Multiple Sclerosis Clinical Trial
Official title:
Targeting Residual Activity By Precision, Biomarker-Guided Combination Therapies of Multiple Sclerosis (TRAP-MS)
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.
Status | Recruiting |
Enrollment | 250 |
Est. completion date | January 1, 2029 |
Est. primary completion date | January 1, 2025 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years and older |
Eligibility | - INCLUSION CRITERIA: - Enrolled in 09-I-0032 protocol. - Clinically definite MS. - Age greater than or equal to 18 years 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). - Because currently only NDS utilizes CombiWISE scale, the progression slopes will be determined from NDS protocols: natural history protocol 09-I-0032 or any of the past NDS clinical trials (protocols 09-I-0197, 10-N-0212, 10-N-0125 and 13-I-0088). Consequently, new patients will be screened to this protocol via 09-I-0032 natural history protocol that contains completely overlapping procedures. - It is possible that after other MS centers start using CombiWISE scale, this progression criterion may be derived from outside data, as long as they are adequately documented. - Subjects of childbearing potential must be willing to use a medically acceptable form of birth control, 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, teriflunomide, interferon beta preparations, dimethyl or monomethyl fumarate and fingolimod) to any high potency drugs (i.e., natalizumab, ocrelizumab, rituximab, alemtuzumab, siponimod, cladribine, ofatumumab, ozanimod, ublituximab 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 teriflunomide (Aubagio) because of risk of hypoglycemia on this combination. - 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. |
Country | Name | City | State |
---|---|---|---|
United States | National Institutes of Health Clinical Center | Bethesda | Maryland |
Lead Sponsor | Collaborator |
---|---|
National Institute of Allergy and Infectious Diseases (NIAID) |
United States,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | 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. | 1.5 years | |
Secondary | Change in CombiWISE progression rates between baseline and monotherapy phase, monotherapy and combination therapy phase and between different drugs. | 1 year | ||
Secondary | Safety and tolerability of individual drugs and their combinations | 1 year | ||
Secondary | 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 | 1 year | ||
Secondary | 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) | 1 year | ||
Secondary | Development of new CSF (combinatorial) biomarkers, new clinical scales, new MRI outcomes will be included in exploratory analyses | 1 year |
Status | Clinical Trial | Phase | |
---|---|---|---|
Completed |
NCT05528666 -
Risk Perception in Multiple Sclerosis
|
||
Completed |
NCT03608527 -
Adaptive Plasticity Following Rehabilitation in Multiple Sclerosis
|
N/A | |
Recruiting |
NCT05532943 -
Evaluate the Safety and Efficacy of Allogeneic Umbilical Cord Mesenchymal Stem Cells in Patients With Multiple Sclerosis
|
Phase 1/Phase 2 | |
Completed |
NCT02486640 -
Evaluation of Potential Predictors of Adherence by Investigating a Representative Cohort of Multiple Sclerosis (MS) Patients in Germany Treated With Betaferon
|
||
Completed |
NCT01324232 -
Safety and Efficacy of AVP-923 in the Treatment of Central Neuropathic Pain in Multiple Sclerosis
|
Phase 2 | |
Completed |
NCT04546698 -
5-HT7 Receptor Implication in Inflammatory Mechanisms in Multiple Sclerosis
|
||
Active, not recruiting |
NCT04380220 -
Coagulation/Complement Activation and Cerebral Hypoperfusion in Relapsing-remitting Multiple Sclerosis
|
||
Completed |
NCT02835677 -
Integrating Caregiver Support Into MS Care
|
N/A | |
Completed |
NCT03686826 -
Feasibility and Reliability of Multimodal Evoked Potentials
|
||
Recruiting |
NCT05964829 -
Impact of the Cionic Neural Sleeve on Mobility in Multiple Sclerosis
|
N/A | |
Withdrawn |
NCT06021561 -
Orofacial Pain in Multiple Sclerosis
|
||
Completed |
NCT03653585 -
Cortical Lesions in Patients With Multiple Sclerosis
|
||
Recruiting |
NCT04798651 -
Pathogenicity of B and CD4 T Cell Subsets in Multiple Sclerosis
|
N/A | |
Active, not recruiting |
NCT05054140 -
Study to Evaluate Efficacy, Safety, and Tolerability of IMU-838 in Patients With Progressive Multiple Sclerosis
|
Phase 2 | |
Completed |
NCT05447143 -
Effect of Home Exercise Program on Various Parameters in Patients With Multiple Sclerosis
|
N/A | |
Recruiting |
NCT06195644 -
Effect of Galvanic Vestibular Stimulation on Cortical Excitability and Hand Dexterity in Multiple Sclerosis Patients
|
Phase 1 | |
Completed |
NCT04147052 -
iSLEEPms: An Internet-Delivered Intervention for Sleep Disturbance in Multiple Sclerosis
|
N/A | |
Completed |
NCT03591809 -
Combined Exercise Training in Patients With Multiple Sclerosis
|
N/A | |
Completed |
NCT03594357 -
Cognitive Functions in Patients With Multiple Sclerosis
|
||
Completed |
NCT03269175 -
BENEFIT 15 Long-term Follow-up Study of the BENEFIT and BENEFIT Follow-up Studies
|
Phase 4 |