Early Aggressive vs Traditional Therapy for Multiple Sclerosis

(TREAT-MS Trial)

Recruiting at 48 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

900 Participants Needed

Trial Summary

What is the purpose of this trial?

FDA-approved multiple sclerosis (MS) disease-modifying therapies (DMTs) target the relapsing phase of MS but have minimal impact once the progressive phase has begun. It is unclear if, in the relapsing phase, there is an advantage of early aggressive therapy with respect to preventing long-term disability. The infectious risks and other complications associated with higher-efficacy treatments highlight the need to quantify their effectiveness in preventing disability. The TRaditional versus Early Aggressive Therapy for MS (TREAT-MS) trial is a pragmatic, randomized controlled trial that has two primary aims: 1) to evaluate, jointly and independently among patients deemed at higher risk vs. lower risk for disability accumulation, whether an "early aggressive" therapy approach, versus starting with a traditional, first-line therapy, influences the intermediate-term risk of disability, and 2) to evaluate if, among patients deemed at lower risk for disability who start on first-line MS therapies but experience breakthrough disease, those who switch to a higher-efficacy versus a new first-line therapy have different intermediate-term risk of disability.

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.

What data supports the idea that Early Aggressive vs Traditional Therapy for Multiple Sclerosis is an effective treatment?

The available research shows that early aggressive therapy for multiple sclerosis can be more effective than traditional therapy. One study found that early highly effective treatment is better than waiting to escalate treatment later. Another study showed that a combined aggressive treatment approach led to improvement in 77.8% of patients and reduced the frequency of relapses. This suggests that starting treatment early with a strong approach can help stabilize the condition and improve patient outcomes. ^{1 2 3 4 5}

What data supports the effectiveness of the treatment for aggressive multiple sclerosis?

Research suggests that starting early with a highly effective treatment can benefit patients with aggressive multiple sclerosis, potentially stabilizing their condition and reducing the frequency of relapses. A study found that a combined therapy approach, using drugs with different mechanisms, improved patient outcomes in 77.8% of cases. ^{1 2 3 4 5}

What safety data exists for early aggressive vs traditional therapy for multiple sclerosis?

The safety data for early aggressive therapy in multiple sclerosis is limited and largely based on short-term studies. Early aggressive therapy involves starting treatment with high-efficacy drugs that have a less favorable side-effect profile, aiming to maximize long-term benefits. Traditional therapy, or escalation strategy, starts with drugs of lower efficacy and side effects, escalating to stronger drugs if needed. The evidence supporting these strategies is not definitive, and the debate on their safety and efficacy remains open. Some studies suggest that early intervention might protect against irreversible damage, but optimal strategies are yet to be defined. ^{2 3 4 6 7}

What safety data exists for early aggressive and traditional therapy in multiple sclerosis?

Early aggressive therapy for multiple sclerosis often involves starting with drugs that have higher efficacy but may have more side effects, while traditional therapy starts with drugs that have fewer side effects and lower efficacy. The safety of these treatments can vary, and while early aggressive therapy might offer more benefits, it also comes with a higher risk of side effects. ^{2 3 4 6 7}

Is Early Aggressive Therapy, Traditional Therapy a promising treatment for multiple sclerosis?

Early Aggressive Therapy is promising because it can stabilize and improve the condition of patients with aggressive multiple sclerosis, reducing the frequency of relapses and potentially preventing long-term disability. ^{2 3 4 5 8}

How does Early Aggressive Therapy differ from Traditional Therapy for multiple sclerosis?

Early Aggressive Therapy for multiple sclerosis involves starting treatment with powerful drugs early on to prevent rapid progression and disability, while Traditional Therapy typically starts with less intense treatments and escalates if needed. This approach aims to protect patients from irreversible damage by intervening before significant disability occurs. ^{2 3 4 5 8}

Research Team

Ellen M. Mowry, MD, MCR

Principal Investigator

Johns Hopkins University

Scott D. Newsome, DO

Principal Investigator

Johns Hopkins University

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

References

1. United States 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. [2023]

2. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Combined therapy of aggressive remitted multiple sclerosis with mitoxantrone in combination with copaxone]. [2016]

3. England pubmed.ncbi.nlm.nih.gov

Aggressive multiple sclerosis (2): Treatment. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Aggressive multiple sclerosis: proposed definition and treatment algorithm. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Aggressive multiple sclerosis (1): Towards a definition of the phenotype. [2020]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Escalation vs. Early Intense Therapy in Multiple Sclerosis. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Association of Immunotherapies With Outcomes in Relapsing-Remitting Multiple Sclerosis. [2016]

8. Italy pubmed.ncbi.nlm.nih.gov

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