, since EBV lytic reactivation occurs in coordination with B-cell differentiation. In vivo, the initiation of plasma cell differentiation provides the physiological trigger for EBV lytic reactivation, and EBV utilizes the plasma cell differentiation program to replicate. As these cells are ineffectively depleted by anti-CD20 treatment, the use of TAF would be highly complementary as an add-on treatment to anti-CD20 therapy.

Anti-EBV therapy with TAF in combination with ocrelizumab or rituximab will therefore provide a synergistic approach to cover the whole EBV reservoir.

The primary aims of the proposed trial are to determine if TAF, at the standard dose of 25 mg/day administered for 12 months:

i) is safe and well-tolerated by individuals with RRMS over a period of treatment of 12 months; ii) leads to an overall improvement in fatigue, as assessed by the Modified Fatigue Impact Scale by 12 months; and iii) causes a reduction in serum concentrations of neurofilament light chain (NfL), a marker of neuronal damage in MS.

Study Overview

• Status: Withdrawn
• Conditions: Fatigue; Multiple Sclerosis, Relapsing-Remitting
• Intervention / Treatment: Drug: Placebo; Drug: TENOFOVIR ALAFENAMIDE FUMARATE 25 Mg ORAL TABLET [VEMLIDY]

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Provision of signed and dated informed consent form
2. Stated willingness and ability to comply with all study procedures and availability for the duration of the study
3. Aged 18+ years
4. Diagnosis of MS using revised 2010 McDonald criteria of clinically definite MS.
5. Receiving treatment with either ocrelizumab or rituximab on a regular twice-yearly schedule. The first infusion must have been received at least 6 months before enrollment.
6. Must report significant fatigue during the past 3 months not due to a cause other than MS.
7. For females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation.
8. For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner.

Exclusion Criteria:

1. Pregnancy or lactation
2. Known allergic reactions to components of TAF
3. Treatment with another investigational drug or other MS-directed intervention such as glatiramer acetate, or dimethyl fumarate within 3 months
4. Positive HIV antibody test, active or latent hepatitis B
5. Relapse and/or steroid treatment within the previous 30 days
6. Baseline EDSS > 7
7. Current symptoms of severe, progressive, or uncontrolled renal, hematologic, gastrointestinal, pulmonary, cardiac, or neurologic disease, or other medical conditions that, in the opinion of the Investigator, might place the subject at unacceptable risk for participation in this study
8. Known history of sleep apnea, narcolepsy, or other significant sleep disorders
9. Recent changes to medications affecting sleep or fatigue or changes in dosage of those medications within 90 days
10. Creatinine clearance (CrCl) <55mL/min, as calculated by the Cockcroft-Gault equation
11. Taking medication with known interactions with tenofovir alafenamide including: Acyclovir, valacyclovir, adefovir, cabozantinib, carbamazepine, cidofovir, cladribine, cobicistat, diclofenac, multiple NSAIDs or chronic high dose NSAIDs, fosphenytoin or phenytoin, ganciclovir, valganciclovir, oxcarbazepine, phenobarbital, primidone, rifabutin, rifampin, rifapentine, sofosbuvir, tipranavir

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo pill	Drug: Placebo; Placebo arm; Other Names: rituximab; ocrelizumab
Experimental: TAF; 25 mg of daily TAF	Drug: TENOFOVIR ALAFENAMIDE FUMARATE 25 Mg ORAL TABLET [VEMLIDY]; The study is designed to add on TAF to anti-CD20 therapies; Other Names: rituximab; Ocrelizumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0	Safety and tolerability of TAF by individuals with RRMS	From baseline to 12 months
Modified Fatigue Impact Scale	Change in Modified Fatigue Impact Scale (MFIS) score (range 0-84, higher is more fatigue)	From baseline to 12 months
serum concentrations of neurofilament light chains (NfL)	Reduction in serum concentrations of neurofilament light chains (NfL), a marker of neuronal damage in MS (pg/ml, the higher the more neuronal damage)	From baseline to 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Multiple Sclerosis Impact Scale-29	Change in Multiple Sclerosis Impact Scale-29 (MSIS-29) score (range 0-100, higher scores are more impactful)	From baseline to 12 months
Short Form 36 Health Survey Questionnaire	Change in Short Form 36 (SF-36) Health Survey Questionnaire (range 0-100, higher scores are healthier)	From baseline to 12 months
Beck Depression Inventory	Change in Beck Depression Inventory (BDI-II) score (range 0-63, higher score indicate more severe depression)	From baseline to 12 months
Perceived Deficits Questionnaire	Change in Self-Reported Cognitive Dysfunction: Perceived Deficits Questionnaire (PDQ)(range 0-80, higher scores indicate more perceived cognitive dysfunction)	From baseline to 12 months
Annualized relapse rate	Number of relapses per year	From baseline to 12 months
Expanded Disability Status Scale	Change in Expanded Disability Status Scale (EDSS) score (range 0-10, higher scores are more disabled)	From baseline to 12 months
Symbol Digit Modality Test	Change in Symbol Digit Modality Test (SDMT)	From baseline to 12 months
Timed 25 Foot Walk	Change in Timed 25 Foot Walk Test (T25-FW) (timed in seconds, longer time is more disabled)	From baseline to 12 months
9-Hole Peg Test	Change in 9-Hole Peg Test (9-HPT)	From baseline to 12 months
Number of new MRI lesions	New active MRI lesions (gadolinium-enhancing, and new or enlarging T2 lesions)	From baseline to 12 months
EBV viral load	Change in EBV viral load in saliva	From baseline to 12 months
EBV titers	Change in anti-EBV antibody titers	Comparison of baseline to 6 months and 12 months

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: Gilead Sciences
• Investigators: Principal Investigator: Michael Levy, MD, PhD, Massachusetts General Hospital

Study record dates

Study Major Dates

• Study Start (Anticipated): September 15, 2022
• Primary Completion (Anticipated): February 14, 2024
• Study Completion (Anticipated): February 14, 2025

Study Registration Dates

• First Submitted: April 30, 2021
• First Submitted That Met QC Criteria: May 6, 2021
• First Posted (Actual): May 10, 2021

Study Record Updates

• Last Update Posted (Actual): November 15, 2022
• Last Update Submitted That Met QC Criteria: November 14, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Tenofovir; Rituximab; Ocrelizumab
• Other Study ID Numbers: 2020P003311

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No