Targeting Residual Activity By Precision, Biomarker-Guided Combination Therapies of Multiple Sclerosis (TRAP-MS)
Primary Purpose
Multiple Sclerosis
Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Pioglitazone
clemastine fumarate
Dantrolene
Pirfenidone
Sponsored by
About this trial
This is an interventional treatment trial for Multiple Sclerosis focused on measuring Targeted Therapy, Multiple Sclerosis, Biomarkers, Combination Therapy, Progressive Multiple Sclerosis
Eligibility 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changing FDA-approved DMT during the duration of this protocol, the drugs administered under this protocol will be withdrawn, to establish new baseline of CSF biomarkers under changed therapy, and, if necessary, to establish new progression rate.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, 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.
Sites / Locations
- National Institutes of Health Clinical CenterRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Combination Therapy
Monotherapy
Arm Description
Any two-drug combination of study interventions
Any of the study Interventions
Outcomes
Primary Outcome Measures
Primary outcome will be change in CombiWISE progression rate at the end of monotherapy plus combination therapy period in comparison to projected baseline disability progression.
CombiWISE will be calculated from EDSS and SNRS scores derived from NeurEx App, to eliminate noise stemming from ambiguities in translating neurological exam to disability scores.
Secondary Outcome Measures
Change in CombiWISE progression rates between baseline and monotherapy phase, monotherapy and combination therapy phase and between different drugs.
Safety and tolerability of individual drugs and their combinations
Change in the rate of ventricular atrophy between baseline, monotherapy and combination therapy periods, measured by linear regression slopes of greater than or equal to 3 time-points for each period
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)
Development of new CSF (combinatorial) biomarkers, new clinical scales, new MRI outcomes will be included in exploratory analyses
Full Information
NCT ID
NCT03109288
First Posted
April 11, 2017
Last Updated
October 20, 2023
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
1. Study Identification
Unique Protocol Identification Number
NCT03109288
Brief Title
Targeting Residual Activity By Precision, Biomarker-Guided Combination Therapies of Multiple Sclerosis (TRAP-MS)
Official Title
Targeting Residual Activity By Precision, Biomarker-Guided Combination Therapies of Multiple Sclerosis (TRAP-MS)
Study Type
Interventional
2. Study Status
Record Verification Date
January 19, 2023
Overall Recruitment Status
Recruiting
Study Start Date
August 11, 2017 (Actual)
Primary Completion Date
January 1, 2025 (Anticipated)
Study Completion Date
January 1, 2029 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
5. 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.
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 prerequisite for a precision-medicine approach to MS.
Using combinatorial cerebrospinal fluid (CSF) biomarkers, we identified and validated molecular diagnostic tests of MS and its progressive stage, tests that correlate with clinical disability and brain atrophy (i.e., molecular tests of MS progression) and tests that predict future rates of disability progression (i.e., molecular tests of MS severity).
These proteomic tests showed that intra-individually heterogeneous processes, different from those that drive MS susceptibility, underlie continuous accumulation of disability and brain atrophy in patients with progressive MS (PMS), or patients with relapsing-remitting (RRMS) treated with current disease-modifying treatments (DMTs). These processes include compartmentalized inflammation, activation of innate immunity such as myeloid lineage, complement and coagulation cascade, toxic astrocytosis, restructuring of the extracellular matrix in the form of fibrosis, and the re-expression (or lack of it) of developmental pathways related to neurogenesis and remyelination. These alternative, likely pathogenic mechanisms are essentially unaffected by current DMTs, consistent with observations of declining efficacy of FDA-approved DMTs with advancing age of MS patients, so that collectively, they offer no benefit on disability progression after age of approximately 53 years. Consequently, the objectives of this protocol are: 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
Subjects with MS who continue to accumulate clinical disability while untreated (e.g., PMS subjects) or on FDA approved immunomodulatory therapies and can 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. The protocol studies drugs whose mechanism of action (MOA) has 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 pharmacodynamic (PD) effects in the intrathecal compartment. Drugs that do not reproducibly effect CSF biomarkers will be dropped from further study (or will be tested in higher dose, if possible), and replaced by new agents under protocol amendments, while drugs with measurable intrathecal PD activity will be combined to evaluate additive or synergistic effects. Subjects who are treated by drugs that were found to be ineffective will be switched to alternative/new drug and their monotherapy or combination therapy period will be restarted with the goal of each subject finishing 18 months of monotherapy and additional 18 months of combination theapy with effective drugs only. 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multiple Sclerosis
Keywords
Targeted Therapy, Multiple Sclerosis, Biomarkers, Combination Therapy, Progressive Multiple Sclerosis
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Factorial Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
250 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Combination Therapy
Arm Type
Experimental
Arm Description
Any two-drug combination of study interventions
Arm Title
Monotherapy
Arm Type
Experimental
Arm Description
Any of the study Interventions
Intervention Type
Drug
Intervention Name(s)
Pioglitazone
Intervention Description
15-45 mg po qd
Intervention Type
Drug
Intervention Name(s)
clemastine fumarate
Intervention Description
8 mg/day (divided into 3 doses of 2, 2, and 4 mg)
Intervention Type
Drug
Intervention Name(s)
Dantrolene
Intervention Description
Up to 200 mg/day (divided into 3 doses of 50mg, 50mg, and 100 mg)
Intervention Type
Drug
Intervention Name(s)
Pirfenidone
Intervention Description
Up to 801 mg po tid. Slow titration over weeks based on tolerability:
267mg po tid x >= 7d 534 mg po tid x >= 7d 801 mg po tid
Primary Outcome Measure Information:
Title
Primary outcome will be change in CombiWISE progression rate at the end of monotherapy plus combination therapy period in comparison to projected baseline disability progression.
Description
CombiWISE will be calculated from EDSS and SNRS scores derived from NeurEx App, to eliminate noise stemming from ambiguities in translating neurological exam to disability scores.
Time Frame
1.5 years
Secondary Outcome Measure Information:
Title
Change in CombiWISE progression rates between baseline and monotherapy phase, monotherapy and combination therapy phase and between different drugs.
Time Frame
1 year
Title
Safety and tolerability of individual drugs and their combinations
Time Frame
1 year
Title
Change in the rate of ventricular atrophy between baseline, monotherapy and combination therapy periods, measured by linear regression slopes of greater than or equal to 3 time-points for each period
Time Frame
1 year
Title
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
Title
Development of new CSF (combinatorial) biomarkers, new clinical scales, new MRI outcomes will be included in exploratory analyses
Time Frame
1 year
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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, 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Michelle D Woodland
Phone
(301) 402-9619
Email
michelle.woodland@nih.gov
First Name & Middle Initial & Last Name or Official Title & Degree
Bibiana Bielekova, M.D.
Phone
(240) 669-2724
Email
bielekovab@mail.nih.gov
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bibiana Bielekova, M.D.
Organizational Affiliation
National Institute of Allergy and Infectious Diseases (NIAID)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)
Phone
800-411-1222
Ext
TTY8664111010
Email
prpl@cc.nih.gov
12. IPD Sharing Statement
Links:
URL
https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2017-I-0083.html
Description
NIH Clinical Center Detailed Web Page
URL
https://go.usa.gov/xP2YY
Description
https://go.usa.gov/xP2YY
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Targeting Residual Activity By Precision, Biomarker-Guided Combination Therapies of Multiple Sclerosis (TRAP-MS)
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