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

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)
Actual Study Start Date :	August 11, 2017
Estimated Primary Completion Date :	June 1, 2030
Estimated Study Completion Date :	June 1, 2030

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, Senior)
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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Contacts

Contact: Rosemarie A Cuento, C.R.N.P.	(301) 451-9284	cuentora@mail.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 Neurological Disorders and Stroke (NINDS)

Investigators

Principal Investigator:	Bibiana Bielekova, M.D.	National Institute of Neurological Disorders and Stroke (NINDS)

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

Responsible Party:	National Institute of Neurological Disorders and Stroke (NINDS)
ClinicalTrials.gov Identifier:	NCT03109288 History of Changes
Other Study ID Numbers:	170083; 17-N-0083
First Posted:	April 12, 2017
Last Update Posted:	April 25, 2018
Last Verified:	April 6, 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 Neurological Disorders and Stroke (NINDS) ):

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