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

• ClinicalTrials.gov Identifier: NCT03109288
• Recruitment Status: Recruiting
• First Posted: April 12, 2017
• Last Update Posted: May 18, 2020
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Multiple Sclerosis	Drug: Pioglitazone; Drug: clemastine fumarate; Drug: Hydroxychloroquine	Phase 1; Phase 2

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 pre-requisite for a precision-medicine approach to MS. We identified and validated molecular diagnostic tests of MS and its progressive stage based on combinatorial cerebrospinal fluid (CSF) biomarkers. These proteomic tests confirmed results from MS genetic susceptibility studies that selective dysregulation of adaptive immunity differentiates MS from healthy and other disease states and that this feature is identical between patients with relapsing-remitting (RRMS) and progressive (PMS) MS. Instead, PMS subjects have higher central nervous system (CNS) tissue damage and higher compartmentalization of immune responses to CNS tissue. We observed that FDA-approved disease modifying therapies (DMTs) only partially normalize biomarkers that differentiate MS from non-MS, consistent with long-term observations that these therapies are generally not curative. We also observed that biomarkers of dysregulated adaptive immunity, whether measured at the untreated stage or after treatment with DMTs, do not predict MS severity. This is again consistent with genetic data that MS-susceptibility alleles do not predict MS phenotype. Instead, statistical modeling of CSF biomarkers against measures of MS disease severity identified alternative processes, such as activation of myeloid lineage, endothelial cells, astrocytes and remodeling of extracellular matrix in the form of fibrosis to influence rate of progression of clinical disability. These processes are only marginally affected by present treatments and cannot be measured by current imaging techniques. Consequently, the objective of this protocol is: 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

Patients with MS who continue to accumulate clinical disability while untreated (e.g. PMS subjects) or on FDA approved immunomodulatory therapies and are able to 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. To start with, we selected four agents, whose mechanism of action (MOA) have 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 pharmacodynamics (PD) effects in the intrathecal compartment. While those drugs that do not reproducibly effect CSF biomarkers will be dropped from further study (or will be tested in higher dose, if possible), drugs with measurable intrathecal PD activity will be combined to evaluate additive or synergistic effects. 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.

Study Design

• 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

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cobination Therapy; Any two-drug combination of study interventions	Drug: Pioglitazone; 15-45 mg po qd; Drug: clemastine fumarate; 2-4mg/day; Drug: Hydroxychloroquine; 200-400 mg qd/bid
Experimental: Monotherapy; Any of the study Interventions	Drug: Pioglitazone; 15-45 mg po qd; Drug: clemastine fumarate; 2-4mg/day; Drug: Hydroxychloroquine; 200-400 mg qd/bid

Outcome Measures

Primary Outcome Measures :

1. Primary outcome will be the change in the 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 scoresderived from NeurEx App, to eliminate noise stemming from ambiguities in translating neurological exam to disability scores.

Secondary Outcome Measures :

1. Change in CombiWISE progression rates between baseline and monotherapy phase, monotherapy and combination therapy phaseand between different drugs. [ Time Frame: 1 year ]
   Change in CombiWISE progression rates between baseline and monotherapy phase, monotherapy and combination therapy phaseand between different drugs.
2. Safety and tolerability of individual drugs and their combinations [ Time Frame: 1 year ]
   Safety and tolerability of individual drugs and their combinations
3. Change in the rate of ventricular atrophy between baseline, monotherapy and combination therapy periods, measured by linear regression slopes greater than or equal to 3 time-points for each period [ Time Frame: 1 year ]
   Change in the rate of ventricular atrophy between baseline, monotherapy and combination therapy periods, measured by linear regression slopes greater than or equal to 3 time-points for each period
4. 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 ]
   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)
5. Development of new CSF (combinatorial) biomarkers, new clinical scales, new MRI outcomes will be included in exploratory analyses [ Time Frame: 1 year ]
   Development of new CSF (combinatorial) biomarkers, new clinical scales, new MRI outcomes will be included in exploratory analyses
6. Change in CombiWISE progression rates between baseline and monotherapy phase, monotherapy and combination therapy phase and between different drugs. [ Time Frame: 1 year ]
   Change in CombiWISE progression rates between baseline and monotherapy phase, monotherapy and combination therapy phase and between different drugs.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

• 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 (Weideman, Tapia-Maltos et al. 2017), 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
• 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
• Breastfeeding

• 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

  • Hydroxychloroquine

    • Retinal disease or retinal changes on OCT; significant vision loss
    • Hepatic impairment
    • Porphyria
    • Hypersensitivity to the drug

  • 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).

Contacts and Locations

Contacts

Contact: Naomie W Gathua, R.N.; (240) 627-3591; naomie.gathua@nih.gov

Locations

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

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Principal Investigator: Bibiana Bielekova, M.D.; National Institute of Allergy and Infectious Diseases (NIAID)

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

https://go.usa.gov/xP2YY 

• 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
• Last Update Posted: May 18, 2020
• Last Verified: March 13, 2020

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) ):

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

Additional relevant MeSH terms:

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; Hydroxychloroquine; Hypoglycemic Agents; Physiological Effects of Drugs; Antimalarials; Antiprotozoal Agents; Antiparasitic Agents; Anti-Infective Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antipruritics; Dermatologic Agents; Histamine H1 Antagonists; Histamine Antagonists; Histamine Agents; Neurotransmitter Agents; Anti-Allergic Agents