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.
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.
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.
Serum alanine transaminase or aspartate transaminase levels which are greater than three times the upper limit of normal values.
Factorial
Cilostazol
Drug100 mg Bid
Leucovorin
Drug10 mg Bid
Pirfenidone
DrugUp 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
Dantrolene
DrugUp to 200 mg/day (divided into 3 doses of 50mg, 50mg, and 100 mg)
Pioglitazone
Drug15-45 mg po qd
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.
Development of new CSF (combinatorial) biomarkers, new clinical scales, new MRI outcomes will be included in exploratory analyses
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)
Safety and tolerability of individual drugs and their combinations
Change in CombiWISE progression rates between baseline and monotherapy phase, monotherapy and combination therapy phase and between different drugs.
Click on the lead sponsor to view all of their trials.
