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

• Register: ClinicalTrials.gov
• Last refreshed on: 8 April 2024
• Main ID: NCT03109288
• Date of registration: 11/04/2017
• Prospective Registration: Yes
• Primary sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Public title: Targeting Residual Activity By Precision, Biomarker-Guided Combination Therapies of Multiple Sclerosis (TRAP-MS)
• Scientific title: Targeting Residual Activity By Precision, Biomarker-Guided Combination Therapies of Multiple Sclerosis (TRAP-MS)
• Date of first enrolment: August 11, 2017
• Target sample size: 250
• Recruitment status: Recruiting
• URL: https://clinicaltrials.gov/ct2/show/NCT03109288
• Study type: Interventional
• Study design: Allocation: Non-Randomized. Intervention model: Factorial Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 1/Phase 2

Countries of recruitment

United States

Contacts

• Name: Bibiana Bielekova, M.D.
• Affiliation: National Institute of Allergy and Infectious Diseases (NIAID)

• Name: Michelle D Woodland

• Name: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)

Key inclusion & exclusion 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withdrawn, to establish new baseline of CSF biomarkers under changed therapy, and, if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.



Age minimum: 18 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Multiple Sclerosis

Intervention(s)

Drug: Pioglitazone

Drug: clemastine fumarate

Drug: Pirfenidone

Drug: Dantrolene

Primary Outcome(s)

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. [Time Frame: 1.5 years]

Secondary Outcome(s)

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]

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]

Change in CombiWISE progression rates between baseline and monotherapy phase, monotherapy and combination therapy phase and between different drugs. [Time Frame: 1 year]

Safety and tolerability of individual drugs and their combinations [Time Frame: 1 year]

Development of new CSF (combinatorial) biomarkers, new clinical scales, new MRI outcomes will be included in exploratory analyses [Time Frame: 1 year]

Secondary ID(s)

17-I-0083

170083

Source(s) of Monetary Support

Please refer to primary and secondary sponsors