Early Aggressive vs Traditional Therapy for Multiple Sclerosis

(TREAT-MS Trial)

Not currently recruiting at 49 trial locations

Overseen By Sharon Lynch, MD

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: Johns Hopkins University

Must not be taking: Rituximab, Ocrelizumab, Teriflunomide, others

Disqualifiers: Pregnancy, Breast-feeding, Chemotherapy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 48 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This clinical trial explores whether starting with strong treatment early, known as Early Aggressive Therapy, is more effective than traditional first-line therapies, referred to as Traditional Therapy, for individuals with relapsing-remitting multiple sclerosis (MS). The trial aims to determine which approach better prevents long-term disability and to evaluate the risks associated with stronger treatments. Individuals diagnosed with relapsing-remitting MS who meet specific health criteria, such as being negative or having low levels of certain antibodies, may qualify for this trial. As an unphased trial, it offers participants the chance to contribute to groundbreaking research that could shape future MS treatment strategies.

Do I need to stop my current medications to join the trial?

Yes, you may need to stop certain medications. If you've been treated with any MS disease-modifying therapy (DMT) in the past 6 months, or specific drugs like rituximab, ocrelizumab, and others, you cannot participate. If you've used teriflunomide in the past 2 years, a rapid washout is required.

Do I need to stop my current medications to join the trial?

The trial requires that you have not been treated with any MS disease-modifying therapy (DMT) in the past 6 months. If you have used teriflunomide in the past 2 years, a rapid washout (time without taking the medication) is needed. Other specific medications are also excluded, so you may need to stop certain treatments to participate.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Previous studies on early aggressive therapy for multiple sclerosis (MS) have shown varying safety levels among different treatments. Ocrelizumab, used in Ocrevus Zunovo, has a safety profile similar to its IV form, though some patients may experience injection site reactions. Alemtuzumab, found in Lemtrada, is not recommended for certain MS patients due to safety concerns.

Natalizumab (Tysabri) is approved for MS but has not been proven safe for individuals under 18. The FDA has approved Cladribine (Mavenclad) and ofatumumab (Kesimpta) for MS, indicating they are generally well-tolerated.

Traditional treatments like glatiramer acetate and beta interferon agents have been used extensively and are commonly prescribed for MS, suggesting they are well-tolerated. Dimethyl fumarate (Tecfidera) and teriflunomide (Aubagio) are also approved for MS and have a known safety record.

Overall, while each treatment can have side effects, many are well-established in treating MS, providing reassurance about their safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the trial comparing early aggressive therapy and traditional therapy for multiple sclerosis because it explores whether hitting the disease hard and fast can yield better outcomes than the usual step-by-step approach. Unlike traditional therapies like interferons and glatiramer acetate, which have been the backbone of MS treatment for years, early aggressive therapies often involve drugs like natalizumab and ocrelizumab that target B and T cells more directly and potently. These aggressive treatments may offer the potential for more rapid and comprehensive control of disease activity, potentially leading to fewer relapses and slower progression of disability. By comparing these strategies head-to-head, the trial could redefine how multiple sclerosis is treated from the onset.

What evidence suggests that this trial's treatments could be effective for multiple sclerosis?

This trial will compare Early Aggressive Therapy with Traditional Therapy for multiple sclerosis (MS). Research has shown that starting strong treatments early, as in the Early Aggressive Therapy arm, can be more effective than traditional methods. Studies indicate that using powerful medications like natalizumab or alemtuzumab from the beginning can reduce the chances of relapses and slow the progression of disability. In the Traditional Therapy arm, treatments such as glatiramer acetate or dimethyl fumarate help manage relapses but may not be as effective in preventing long-term disability. Some evidence suggests that standard treatments can work well for individuals with lower risk, but stronger treatments might be preferable if the disease worsens. Overall, early aggressive treatment is believed to provide better protection against the progression of MS. ^{6 7 8 9 10}

Who Is on the Research Team?

Ellen M. Mowry, MD, MCR

Principal Investigator

Johns Hopkins University

Scott D. Newsome, DO

Principal Investigator

Johns Hopkins University

Are You a Good Fit for This Trial?

This trial is for adults aged 18-60 with relapsing-remitting Multiple Sclerosis who meet specific criteria and have not had chemotherapy in the past year. They must test negative or low positive for JC virus, and negative for Hepatitis B/C, tuberculosis, and HIV.

Inclusion Criteria

You are HIV negative.

You meet 2017 McDonald criteria for relapsing-remitting MS.

I don't have JC virus, hepatitis B or C, or tuberculosis.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either early aggressive therapy or traditional therapy for multiple sclerosis

48 weeks

Regular visits for treatment administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 99 months

Periodic visits for assessments and monitoring

COVID-19 Related Substudy

Evaluation of the impact of COVID-19 on MS outcomes and therapy schedules

48 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Early Aggressive Therapy
• Traditional Therapy

Trial Overview The TREAT-MS trial compares two approaches: 'early aggressive' therapy versus traditional first-line treatments to see which better prevents long-term disability in MS patients at different risk levels of disability accumulation.

How Is the Trial Designed?

Group I: Early Aggressive Therapy Active Control 1 Intervention

Early Aggressive Therapy choices and maximum allowable doses: * Natalizumab/natalizumab-sztn (Tysabri/Tyruko), 300 mg IV q 4 wks * Alemtuzumab (Lemtrada), 12 mg IV daily (QD) for 5 days; 1 yr later: 12 mg IV QD for 3 days * Ocrelizumab (Ocrevus), 300 mg IV every 2 wks (for 2 doses) at initiation; 600 mg IV q 6 mths * Rituximab/rituximab biosimilars (Rituxan/Riabni/Truxima/Ruxience), 1000 mg IV every 2 wks (for 2 doses); may repeat q 16-24 wks * Cladribine (Mavenclad), 3.5 mg per kg body wt orally divided into 2 yrly tmt courses (1.75 mg per kg body wt each yr); yrly tmt course divided into 2 tmt cycles; administer cycle dose as 1-2 tablets QD over 4-5 days * Ofatumumab (Kesimpta), 20 mg SC wkly for wks 0, 1 and 2; 20 mg subcutaneously (SC) mthly starting at wk 4 * Ublituximab-xiiy (Briumvi), 150 mg IV (1st dose); 450 mg IV 2 wks after first dose; 450 mg IV q 24 wks * Ocrelizumab and hyaluronidase-ocsq (Ocrevus Zunovo), 920 mg ocrelizumab and 23,000 U hyaluronidase SC q 6 months

Group II: Traditional Therapy Active Control 1 Intervention

Traditional Therapy choices and maximum allowable doses: * Glatiramer acetate (Copaxone, Glatopa, and other generics), 20 mg SC daily, or 40 mg SC 3 times a wk * Intramuscular (IM) interferon (Avonex), 30 mcg IM weekly * SC interferon (Betaseron, Extavia, Rebif), 0.25 mg SC every other day (Betaseron, Extavia); 44 mcg SC 3 times a wk (Rebif) * Pegylated interferon (Plegridy), 125 mcg SC every 14 days * Teriflunomide (Aubagio), 14 mg PO QD * Dimethyl fumarate (Tecfidera and generics), 240 mg PO twice a day (BID) * Diroximel fumarate (Vumerity), 462 mg PO BID * Monomethyl fumarate (Bafiertam), 190 mg PO BID * Fingolimod (Gilenya and generics), 0.5 mg PO QD * Siponimod (Mayzent), 1 mg PO QD or 2 mg PO QD * Ozanimod (Zeposia), 0.92 mg PO QD * Ponesimod (Ponvory), 20 mg PO QD * Fingolimod ODT (Tascenso), 0.25 mg PO QD if \<=40 kg; 0.5 mg PO QD if \> 40 kg

Early Aggressive Therapy is already approved in United States for the following indications:

Approved in United States as Ocrevus (ocrelizumab) for:

• Relapsing forms of multiple sclerosis (MS)
• Primary progressive MS

Approved in United States as Briumvi (ublituximab-xiiy) for:

• Relapsing forms of multiple sclerosis (MS)
• Active secondary-progressive MS

Approved in United States as Lemtrada (alemtuzumab) for:

• Relapsing forms of multiple sclerosis (MS)

Who Is Running the Clinical Trial?

Johns Hopkins University

Lead Sponsor

Trials

2,366

Recruited

15,160,000+

Patient-Centered Outcomes Research Institute

Collaborator

Trials

592

Recruited

27,110,000+

National Multiple Sclerosis Society

Collaborator

Trials

100

Recruited

10,600+

Published Research Related to This Trial

Starting treatment with ofatumumab (OMB) immediately or switching to it early after one year on other therapies leads to better clinical outcomes in relapsing multiple sclerosis, including fewer relapses and higher employment rates, compared to delaying treatment or not switching at all.

The cost analysis shows that while immediate OMB treatment has higher drug costs, these are nearly offset by reduced patient care costs and productivity losses, making it a cost-effective option in the long run.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparing the long-term clinical and economic impact of ofatumumab versus dimethyl fumarate and glatiramer acetate in patients with relapsing multiple sclerosis: A cost-consequence analysis from a societal perspective in Germany. Koeditz, D., Frensch, J., Bierbaum, M., et al.[2023]

Patients with their first attack of multiple sclerosis (MS) may be at different stages of the disease, which affects treatment decisions; early-stage patients may benefit from standard first-line immunomodulating agents, while those with more advanced damage may require more aggressive therapies.

The paper emphasizes the importance of tailoring treatment strategies based on the patient's disease phase, advocating for either induction with stronger treatments or a step-up approach from first-line agents to more potent options as needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Induction vs. escalation of therapy for relapsing multiple sclerosis: the evidence. Freedman, MS.[2021]

Aggressive multiple sclerosis (MS) is characterized by frequent and severe relapses, leading to significant disability early in the disease, but there is currently no unified definition for this subgroup of patients.

Early intervention with highly effective treatments is generally recommended for aggressive MS, yet there is a lack of comprehensive data on the best therapeutic approaches, highlighting the need for further research to address these gaps.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aggressive multiple sclerosis (2): Treatment. Arrambide, G., Iacobaeus, E., Amato, MP., et al.[2023]

The current treatment strategies for multiple sclerosis (MS) are debated, with two main approaches: the escalation strategy, which starts with low-efficacy drugs and moves to higher-efficacy options if needed, and the early intense therapy strategy, which begins with high-efficacy drugs despite their potential side effects.

Evidence supporting the escalation strategy is primarily based on short-term studies and does not adequately address the disease's heterogeneity or the limited impact of relapses on long-term outcomes, leaving the effectiveness of both strategies still uncertain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Escalation vs. Early Intense Therapy in Multiple Sclerosis. Casanova, B., Quintanilla-Bordás, C., Gascón, F.[2022]

There is currently no consensus on how to define and manage aggressive multiple sclerosis (MS), a subtype characterized by rapid disability accumulation, which was discussed in a 2018 workshop by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

The workshop emphasized the urgent need for future research to identify imaging and molecular biomarkers that could help define aggressive MS and guide its treatment, as existing definitions and management strategies remain inadequate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aggressive multiple sclerosis (1): Towards a definition of the phenotype. Iacobaeus, E., Arrambide, G., Amato, MP., et al.[2020]

Alemtuzumab, natalizumab, and fingolimod are the most effective immunotherapies for preventing relapses in patients with relapsing-remitting multiple sclerosis, although their impact on preventing disability worsening is uncertain.

Fingolimod carries a high risk of treatment discontinuation due to adverse events, highlighting the importance of monitoring for side effects in patients undergoing this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of Immunotherapies With Outcomes in Relapsing-Remitting Multiple Sclerosis. Tramacere, I., Del Giovane, C., Filippini, G.[2016]

In a study of nine patients with aggressive multiple sclerosis, a combined therapy using immunosuppressive drugs followed by immunomodulators led to a stabilization and improvement in the patients' condition by 77.8%.

The treatment approach, which included drugs with opposing mechanisms of action (mitoxantrone and copaxone), effectively reduced the frequency of disease exacerbations, highlighting the potential of tailored combination therapies in managing aggressive multiple sclerosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Combined therapy of aggressive remitted multiple sclerosis with mitoxantrone in combination with copaxone]. Sazonov, DV., Malkova, NA., Bulatova, EV., et al.[2016]

Identifying patients at risk for aggressive multiple sclerosis (MS) early is crucial, as it allows for timely intervention that may prevent irreversible damage and disability.

Aggressive MS leads to rapid disability progression, making it essential to develop effective treatment strategies for this subset of patients, as current therapies for secondary progressive MS are limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aggressive multiple sclerosis: proposed definition and treatment algorithm. Rush, CA., MacLean, HJ., Freedman, MS.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10769939/

Multiple sclerosis: time for early treatment with high-efficacy ... The benefits of early treatment are also observed with older, aggressive immunosuppressive drugs [70]. In a propensity-matched study fewer ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03500328

Study Details | NCT03500328 | Traditional Versus Early ... The TRaditional versus Early Aggressive Therapy for MS (TREAT-MS) trial is a pragmatic, randomized controlled trial that has two primary aims.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8121641/

Early Aggressive Treatment Approaches for Multiple Sclerosis Two clinical trials, the TRaditional versus Early Aggressive Therapy for MS (TREAT-MS) trial and the Determining the Effectiveness of earLy ...

4. cda-amc.ca cda-amc.ca/sites/default/files/2024-03/ht0038_draft-report_for-stakeholder-feedback.pdf

Alemtuzumab, Cladribine, Fingolimod, Natalizumab, and ... NCT03500328: Traditional versus early aggressive therapy for Multiple. Sclerosis trial (TREAT-MS). ClinicalTrials.gov. Bethesda (MD): U.S. National Library ...

5. link.springer.com link.springer.com/article/10.1007/s00415-024-12305-4

Early use of high-efficacy therapies in multiple sclerosis ... This has led to a shift toward an early aggressive or proactive treatment approach, where patients are initiated on HETs (often at diagnosis) to ...

6. aetna.com aetna.com/cpb/medical/data/200_299/0264.html

Multiple Sclerosis - Medical Clinical Policy Bulletins The safety profile of Ocrevus Zunovo was found to be consistent with the safety profile of Ocrevus IV, with the exception of injection reactions. The most ...

7. caresource.com caresource.com/documents/medicare-multi-policy-pharmacy-tysabri-20250326.pdf

Multiple Sclerosis and Crohn's Disease - Tysabri UM ... The safety and effectiveness in patients with MS or Crohn's disease < 18 years of age have not been established. Disease Overview. Multiple ...

8. myprime.com myprime.com/content/dam/prime/memberportal/forms/AuthorForms/BCBSKS/Program_Summaries/KS_MDC_Healthcare_Administered_Multiple_Sclerosis_ProgSum.pdf

Healthcare Administered Multiple Sclerosis Medical Drug ... Limitations of Use: Lemtrada is not recommended for use in patients with clinically isolated syndrome (CIS) because of its safety profile. 1.

9. static.cigna.com static.cigna.com/assets/chcp/pdf/coveragePolicies/pharmacy/ip_0213_coveragepositioncriteria_alemtuzumab.pdf

Multiple Sclerosis - Lemtrada 1. Lemtrada is not recommended for use in patients with clinically isolated syndrome because of its safety profile. Due to its safety profile, use of Lemtrada ...

10. gene.com gene.com/media/news-features/fda-approves-first-and-only-twice-a-year-10-minute-subcutaneous-injection-for-people-with-relapsing-and-progressive-multiple-sclerosis

FDA Approves the First and Only Twice-A-Year 10-Minute ... The safety profile of Ocrevus Zunovo was consistent with the well-established safety profile of Ocrevus IV, with the exception of injection ...