Fatigue, Multiple Sclerosis, Relapsing-Remitting
Conditions
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.
Interventions
DRUGTENOFOVIR ALAFENAMIDE FUMARATE 25 Mg ORAL TABLET [VEMLIDY]
The study is designed to add on TAF to anti-CD20 therapies
DRUGPlacebo
Placebo arm
Sponsors
Gilead Sciences
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | From baseline to 12 months | Safety and tolerability of TAF by individuals with RRMS |
| Modified Fatigue Impact Scale | From baseline to 12 months | Change in Modified Fatigue Impact Scale (MFIS) score (range 0-84, higher is more fatigue) |
| serum concentrations of neurofilament light chains (NfL) | 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
| Measure | Time frame | Description |
|---|---|---|
| Beck Depression Inventory | From baseline to 12 months | Change in Beck Depression Inventory (BDI-II) score (range 0-63, higher score indicate more severe depression) |
| Perceived Deficits Questionnaire | 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) |
| Annualized relapse rate | From baseline to 12 months | Number of relapses per year |
| Symbol Digit Modality Test | From baseline to 12 months | Change in Symbol Digit Modality Test (SDMT) |
| Expanded Disability Status Scale | From baseline to 12 months | Change in Expanded Disability Status Scale (EDSS) score (range 0-10, higher scores are more disabled) |
| 9-Hole Peg Test | From baseline to 12 months | Change in 9-Hole Peg Test (9-HPT) |
| Number of new MRI lesions | From baseline to 12 months | New active MRI lesions (gadolinium-enhancing, and new or enlarging T2 lesions) |
| EBV viral load | From baseline to 12 months | Change in EBV viral load in saliva |
| EBV titers | Comparison of baseline to 6 months and 12 months | Change in anti-EBV antibody titers |
| Timed 25 Foot Walk | From baseline to 12 months | Change in Timed 25 Foot Walk Test (T25-FW) (timed in seconds, longer time is more disabled) |
| Multiple Sclerosis Impact Scale-29 | From baseline to 12 months | Change in Multiple Sclerosis Impact Scale-29 (MSIS-29) score (range 0-100, higher scores are more impactful) |
| Short Form 36 Health Survey Questionnaire | From baseline to 12 months | Change in Short Form 36 (SF-36) Health Survey Questionnaire (range 0-100, higher scores are healthier) |
Countries
United States
Outcome results
None listed