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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 18, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )

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

Show Show detailed description

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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

Resource links provided by the National Library of Medicine


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




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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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).

Information from the National Library of Medicine

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


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

Locations
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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
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Principal Investigator: Bibiana Bielekova, M.D. National Institute of Allergy and Infectious Diseases (NIAID)
Additional Information:
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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 18, 2020
Last Verified: March 13, 2020

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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:
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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