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

Primary Purpose

Multiple Sclerosis, Relapsing-Remitting, Fatigue

Status

Withdrawn

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

TENOFOVIR ALAFENAMIDE FUMARATE 25 Mg ORAL TABLET [VEMLIDY]

Placebo

About this trial

This is an interventional treatment trial for Multiple Sclerosis, Relapsing-Remitting

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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.

Exclusion Criteria:

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

Sites / Locations

Massachusetts General Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

TAF

Placebo

Arm Description

25 mg of daily TAF

Placebo pill

Outcomes

Primary Outcome Measures

Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Safety and tolerability of TAF by individuals with RRMS

Modified Fatigue Impact Scale

Change in Modified Fatigue Impact Scale (MFIS) score (range 0-84, higher is more fatigue)

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)

Secondary Outcome Measures

Multiple Sclerosis Impact Scale-29

Change in Multiple Sclerosis Impact Scale-29 (MSIS-29) score (range 0-100, higher scores are more impactful)

Short Form 36 Health Survey Questionnaire

Change in Short Form 36 (SF-36) Health Survey Questionnaire (range 0-100, higher scores are healthier)

Beck Depression Inventory

Change in Beck Depression Inventory (BDI-II) score (range 0-63, higher score indicate more severe depression)

Perceived Deficits Questionnaire

Change in Self-Reported Cognitive Dysfunction: Perceived Deficits Questionnaire (PDQ)(range 0-80, higher scores indicate more perceived cognitive dysfunction)

Annualized relapse rate

Number of relapses per year

Expanded Disability Status Scale

Change in Expanded Disability Status Scale (EDSS) score (range 0-10, higher scores are more disabled)

Symbol Digit Modality Test

Change in Symbol Digit Modality Test (SDMT)

Timed 25 Foot Walk

Change in Timed 25 Foot Walk Test (T25-FW) (timed in seconds, longer time is more disabled)

9-Hole Peg Test

Change in 9-Hole Peg Test (9-HPT)

Number of new MRI lesions

New active MRI lesions (gadolinium-enhancing, and new or enlarging T2 lesions)

EBV viral load

Change in EBV viral load in saliva

EBV titers

Change in anti-EBV antibody titers

Full Information

NCT ID

NCT04880577

First Posted

April 30, 2021

Last Updated

November 14, 2022

Sponsor

Massachusetts General Hospital

Collaborators

Gilead Sciences

1. Study Identification

Unique Protocol Identification Number

NCT04880577

Brief Title

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

2. Study Status

Record Verification Date

November 2022

Overall Recruitment Status

Withdrawn

Why Stopped

Funding

Study Start Date

September 15, 2022 (Anticipated)

Primary Completion Date

February 14, 2024 (Anticipated)

Study Completion Date

February 14, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Massachusetts General Hospital

Collaborators

Gilead Sciences

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Multiple Sclerosis, Relapsing-Remitting, Fatigue

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

TAF

Arm Type

Experimental

Arm Description

25 mg of daily TAF

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Placebo pill

Intervention Type

Drug

Intervention Name(s)

TENOFOVIR ALAFENAMIDE FUMARATE 25 Mg ORAL TABLET [VEMLIDY]

Other Intervention Name(s)

Ocrelizumab, rituximab

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Placebo

Other Intervention Name(s)

ocrelizumab, rituximab

Intervention Description

Placebo arm

Primary Outcome Measure Information:

Title

Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

Description

Safety and tolerability of TAF by individuals with RRMS

Time Frame

From baseline to 12 months

Title

Modified Fatigue Impact Scale

Description

Change in Modified Fatigue Impact Scale (MFIS) score (range 0-84, higher is more fatigue)

Time Frame

From baseline to 12 months

Title

serum concentrations of neurofilament light chains (NfL)

Description

Reduction in serum concentrations of neurofilament light chains (NfL), a marker of neuronal damage in MS (pg/ml, the higher the more neuronal damage)

Time Frame

From baseline to 12 months

Secondary Outcome Measure Information:

Title

Multiple Sclerosis Impact Scale-29

Description

Change in Multiple Sclerosis Impact Scale-29 (MSIS-29) score (range 0-100, higher scores are more impactful)

Time Frame

From baseline to 12 months

Title

Short Form 36 Health Survey Questionnaire

Description

Change in Short Form 36 (SF-36) Health Survey Questionnaire (range 0-100, higher scores are healthier)

Time Frame

From baseline to 12 months

Title

Beck Depression Inventory

Description

Change in Beck Depression Inventory (BDI-II) score (range 0-63, higher score indicate more severe depression)

Time Frame

From baseline to 12 months

Title

Perceived Deficits Questionnaire

Description

Change in Self-Reported Cognitive Dysfunction: Perceived Deficits Questionnaire (PDQ)(range 0-80, higher scores indicate more perceived cognitive dysfunction)

Time Frame

From baseline to 12 months

Title

Annualized relapse rate

Description

Number of relapses per year

Time Frame

From baseline to 12 months

Title

Expanded Disability Status Scale

Description

Change in Expanded Disability Status Scale (EDSS) score (range 0-10, higher scores are more disabled)

Time Frame

From baseline to 12 months

Title

Symbol Digit Modality Test

Description

Change in Symbol Digit Modality Test (SDMT)

Time Frame

From baseline to 12 months

Title

Timed 25 Foot Walk

Description

Change in Timed 25 Foot Walk Test (T25-FW) (timed in seconds, longer time is more disabled)

Time Frame

From baseline to 12 months

Title

9-Hole Peg Test

Description

Change in 9-Hole Peg Test (9-HPT)

Time Frame

From baseline to 12 months

Title

Number of new MRI lesions

Description

New active MRI lesions (gadolinium-enhancing, and new or enlarging T2 lesions)

Time Frame

From baseline to 12 months

Title

EBV viral load

Description

Change in EBV viral load in saliva

Time Frame

From baseline to 12 months

Title

EBV titers

Description

Change in anti-EBV antibody titers

Time Frame

Comparison of baseline to 6 months and 12 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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. Exclusion Criteria: 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Michael Levy, MD, PhD

Organizational Affiliation

Massachusetts General Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

Massachusetts General Hospital

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02114

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

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

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