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

NCT04880577 | Withdrawn Phase 2 DMC FDA Drug

• 1 other identifier: 2020P003311
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Multiple Sclerosis, Relapsing-Remitting; Fatigue

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (12)

• Multiple Sclerosis Impact Scale-29

  From baseline to 12 months

• Short Form 36 Health Survey Questionnaire

  From baseline to 12 months

• Beck Depression Inventory

  From baseline to 12 months

• Perceived Deficits Questionnaire

  From baseline to 12 months

• Annualized relapse rate

  From baseline to 12 months

Study Arms (2)

TAF

EXPERIMENTAL

25 mg of daily TAF

Drug: TENOFOVIR ALAFENAMIDE FUMARATE 25 Mg ORAL TABLET [VEMLIDY]

Placebo

PLACEBO COMPARATOR

Placebo pill

Drug: Placebo

Interventions

TENOFOVIR ALAFENAMIDE FUMARATE 25 Mg ORAL TABLET [VEMLIDY] DRUG

The study is designed to add on TAF to anti-CD20 therapies

Also known as: Ocrelizumab, rituximab

TAF

Placebo DRUG

Placebo arm

Also known as: ocrelizumab, rituximab

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of signed and dated informed consent form
• Stated willingness and ability to comply with all study procedures and availability for the duration of the study
• Aged 18+ years
• Diagnosis of MS using revised 2010 McDonald criteria of clinically definite MS.
• 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.
• Must report significant fatigue during the past 3 months not due to a cause other than MS.
• 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.
• For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner.

You may not qualify if:

• Pregnancy or lactation
• Known allergic reactions to components of TAF
• Treatment with another investigational drug or other MS-directed intervention such as glatiramer acetate, or dimethyl fumarate within 3 months
• Positive HIV antibody test, active or latent hepatitis B
• Relapse and/or steroid treatment within the previous 30 days
• Baseline EDSS \> 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
• Known history of sleep apnea, narcolepsy, or other significant sleep disorders
• Recent changes to medications affecting sleep or fatigue or changes in dosage of those medications within 90 days
• Creatinine clearance (CrCl) \<55mL/min, as calculated by the Cockcroft-Gault equation
• 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

Sponsors & Collaborators

• Massachusetts General Hospital: lead
• Gilead Sciences: collaborator

Study Sites (1)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

MeSH Terms

Conditions

Multiple Sclerosis, Relapsing-Remitting; Fatigue

Interventions

Tablets; tenofovir alafenamide; ocrelizumab; Rituximab

Condition Hierarchy (Ancestors)

Multiple Sclerosis; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Dosage Forms; Pharmaceutical Preparations; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Michael Levy, MD, PhD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: April 30, 2021
• First Posted: May 10, 2021
• Study Start: September 15, 2022
• Primary Completion: February 14, 2024
• Study Completion: February 14, 2025
• Last Updated: November 15, 2022

Record last verified: 2022-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)