Recruiting
Phase 1
Phase 2

Combination Therapies

Sponsor:

National Institute of Allergy and Infectious Diseases (NIAID)

Code:

NCT03109288

Conditions

Multiple Sclerosis

Eligibility Criteria

Sex: All

Age: 18 - 70+

Healthy Volunteers: Not accepted

Interventions

Cilostazol

Leucovorin

Pirfenidone

Dantrolene

Pioglitazone

Study Details

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.

Conditions

Multiple Sclerosis

Study ID

NCT03109288

Start date

Aug 11, 2017

Status verified date

Mar 26, 2026

Completion date

Jan 1, 2029

Anticipated

Primary completion date

Jan 1, 2027

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: All

Age: 18 - 70+

Healthy Volunteers: Not accepted

  • INCLUSION CRITERIA:
  • Enrolled in 09-I-0032 protocol.
  • Clinically definite MS.
  • Age >=18 years at time of study enrollment.
  • Expanded Disability Status Scale (EDSS) 1.0-7.5.
  • For progressive MS cohort enrollment:

  • Documented sustained clinical progression of at least 0.5 CombiWISE points/year on stable therapy (or untreated)

  • If follow-up is <3 years, CombiWISE progression slopes are measured by >= 4 time points regression analysis of CombiWISE values spanning at least 18 months (1.5 years)
  • If follow-up is >=3 years, CombiWISE progression slopes are measured by >= 2 time-points regression analysis of CombiWISE values spanning at least 36 months (3 years)
  • Because currently only NDS utilizes CombiWISE scale, the progression slopes will be determined 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.
  • For non-progressing MS with residual disability cohort enrollment:

  • CombiWISE slope on stable therapy (derived identically as in progressive MS cohort) >0 and <0.5 CombiWISE units/year (i.e., neurological deficit that is no longer improving)
  • CombiWISE at the end of screening period >10 (i.e., sustained residual disability)
  • Women who can become pregnant must be willing to use a medically acceptable form of birth control, while being treated on this study.
  • Patients on current FDA-approved DMTs 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 >= 1.5 year baseline period on new DMT to verify that the rate of progression remains >=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., any B-cell depleting agents, natalizumab, alemtuzumab, siponimod, ozanimod and cladribine). 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 < 3 000/mm\^3.
  • Platelet count < 85 000/mm\^3.
  • Serum creatinine level > 2.0 mg/dL and eGFR (glomerular filtration rate) < 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 specific agent (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.
  • Cilostazol

  • Hypersensitivity to the drug.
  • Congestive heart failure.
  • Hemostatic disorder/active bleeding.
  • Taking any S1P inhibitor (i.e., fingolimod, ozanimod, Siponimod or ponesimod) due to additive risk for QTc interval prolongation and thus increasing risk of arrythmia.
  • Leucovorin

  • Hypersensitivity to the drug.
  • Colorectal cancer (active).
  • Vitamin B12 deficiency

Study Design

Enrollment

250 participants

Anticipated

Allocation

Non randomized

Intervention Model

Factorial

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

experimental: Combination Therapy

Any two-drug combination of study interventions

experimental: Monotherapy

Any of the study Interventions

Interventions

Cilostazol

100 mg Bid

Leucovorin

10 mg Bid

Pirfenidone

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

Dantrolene

Up to 200 mg/day (divided into 3 doses of 50mg, 50mg, and 100 mg)

Pioglitazone

15-45 mg po qd

Primary outcome measure

  • 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 ]

Central Contacts and Locations

Central contacts

Michelle D Woodland

(301) 402-9619michelle.woodland@nih.gov

Bibiana Bielekova, M.D.

(240) 669-2724bielekovab@mail.nih.gov

Locations

National Institutes of Health Clinical Center

Recruiting

Bethesda, Maryland, United States, 20892

Contacts

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

800-411-1222prpl@cc.nih.gov

More Information

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

Last update posted

Aug 27, 2026

Last verified

Mar 26, 2026

Keywords

  • Targeted Therapy
  • Multiple Sclerosis
  • Biomarkers
  • Combination Therapy
  • Progressive Multiple Sclerosis

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-10. This information was provided to ClinicalTrials.gov by National Institute of Allergy and Infectious Diseases (NIAID) on 2026-08-27.