This study is currently recruiting participants.
Number
17-I-0083
Sponsoring Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Recruitment Detail
Type: Participants currently recruited/enrolled Gender: Male & Female Min Age: 18 Max Age: N/A
Referral Letter Required
No
Population Exclusion(s)
Pregnant Women;Fetuses;Children
Keywords
Targeted Therapy; Multiple Sclerosis; Biomarkers; Combination Therapy; Progressive Multiple Sclerosis
Recruitment Keyword(s)
None
Condition(s)
Multiple Sclerosis
Investigational Drug(s)
Investigational Device(s)
Intervention(s)
Drug: Pioglitazone Drug: clemastine fumarate Drug: Dantrolene Drug: Pirfenidone
Supporting Site
National Institute of Allergy and Infectious Diseases
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.
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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, 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 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 -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). -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.
-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, 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
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
-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).
-Dantrolene
--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
--Hepatic impairment/active hepatic disease (cannot be paired with dantrolene due to risk of cumulative hepatoxicity).
--Smoking.
Principal Investigator
Referral Contact
For more information:
Additional Linkshttps://go.usa.gov/xP2YY