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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 : July 19, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )

Study Description
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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 75 who:

Are in protocol 09-N-0032

Have progressive MS

Can stand and walk a few steps

Take an MS drug

Design:

Participants will be screened in protocol 09-N-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: Montelukast Drug: Losartan Drug: Hydroxychloroquine Phase 1 Phase 2

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Study Design
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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)
Estimated Study Start Date : July 24, 2018
Estimated Primary Completion Date : June 1, 2030
Estimated Study Completion Date : June 1, 2030

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Pioglitazone
Pioglitazone Monotherapy
 Drug: Pioglitazone
15-45 mg po qd
Experimental: Montelukast
Montelukast Monotherapy
 Drug: Montelukast
10mg qd
Experimental: Losartan
Losartan Monotherapy
 Drug: Losartan
50-100mg/day (can be divided bid)
Experimental: Hydroxychloroquine
Hydroxychloroquine Monotherapy
 Drug: Hydroxychloroquine
200-400 mg qd/bid


Outcome Measures
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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: Study Completion ]

Secondary Outcome Measures :
  1. Safety and tolerability of individual drugs and their combinations [ Time Frame: Study Completion ]
  2. 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: Study Completion ]
  3. 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: Study Completion ]
  4. Development of new CSF (combinatorial) biomarkers, new clinical scales, new MRI outcomes will be included in exploratory analyses [ Time Frame: Study Completion ]

Eligibility Criteria
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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-N-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 has to 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, but the patient will have an option to repeat the entire process: 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 and then can be matched to the same monotherapy or combination therapy regimen s/he was 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/mm3
  • Platelet count less than 85 000/mm3

  • 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

    • Montelukast

      ----Hypersensitivity to the drug

    • Hydroxychloroquine

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

    • Losartan

      • Hypersensitivity to drug
      • Renal impairment
      • Hepatic impairment
      • Congestive heart failure
Contacts and Locations
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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
Contact: Naomie W Gathua, R.N. (301) 496-7691 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 Neurological Disorders and Stroke (NINDS)
More Information
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Additional Information:
NIH Clinical Center Detailed Web Page  This link exits the ClinicalTrials.gov site

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT03109288     History of Changes
Other Study ID Numbers: 170083
17-I-0083
First Posted: April 12, 2017    Key Record Dates
Last Update Posted: July 19, 2018
Last Verified: July 13, 2018

Studies a U.S. FDA-regulated Drug Product: Yes
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

Additional relevant MeSH terms:
Sclerosis
Multiple Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Pioglitazone
Losartan
Montelukast
Hydroxychloroquine
Hypoglycemic Agents
Physiological Effects of Drugs
 Anti-Arrhythmia Agents
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Anti-Asthmatic Agents
Respiratory System Agents
Leukotriene Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Cytochrome P-450 CYP1A2 Inducers
Cytochrome P-450 Enzyme Inducers
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents