Targeting Residual Activity By Precision, Biomarker-Guided Combination Therapies of Multiple Sclerosis (TRAP-MS)
- Conditions
- Multiple Sclerosis
- Interventions
- Registration Number
- NCT03109288
- 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.
- Detailed Description
Objective
Multiple inflammatory and neurodegenerative mechanisms drive progression of disability in fully established multiple sclerosis (MS); therefore, it is unlikely that a single therapeutic agent will be curative. Analogous to cardiovascular diseases, effective treatments for evolved MS will likely require individualized combination therapies that target pathogenic processes active in the particular patient. Ability to reliably measure such pathogenic processes in living patients is a prerequisite for a precision-medicine approach to MS.
Using combinatorial cerebrospinal fluid (CSF) biomarkers, we identified and validated molecular diagnostic tests of MS and its progressive stage, tests that correlate with clinical disability and brain atrophy (i.e., molecular tests of MS progression) and tests that predict future rates of disability progression (i.e., molecular tests of MS severity).
These proteomic tests showed that intra-individually heterogeneous processes, different from those that drive MS susceptibility, underlie continuous accumulation of disability and brain atrophy in patients with progressive MS (PMS), or patients with relapsing-remitting (RRMS) treated with current disease-modifying treatments (DMTs). These processes include compartmentalized inflammation, activation of innate immunity such as myeloid lineage, complement and coagulation cascade, toxic astrocytosis, restructuring of the extracellular matrix in the form of fibrosis, and the re-expression (or lack of it) of developmental pathways related to neurogenesis and remyelination. These alternative, likely pathogenic mechanisms are essentially unaffected by current DMTs, consistent with observations of declining efficacy of FDA-approved DMTs with advancing age of MS patients, so that collectively, they offer no benefit on disability progression after age of approximately 53 years. Consequently, the objectives of this protocol are: 1. To develop clinical trial methodology that allows economical screening of prospective therapeutic agents for their efficacy on biological processes related to MS disease severity using CSF biomarkers; 2. To develop knowledge base of intrathecal effects of current DMTs and novel treatments targeting varied mechanisms of MS progression; and 3. To establish and validate framework for development of effective combination therapies for MS via precision-medicine paradigm.
Study population
Subjects with MS who continue to accumulate clinical disability while untreated (e.g., PMS subjects) or on FDA approved immunomodulatory therapies and can travel to NIH every 6 months and undergo serial lumbar punctures (LP).
Design
The protocol has an adaptable workflow that allows simultaneous assessments of multiple therapeutic agents while maximizing potential therapeutic benefit to the studied subjects and providing knowledge necessary for rational development of future combination therapies for MS. The protocol studies drugs whose mechanism of action (MOA) has the potential to inhibit identified processes underlying MS disease severity. Patients will be assigned to one of the drugs that are not contra-indicated based on existing comorbidities and to which the patient has a therapeutic target (e.g., treatment that inhibits activation of myeloid lineage will be assigned only to patients who have elevated CSF biomarkers of myeloid lineage). Longitudinal measurements of CSF biomarkers will determine if the applied treatment(s) exert the desired pharmacodynamic (PD) effects in the intrathecal compartment. Drugs that do not reproducibly effect CSF biomarkers will be dropped from further study (or will be tested in higher dose, if possible), and replaced by new agents under protocol amendments, while drugs with measurable intrathecal PD activity will be combined to evaluate additive or synergistic effects. Subjects who are treated by drugs that were found to be ineffective will be switched to alternative/new drug and their monotherapy or combination therapy period will be restarted with the goal of each subject finishing 18 months of monotherapy and either continuing monotherapy for an additional 18 months or starting a combination therapy for 18 months with effective drugs only. Safety, tolerability, and pilot clinical/imaging efficacy data will evaluate surrogacy of the biomarkers and collect data for power analysis for future definitive trials. The increased understanding of biomarker biology will be utilized to derive process-specific combinatorial biomarkers and biomarker signatures predictive of clinical efficacy.
Outcome measures
Primary outcome will be the change in Combinatorial Weight-adjusted disability scale (CombiWISE) progression at the end of monotherapy + combination therapy period in comparison to projected baseline disability progression. The acquired longitudinal data will be used for assessment of biomarker surrogacy, for identification and validation of PD markers for development of new therapeutic entities and for power analysis of future/definitive clinical trials.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 250
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- FACTORIAL
- Arm && Interventions
Group Intervention Description Combination Therapy Pioglitazone Any two-drug combination of study interventions Combination Therapy clemastine fumarate Any two-drug combination of study interventions Combination Therapy Pirfenidone Any two-drug combination of study interventions Monotherapy clemastine fumarate Any of the study Interventions Combination Therapy Dantrolene Any two-drug combination of study interventions Monotherapy Pioglitazone Any of the study Interventions Monotherapy Dantrolene Any of the study Interventions Monotherapy Pirfenidone Any of the study Interventions
- Primary Outcome Measures
Name Time Method 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 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.
- Secondary Outcome Measures
Name Time Method Change in CombiWISE progression rates between baseline and monotherapy phase, monotherapy and combination therapy phase and between different drugs. 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 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 1 year Development of new CSF (combinatorial) biomarkers, new clinical scales, new MRI outcomes will be included in exploratory analyses 1 year
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States