Targeting Residual Activity By Precision, Biomarker-Guided Combination Therapies of Multiple Sclerosis (TRAP-MS)
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ClinicalTrials.gov Identifier: NCT03109288 |
Recruitment Status :
Recruiting
First Posted : April 12, 2017
Last Update Posted : May 20, 2022
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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.
Condition or disease | Intervention/treatment | Phase |
---|---|---|
Multiple Sclerosis | Drug: Pioglitazone Drug: clemastine fumarate Drug: Dantrolene Drug: Pirfenidone | Phase 1 Phase 2 |

Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 250 participants |
Allocation: | Non-Randomized |
Intervention Model: | Factorial Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
Official Title: | Targeting Residual Activity By Precision, Biomarker-Guided Combination Therapies of Multiple Sclerosis (TRAP-MS) |
Actual Study Start Date : | August 11, 2017 |
Estimated Primary Completion Date : | January 1, 2025 |
Estimated Study Completion Date : | January 1, 2029 |

Arm | Intervention/treatment |
---|---|
Experimental: Combination Therapy
Any two-drug combination of study interventions
|
Drug: Pioglitazone
15-45 mg po qd Drug: clemastine fumarate 8 mg/day (divided into 3 doses of 2, 2, and 4 mg) Drug: Dantrolene Up to 200 mg/day (divided into 3 doses of 50mg, 50mg, and 100 mg) 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 |
Experimental: Monotherapy
Any of the study Interventions
|
Drug: Pioglitazone
15-45 mg po qd Drug: clemastine fumarate 8 mg/day (divided into 3 doses of 2, 2, and 4 mg) Drug: Dantrolene Up to 200 mg/day (divided into 3 doses of 50mg, 50mg, and 100 mg) 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 |
- 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. [ Time Frame: 1.5 years ]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.
- Change in CombiWISE progression rates between baseline and monotherapy phase, monotherapy and combination therapy phase and between different drugs. [ Time Frame: 1 year ]
- Safety and tolerability of individual drugs and their combinations [ Time Frame: 1 year ]
- Change in the rate of ventricular atrophy between baseline, monotherapy and combination therapy periods, measured by linear regression slopes of greater than or equal to 3 time-points for each period [ Time Frame: 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) [ Time Frame: 1 year ]
- Development of new CSF (combinatorial) biomarkers, new clinical scales, new MRI outcomes will be included in exploratory analyses [ Time Frame: 1 year ]

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Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
- INCLUSION CRITERIA:
- Enrolled in 09-I-0032 protocol
- Clinically definite MS
- Age greater than or equal to 18 at time of study enrollment
- Expanded Disability Status Scale (EDSS) 1.0-7.5
- Documented sustained clinical progression of at least 0.5 CombiWISE points/year (measured by greater than or equal to 4 time-points regression analysis of CombiWISE values spanning at least 1.5 years in total)
- Subjects of childbearing potential must be willing to use a medically acceptable form of birth control, which includes abstinence, while being treated on this study
- Patients who desire to continue their current FDA-approved DMTs based on its perceived (partial) therapeutic benefit 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 greater than or equal to 1.5 year baseline period on new DMT to verify that the rate of progression remains greater than or equal to 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, teriflunamide, interferon beta preparations, dimethyl fumarate and fingolimod) to any high potency drugs (i.e., natalizumab, ocrelizumab, rituximab, alemtuzumab, siponimod and mitoxantrone). 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
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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 less than 3,000/mm^3
- Platelet count less than 85,000/mm^3
- Serum creatinine level greater than 2.0 mg/dl and eGFR (glomerular filtration rate) less than 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 one of the 4 tested agents (these are not exclusions from the trial)
-
Pioglitazone
- Congestive heart failure
- History of bladder carcinoma
- Type 1 diabetes
- Hypersensitivity to the drug
- Taking teriflunamide (Aubagio) because of risk of hypoglycemia on this combination
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Clemastine
- Hypersensitivity to the drug.
- Lack of demyelinated axons that could be measured as abnormally-prolonged electrical conduction in at least one of several neurological pathways: visual pathways measured by visual evoked potentials (VEPs), motor pathway measured by central motor conduction time (CMCT) and sensory pathway measured by somatosensory evoked potential (SSEP).
-
Dantrolene
- Hypersensitivity to the drug.
- Hepatic impairment/active hepatic disease (cannot be paired with pirfenidone due to risk of cumulative hepatoxicity).
- Persistent elevation of LFTs.
- History of previous drug/medication or alcohol-related liver toxicities.
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Pirfenidone
- Hypersensitivity to the drug.
- Hepatic impairment/active hepatic disease (cannot be paired with dantrolene due to risk of cumulative hepatoxicity).
- Persistent elevation of LFTs.
- Smoking.

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03109288
Contact: Michelle D Woodland | (301) 402-9619 | michelle.woodland@nih.gov | |
Contact: Bibiana Bielekova, M.D. | (240) 669-2724 | bielekovab@mail.nih.gov |
United States, Maryland | |
National Institutes of Health Clinical Center | Recruiting |
Bethesda, Maryland, United States, 20892 | |
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR) 800-411-1222 ext TTY8664111010 prpl@cc.nih.gov |
Principal Investigator: | Bibiana Bielekova, M.D. | National Institute of Allergy and Infectious Diseases (NIAID) |
Responsible Party: | National Institute of Allergy and Infectious Diseases (NIAID) |
ClinicalTrials.gov Identifier: | NCT03109288 |
Other Study ID Numbers: |
170083 17-I-0083 |
First Posted: | April 12, 2017 Key Record Dates |
Last Update Posted: | May 20, 2022 |
Last Verified: | February 23, 2022 |
Studies a U.S. FDA-regulated Drug Product: | No |
Studies a U.S. FDA-regulated Device Product: | No |
Targeted Therapy Multiple Sclerosis Biomarkers Combination Therapy Progressive Multiple Sclerosis |
Multiple Sclerosis Sclerosis Pathologic Processes Demyelinating Autoimmune Diseases, CNS Autoimmune Diseases of the Nervous System Nervous System Diseases Demyelinating Diseases Autoimmune Diseases Immune System Diseases Pioglitazone Clemastine Pirfenidone Dantrolene Hypoglycemic Agents Physiological Effects of Drugs |
Analgesics Sensory System Agents Peripheral Nervous System Agents Anti-Inflammatory Agents, Non-Steroidal Analgesics, Non-Narcotic Anti-Inflammatory Agents Antirheumatic Agents Antineoplastic Agents Antipruritics Dermatologic Agents Histamine H1 Antagonists Histamine Antagonists Histamine Agents Neurotransmitter Agents Molecular Mechanisms of Pharmacological Action |