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

NCT03109288 | Recruiting Phase 1

• 2 other identifiers: 17008317-I-0083
• Study Type: interventional
• Target: 250
• Locations: 1 country
• Sites: 1

Brief 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....

Conditions

Multiple Sclerosis

Keywords

Targeted Therapy; Multiple Sclerosis; Biomarkers; Combination Therapy; Progressive Multiple Sclerosis

Outcome Measures

Primary Outcomes (1)

• 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.

  CombiWISE will be calculated from EDSS and SNRS scores derived from NeurEx App, to eliminate noise stemming from ambiguities in translating neurological exam to disability scores.

  1.5 years

Secondary Outcomes (4)

• 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

Study Arms (2)

Combination Therapy

EXPERIMENTAL

Any two-drug combination of study interventions

Drug: Cilostazol; Drug: Leucovorin; Drug: Pirfenidone; Drug: Dantrolene; Drug: Pioglitazone

Monotherapy

EXPERIMENTAL

Any of the study Interventions

Drug: Cilostazol; Drug: Leucovorin; Drug: Pirfenidone; Drug: Dantrolene; Drug: Pioglitazone

Interventions

Pioglitazone DRUG

15-45 mg po qd

Combination Therapy; Monotherapy

Dantrolene DRUG

Up to 200 mg/day (divided into 3 doses of 50mg, 50mg, and 100 mg)

Combination Therapy; Monotherapy

Pirfenidone DRUG

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

Combination Therapy; Monotherapy

Cilostazol DRUG

100 mg Bid

Combination Therapy; Monotherapy

Leucovorin DRUG

10 mg Bid

Combination Therapy; Monotherapy

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• Pioglitazone
• Congestive heart failure.
• History of bladder carcinoma.
• Type 1 diabetes.
• Hypersensitivity to the drug.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

RECRUITING

Related Publications (1)

• Kocot J, Kosa P, Ashida S, Pirjanian NA, Goldbach-Mansky R, Peterson K, Fossati V, Holland SM, Bielekova B. Clemastine fumarate accelerates accumulation of disability in progressive multiple sclerosis by enhancing pyroptosis. J Clin Invest. 2025 May 15;135(10):e183941. doi: 10.1172/JCI183941. eCollection 2025 May 15.

  PMID: 40371642 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page
• https://go.usa.gov/xP2YY

MeSH Terms

Conditions

Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive

Interventions

Cilostazol; Leucovorin; pirfenidone; Dantrolene; Pioglitazone

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Tetrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Coenzymes; Enzymes and Coenzymes; Hydantoins; Imidazolidines; Imidazoles; Thiazolidinediones; Thiazoles; Sulfur Compounds; Organic Chemicals

Study Officials

• Bibiana Bielekova, M.D.

  National Institute of Allergy and Infectious Diseases (NIAID)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Michelle D Woodland

CONTACT

(301) 402-9619; michelle.woodland@nih.gov

Bibiana Bielekova, M.D.

CONTACT

(240) 669-2724; bielekovab@mail.nih.gov

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 11, 2017
• First Posted: April 12, 2017
• Study Start: August 11, 2017
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2029
• Last Updated: April 1, 2026

Record last verified: 2026-03-26

Locations

US (1)