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

Phase 2

Withdrawn

• Conditions: Multiple Sclerosis, Relapsing-Remitting; Fatigue
• Interventions: Drug: Placebo; Drug: TENOFOVIR ALAFENAMIDE FUMARATE 25 Mg ORAL TABLET [VEMLIDY]

• Registration Number: NCT04880577
• Lead Sponsor: 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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2021-04-30
• Study First Submitted QC: 2021-05-06
• Study First Posted: 2021-05-10
• Study Start: 2022-09-15
• Status Verified: 2022-11
• Last Update Submitted: 2022-11-14
• Last Update Posted: 2022-11-15
• Primary Completion: 2024-02-14
• Study Completion: 2025-02-14

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Placebo pill
TAF	TENOFOVIR ALAFENAMIDE FUMARATE 25 Mg ORAL TABLET [VEMLIDY]	25 mg of daily TAF

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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)
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
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)
Symbol Digit Modality Test	From baseline to 12 months	Change in Symbol Digit Modality Test (SDMT)
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)
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

Trial Locations

Locations (1)

Massachusetts General Hospital; 🇺🇸 Boston, Massachusetts, United States