Clinical trial NCT04880577: Tenofovir Alafenamide for Treatment of Symptoms and Neuroprotection in Relapsing Remitting Multiple Sclerosis
Official title: Tenofovir Alafenamide for Treatment of Symptoms and Neuroprotection in Relapsing Remitting Multiple Sclerosis
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: Multiple Sclerosis, Relapsing-Remitting
Fatigue
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: Gilead Sciences
First posted: 2021-05-10
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
timeFrame: From baseline to 12 months
measure: Modified Fatigue Impact Scale
timeFrame: From baseline to 12 months
measure: serum concentrations of neurofilament light chains (NfL)
timeFrame: From baseline to 12 months
Secondary outcomes:
measure: Multiple Sclerosis Impact Scale-29
timeFrame: From baseline to 12 months
measure: Short Form 36 Health Survey Questionnaire
timeFrame: From baseline to 12 months
measure: Beck Depression Inventory
timeFrame: From baseline to 12 months
measure: Perceived Deficits Questionnaire
timeFrame: From baseline to 12 months
measure: Annualized relapse rate
timeFrame: From baseline to 12 months
measure: Expanded Disability Status Scale
timeFrame: From baseline to 12 months
measure: Symbol Digit Modality Test
timeFrame: From baseline to 12 months
measure: Timed 25 Foot Walk
timeFrame: From baseline to 12 months
measure: 9-Hole Peg Test
timeFrame: From baseline to 12 months
measure: Number of new MRI lesions
timeFrame: From baseline to 12 months
measure: EBV viral load
timeFrame: From baseline to 12 months
measure: EBV titers
timeFrame: Comparison of baseline to 6 months and 12 months
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
Study officials:
affiliation: Massachusetts General Hospital
name: Michael Levy, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: