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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04880577
Recruitment Status : Suspended (Funding)
First Posted : May 10, 2021
Last Update Posted : August 31, 2022
Sponsor:
Collaborator:
Gilead Sciences
Information provided by (Responsible Party):
Michael, Levy M.D.,Ph.D., Massachusetts General Hospital

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.


Condition or disease Intervention/treatment Phase
Multiple Sclerosis, Relapsing-Remitting Fatigue Drug: TENOFOVIR ALAFENAMIDE FUMARATE 25 Mg ORAL TABLET [VEMLIDY] Drug: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Tenofovir Alafenamide for Treatment of Symptoms and Neuroprotection in Relapsing Remitting Multiple Sclerosis
Estimated Study Start Date : September 15, 2022
Estimated Primary Completion Date : February 14, 2024
Estimated Study Completion Date : February 14, 2025


Arm Intervention/treatment
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:
  • Ocrelizumab
  • rituximab

Placebo Comparator: Placebo
Placebo pill
Drug: Placebo
Placebo arm
Other Names:
  • ocrelizumab
  • rituximab




Primary Outcome Measures :
  1. Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: From baseline to 12 months ]
    Safety and tolerability of TAF by individuals with RRMS

  2. Modified Fatigue Impact Scale [ Time Frame: From baseline to 12 months ]
    Change in Modified Fatigue Impact Scale (MFIS) score (range 0-84, higher is more fatigue)

  3. serum concentrations of neurofilament light chains (NfL) [ Time Frame: From baseline to 12 months ]
    Reduction in serum concentrations of neurofilament light chains (NfL), a marker of neuronal damage in MS (pg/ml, the higher the more neuronal damage)


Secondary Outcome Measures :
  1. Multiple Sclerosis Impact Scale-29 [ Time Frame: From baseline to 12 months ]
    Change in Multiple Sclerosis Impact Scale-29 (MSIS-29) score (range 0-100, higher scores are more impactful)

  2. Short Form 36 Health Survey Questionnaire [ Time Frame: From baseline to 12 months ]
    Change in Short Form 36 (SF-36) Health Survey Questionnaire (range 0-100, higher scores are healthier)

  3. Beck Depression Inventory [ Time Frame: From baseline to 12 months ]
    Change in Beck Depression Inventory (BDI-II) score (range 0-63, higher score indicate more severe depression)

  4. Perceived Deficits Questionnaire [ Time Frame: From baseline to 12 months ]
    Change in Self-Reported Cognitive Dysfunction: Perceived Deficits Questionnaire (PDQ)(range 0-80, higher scores indicate more perceived cognitive dysfunction)

  5. Annualized relapse rate [ Time Frame: From baseline to 12 months ]
    Number of relapses per year

  6. Expanded Disability Status Scale [ Time Frame: From baseline to 12 months ]
    Change in Expanded Disability Status Scale (EDSS) score (range 0-10, higher scores are more disabled)

  7. Symbol Digit Modality Test [ Time Frame: From baseline to 12 months ]
    Change in Symbol Digit Modality Test (SDMT)

  8. Timed 25 Foot Walk [ Time Frame: From baseline to 12 months ]
    Change in Timed 25 Foot Walk Test (T25-FW) (timed in seconds, longer time is more disabled)

  9. 9-Hole Peg Test [ Time Frame: From baseline to 12 months ]
    Change in 9-Hole Peg Test (9-HPT)

  10. Number of new MRI lesions [ Time Frame: From baseline to 12 months ]
    New active MRI lesions (gadolinium-enhancing, and new or enlarging T2 lesions)

  11. EBV viral load [ Time Frame: From baseline to 12 months ]
    Change in EBV viral load in saliva

  12. EBV titers [ Time Frame: Comparison of baseline to 6 months and 12 months ]
    Change in anti-EBV antibody titers



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04880577


Locations
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United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Sponsors and Collaborators
Massachusetts General Hospital
Gilead Sciences
Investigators
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Principal Investigator: Michael Levy, MD, PhD Massachusetts General Hospital
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Responsible Party: Michael, Levy M.D.,Ph.D., Associate Professor, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT04880577    
Other Study ID Numbers: 2020P003311
First Posted: May 10, 2021    Key Record Dates
Last Update Posted: August 31, 2022
Last Verified: August 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Multiple Sclerosis
Multiple Sclerosis, Relapsing-Remitting
Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Tenofovir
Rituximab
Ocrelizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antiviral Agents
Anti-Infective Agents
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents