Targeting Residual Activity By Precision, Biomarker-Guided Combination Therapies of Multiple Sclerosis (TRAP-MS)

Plain English Summary

Targeting Residual Activity By Precision, Biomarker-Guided Combination Therapies of Multiple Sclerosis (TRAP-MS) is a Phase 2 clinical trial sponsored by National Institute of Allergy and Infectious Diseases (NIAID) studying Multiple Sclerosis. This trial investigates if specific drug combinations can reduce inflammation and disease activity in people with Multiple Sclerosis (MS). It is designed for individuals aged 18 and older who have been diagnosed with MS and are experiencing ongoing disease progression. Participants will receive one of four study drugs, potentially followed by a second drug or a combination, for up to 18 months, with regular check-ups for up to 6 years. Alternative treatments for MS include various disease-modifying therapies (DMTs) that aim to reduce relapse frequency and slow disability progression. The trial aims to enroll 250 participants.

Official Summary

Background: In people with multiple sclerosis (MS), brain and cerebrospinal fluid (CSF) biomarkers indicate inflammation or disease. Researchers want to see if 4 drugs given alone or combined affect MS biomarkers. They want to see if a change in biomarker levels can predict which drugs a person with MS might respond to. Objective: To see if signs of inflammation in CSF help predict a person s response to different drugs. Eligibility: People ages 18 and older who: * Are in protocol 09-I-0032 * Have progressive MS * Can stand and walk a few steps * Take an MS drug Design: Participants will be screened in protocol 09-I-0032. Participants will take 1 of the 4 study drugs. Researchers will call after 1 month to see how they are doing. Some will start a second drug. They may take each drug or combination for up to 18 months. Participants will have 2 visits a year for up to 6 years. Visits include: * Medical history * Physical exam * Blood and heart tests * X-rays and scans * Eye exam and tear collection * Lumbar puncture: A needle inserted between back bones removes some CSF. * Lymphocytapheresis: Blood is removed through a needle in one arm and run through a machine. The blood is returned through a needle in the other arm. * A sensor on the forehead records blood flow and oxygen use. * Participants may get a device for testing at home. Participants will stop taking the drugs if they have taken 2 drugs together for 18 months or if they do not do well on the drugs. Participants will be called 3 months later to see how they are doing.

Who Can Participate

Here is what you need to know about eligibility for this trial. You can join if you are 18 or older, have a confirmed diagnosis of MS, and are experiencing some level of disability or progression. Individuals with significant other medical conditions that could interfere with the study or pose a safety risk will not be eligible. Women who can become pregnant must agree to use reliable birth control during the study. Certain blood test results, including liver enzymes, white blood cell count, platelet count, and kidney function, must be within acceptable ranges. This trial is studying Multiple Sclerosis, so participants generally need a confirmed diagnosis. The trial is currently accepting new participants.

What They're Measuring

The primary outcome measures how the drugs affect the rate at which your MS disability progresses, indicating if the treatments are slowing down the worsening of your condition. The specific primary outcome measures are: Primary outcome will be change in CombiWISE progression rate at the end of monotherapy plus combination therapy period in comparison to projected baseline disability progression. (1.5 years). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 2, which tests whether the treatment actually works against the target condition. Phase 2 trials involve 100-300 patients and continue to monitor safety while evaluating effectiveness. This phase often tests different dosages to find the optimal amount. About 33% of Phase 2 drugs advance to Phase 3. If successful, the treatment will move to large-scale Phase 3 trials needed for FDA approval.

Why This Trial Matters

This trial is important because it aims to identify personalized treatment strategies for MS by using biomarkers to predict which drug combinations will be most effective, addressing a gap in current Phase 2 success would typically lead to larger Phase 3 trials needed for regulatory approval. This research targets Multiple Sclerosis, where improved treatment options are needed.

Investor Insight

This Phase 2 trial, sponsored by the NIAID, explores novel combination therapies for MS, a condition with a significant market for treatments, suggesting potential for future drug development and inve Phase 2 trials have approximately a 15-20% chance of eventually gaining FDA approval.

Is This Trial Right for Me?

Ask your doctor about the specific drugs being tested, potential side effects, and how your current MS medication might interact with the study drugs. Participation involves regular visits for physical exams, blood tests, scans, and potentially lumbar punctures to collect spinal fluid, which helps researchers monitor disease activity. You may be asked to use a device at home to track your condition, and your commitment to attending all scheduled appointments is crucial for the study's success. This trial is currently recruiting participants. The trial is being conducted at 1 site. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: NON_RANDOMIZED
• Model: FACTORIAL
• Masking: NONE
• Enrollment: 250 participants

Interventions

• DRUG: Cilostazol — 100 mg Bid
• DRUG: Leucovorin — 10 mg Bid
• DRUG: Pirfenidone — Up to 801 mg po tid. Slow titration over weeks based on tolerability: 267mg po tid x \>= 7d 534 mg po tid x \>= 7d 801 mg po tid
• DRUG: Dantrolene — Up to 200 mg/day (divided into 3 doses of 50mg, 50mg, and 100 mg)
• DRUG: Pioglitazone — 15-45 mg po qd

Primary Outcomes

• Primary outcome will be change in CombiWISE progression rate at the end of monotherapy plus combination therapy period in comparison to projected baseline disability progression. (1.5 years)

Secondary Outcomes

• Development of new CSF (combinatorial) biomarkers, new clinical scales, new MRI outcomes will be included in exploratory analyses (1 year)
• Correlations between change(s) in CSF biomarkers and clinical efficacy (systems biology approach analyzing drugs/combinations separately and combining all drugs/combinations to a single larger cohort; exploratory analysis) (1 year)
• Safety and tolerability of individual drugs and their combinations (1 year)
• Change in CombiWISE progression rates between baseline and monotherapy phase, monotherapy and combination therapy phase and between different drugs. (1 year)

Full Eligibility Criteria

* INCLUSION CRITERIA:
* Enrolled in 09-I-0032 protocol.
* Clinically definite MS.
* Age \>=18 years at time of study enrollment.
* Expanded Disability Status Scale (EDSS) 1.0-7.5.
* For progressive MS cohort enrollment:

  * Documented sustained clinical progression of at least 0.5 CombiWISE points/year on stable therapy (or untreated)

    * If follow-up is \<3 years, CombiWISE progression slopes are measured by \>= 4 time points regression analysis of CombiWISE values spanning at least 18 months (1.5 years)
    * If follow-up is \>=3 years, CombiWISE progression slopes are measured by \>= 2 time-points regression analysis of CombiWISE values spanning at least 36 months (3 years)
  * Because currently only NDS utilizes CombiWISE scale, the progression slopes will be determined via 09-I-0032 natural history protocol that contains completely overlapping procedures.
  * It is possible that after other MS centers start using CombiWISE scale, this progression criterion may be derived from outside data, as long as they are adequately documented.
* For non-progressing MS with residual disability cohort enrollment:

  * CombiWISE slope on stable therapy (derived identically as in progressive MS cohort) \>0 and \<0.5 CombiWISE units/year (i.e., neurological deficit that is no longer improving)
  * CombiWISE at the end of screening period \>10 (i.e., sustained residual disability)
* Women who can become pregnant must be willing to use a medically acceptable form of birth control, while being treated on this study.
* Patients on current FDA-approved DMTs will be enrolled with the understanding that the underlying FDA-approved therapy must remain stable during this protocol. If patient desires and/or his/her medical condition requires changing FDA-approved DMT during the duration of this protocol, the drugs administered under this protocol will be withdrawn, to establish new baseline of CSF biomarkers under changed therapy, and, if necessary, to establish new progression rate. New baseline of CSF biomarkers on changed therapy can be established after 6 months of new therapy.

  * Because the efficacy of current DMTs decreases with patient s age so that on average, zero percent efficacy on disability progression occurs after age 53, only those patients who change to higher potency therapy (i.e., treatment escalation) before age 53 will need to repeat the entire process of establishing baseline progression rate: go back to \>= 1.5 year baseline period on new DMT to verify that the rate of progression remains \>=0.5 CombiWISE points/year.
  * Following therapeutic change that occurs before age 53 will be considered treatment escalation: 1. Initiation of any FDA-approved DMT in previously untreated subject or 2. Change from any low potency (i.e., copaxone, teriflunomide, interferon beta preparations, dimethyl or monomethyl fumarate and fingolimod) to any high potency drugs (i.e., any B-cell depleting agents, natalizumab, alemtuzumab, siponimod, ozanimod and cladribine). All other therapy changes (i.e., parallel change from low efficacy to low efficacy or from high efficacy to high efficacy, as well as discontinuation of treatment after age 53) will require new CSF baseline (6 months after such therapy change), but will not require 18 months to calculate new CombiWISE slope.
  * After new CSF baseline, and, if necessary, new CombiWISE progression slopes are established, patient can be matched to the same monotherapy or combination therapy regimen they were on before the immunomodulatory DMT change.
* Willing and able to participate in all aspects of the protocol.
* Able and willing to provide informed consent.

EXCLUSION CRITERIA:

* Clinically significant medical disorders that, in the judgment of the investigators, could expose the patient to undue risk of harm or prevent the patient from safely completing all required elements of the study (such as, but not limited to significant cerebrovascular disease, ischemic cardiomyopathy, clotting disorder, other neurodegenerative disorder, substance abuse or significant psychiatric disorder such as depression with suicidal ideations, unable to perform or tolerate MRI examinations).
* Clinically significant medical disorders, other than MS that require chronic treatment with immunosuppressive or immunomodulatory agents.
* Pregnancy or breastfeeding.
* Abnormal screening/baseline blood tests exceeding any of the limits defined below:

  * Serum alanine transaminase or aspartate transaminase levels which are greater than three times the upper limit of normal values.
  * Total white blood cell count \< 3 000/mm\^3.
  * Platelet count \< 85 000/mm\^3.
  * Serum creatinine level \> 2.0 mg/dL and eGFR (glomerular filtration rate) \< 60.
  * Serological evidence of HIV, HTLV-1 or active hepatitis A, B or C.
  * Positive pregnancy test.

Following drug-specific exclusion criteria will be applied when assigning specific agent (these are not exclusions from the trial):

* Pioglitazone

  *

Trial Locations

• National Institutes of Health Clinical Center, Bethesda, Maryland, United States

Frequently Asked Questions

Related Conditions

• Multiple Sclerosis
• Neuromyelitis Optica Spectrum Disorder
• Autoimmune Encephalitis
• Myasthenia Gravis
• Lupus Erythematosus
• Rheumatoid Arthritis
• Psoriasis
• Inflammatory Bowel Disease
• Sjogren's Syndrome
• Guillain-Barre Syndrome

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