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

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

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....

Objective:

Multiple pathogenic 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 mechanisms in living subjects is a prerequisite for a precisionmedicine approach to MS.

We have already demonstrated the clinical utility of combinatorial cerebrospinal fluid (CSF) biomarkers for diagnosing, staging and prognosticating MS. In an external validation study by the multicenter SPINal fluid COnsortium for Multiple Sclerosis (SPINCOMS), these proteomic molecular tests outperformed traditional phenomenological approaches in diagnostic and staging accuracy and also predicted future disability.

These proteomic tests revealed substantial intra-individual heterogeneity in the candidate mechanisms of MS progression, which are largely distinct from those underlying MS susceptibility. Identified progression-related processes include compartmentalized inflammation; activation of innate immunity (e.g., myeloid lineage, complement, and coagulation cascades); continuous damage to CNS epithelial barriers; toxic astrogliosis; fibrotic remodeling of the extracellular matrix; and altered expression of pathways involved in synaptogenesis, neurogenesis, and remyelination. These mechanisms are largely unaffected by current FDA-approved DMTs, consistent with their declining efficacy as patients age-ultimately providing no measurable group benefit on disability progression beyond approximately 55 years of age.

Accordingly, the objectives of this protocol are to:

• Develop clinical trial methodology for economical screening of therapeutic agents targeting candidate pathogenic mechanisms of MS using CSF biomarkers.
• Build a knowledge base on the intrathecal effects of current DMTs and emerging treatments on candidate pathogenic (and reparative) mechanisms of MS.
• Establish and validate framework for designing effective and safe combination therapies for MS within a precision medicine paradigm.

Study population:

• Progressive MS (ProgMS): People with MS (pwMS) who exhibit ongoing clinical disability progression despite treatment with FDA-approved DMTs, or while untreated, either due to age over 55y, prior DMT failure, or personal choice to forgo treatment. The therapeutic goal in this cohort is to slow the rate of disability progression.
• Non-progressing MS with residual disability: pwMS with no/very low measurable disease progression while on FDA-approved DMTs (or untreated), but who continue to experience residual disability. The therapeutic goal in this cohort is to improve existing disability.

Design:

The protocol employs an adaptable workflow that enables simultaneous evaluation of multiple therapeutic agents, maximizing potential benefit to participants while generating knowledge essential for the rational development of future combination therapies for MS. It focuses on drugs with mechanisms of action (MOAs) targeting biological processes that underlie MS severity.

Participants will be assigned to therapies based on individual therapeutic targets and comorbidities. Longitudinal CSF biomarker measurements will assess whether assigned treatments elicit the desired pharmacodynamic (PD) effects within the intrathecal compartment.

Agents that fail to reproducibly modulate their intended CSF targets will be discontinued (or tested at higher doses, if feasible) and replaced under protocol amendments. Agents that demonstrate measurable and desired intrathecal PD activity will be evaluated in combination to assess additive or synergistic effects.

Participants receiving discontinued/ineffective agents or not tolerating assigned treatment will be transitioned to alternative treatments, restarting their monotherapy or combination therapy periods, with the aim of each subject completing 18 months of monotherapy followed by either continued monotherapy or 18 months of combination therapy using only effective agents. Participants who complete 36 months of treatment may be re-enrolled to evaluate new therapeutic agents as they become available.

Safety, tolerability, and preliminary clinical/imaging outcomes will inform the surrogacy of CSF biomarkers and guide power calculations for future definitive trials. In parallel, enhanced understanding of biomarker biology will support the development of process-specific combinatorial biomarkers and 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.

• 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

  • Congestive heart failure.
  • History of bladder carcinoma.
  • Type 1 diabetes.
  • Hypersensitivity to the drug.
  • Taking teriflunomide (Aubagio) because of risk of hypoglycemia on this combination.

• 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.

• 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.

• Cilostazol

  • Hypersensitivity to the drug.
  • Congestive heart failure.
  • Hemostatic disorder/active bleeding.
  • Taking any S1P inhibitor (i.e., fingolimod, ozanimod, Siponimod or ponesimod) due to additive risk for QTc interval prolongation and thus increasing risk of arrythmia.

• Leucovorin

  • Hypersensitivity to the drug.
  • Colorectal cancer (active).
  • Vitamin B12 deficiency