Combination Therapies for Multiple Sclerosis

Overseen By Bibiana Bielekova, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must be taking: MS drugs

Must not be taking: Immunosuppressants, Immunomodulators

Disqualifiers: Cerebrovascular disease, Cardiomyopathy, Clotting disorder, Neurodegenerative disorder, Substance abuse, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 4

250 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how different drug combinations affect inflammation markers in people with multiple sclerosis (MS). Researchers aim to determine if changes in these markers can predict treatment response. Participants will try one or more drugs from a set of four: Clemastine Fumarate (an antihistamine), Dantrolene (a muscle relaxant), Pioglitazone (a diabetes medication), or Pirfenidone (an antifibrotic drug), either alone or in combination. Individuals with progressive MS who can stand and walk a few steps and are currently taking an MS medication might be suitable for this trial. As a Phase 1, Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking MS treatment advancements.

Will I have to stop taking my current medications?

The trial requires that participants keep their current MS medication stable during the study. If you need to change your medication, the study drugs will be stopped to establish a new baseline before continuing.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

In earlier studies, clemastine fumarate, a common allergy medicine, showed promise in repairing nerve damage in multiple sclerosis (MS). However, some research found it might accelerate disability progression in certain MS patients, causing some to worsen more quickly while taking it.

For dantrolene, studies show it can cause muscle weakness and breathing problems. Although already approved for treating muscle issues, these side effects are important to consider.

Pioglitazone, used for diabetes, offers anti-inflammatory benefits. It is generally safe, but the FDA has highlighted a potential increased risk of bladder cancer in safety reviews.

Pirfenidone has been tested for other diseases and is usually well-tolerated. Some individuals might experience stomach problems or skin reactions, but these are typically manageable.

These drugs are still under study for MS, so their safety and side effects are being closely monitored. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for multiple sclerosis because they explore new ways to tackle the disease. Unlike traditional therapies that often focus on modulating the immune system, these investigational drugs—Clemastine Fumarate, Dantrolene, Pioglitazone, and Pirfenidone—each bring something unique to the table. Clemastine Fumarate is thought to promote myelin repair, which is crucial for nerve protection. Dantrolene, typically used for muscle spasticity, may help by reducing cellular stress. Pioglitazone and Pirfenidone, on the other hand, have anti-inflammatory properties that could provide neuroprotection. By combining these mechanisms, the treatments offer hope for improved outcomes and potentially slowing disease progression.

What evidence suggests that this trial's treatments could be effective for multiple sclerosis?

Research has shown that the four drugs have different effects on treating multiple sclerosis (MS). In this trial, participants may receive Clemastine fumarate, which might help repair myelin, the protective layer around nerves, but could also increase disability in people with progressive MS. Another option is Dantrolene, which has reduced muscle stiffness and spasms, potentially improving movement in MS patients. Pioglitazone, also under study, may have anti-inflammatory effects, possibly reducing MS symptoms, with some patients seeing improvements. Although pirfenidone is mainly used for lung conditions, it is another treatment option, as studies suggest it might slow disease progression and could be helpful for MS. These findings indicate that each drug may offer different benefits for MS, but their effectiveness can vary from person to person. ^{1 2 4 6 7}

Who Is on the Research Team?

Bibiana Bielekova, M.D.

Principal Investigator

National Institute of Allergy and Infectious Diseases (NIAID)

Are You a Good Fit for This Trial?

Adults over 18 with progressive MS, able to walk a few steps, and currently in protocol 09-I-0032 can join. They must have shown MS progression and agree to birth control if applicable. Participants can continue their FDA-approved MS drugs but may need to stop if they change treatments.

Inclusion Criteria

My condition has worsened by at least 0.5 points/year over 1.5 years.

My disability level is moderate to severe but I can still perform some daily activities.

I am willing to keep my current FDA-approved MS treatment stable during the study.

Exclusion Criteria

I am not allergic to Dantrolene, have no liver problems, and no history of liver issues caused by drugs or alcohol.

I am not allergic to Pirfenidone, do not have liver disease, my liver tests are normal, and I do not smoke.

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

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Monotherapy

Participants receive one of the study drugs for up to 18 months, with regular assessments of CSF biomarkers to determine drug efficacy.

18 months

2 visits per year (in-person)

Combination Therapy

Participants may start a second drug, continuing for an additional 18 months if the first drug is effective.

18 months

2 visits per year (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with a call 3 months after stopping the drugs.

3 months

What Are the Treatments Tested in This Trial?

Interventions

• Clemastine Fumarate
• Dantrolene
• Pioglitazone
• Pirfenidone

Trial Overview The trial tests whether Dantrolene, Pirfenidone, Pioglitazone, or clemastine fumarate alone or combined affect MS biomarkers in the brain/CSF. It aims to predict drug response based on these biomarker changes during up to an 18-month treatment period.

How Is the Trial Designed?

Group I: Monotherapy Experimental Treatment 4 Interventions

Any of the study Interventions

Group II: Combination Therapy Experimental Treatment 4 Interventions

Any two-drug combination of study interventions

Clemastine Fumarate is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Clemastine for:

• Allergic rhinitis
• Urticaria
• Pruritus

Approved in European Union as Clemastine for:

• Allergic rhinitis
• Urticaria
• Pruritus

Approved in Canada as Clemastine for:

• Allergic rhinitis
• Urticaria
• Pruritus

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Published Research Related to This Trial

The combination therapy of S-1 and paclitaxel (PTX) showed promising efficacy in patients with previously treated non-small cell lung cancer (NSCLC), achieving a response rate of 27.5% and a disease control rate of 75% among 40 enrolled patients.

The treatment was associated with manageable safety profiles, with only mild to moderate toxicities reported, such as grade 3/4 anemia in 12% of patients, and no treatment-related deaths, indicating that this combination therapy is a feasible option for NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of S-1 and Paclitaxel Combination Therapy in Patients with Previously Treated Non-Small Cell Lung Cancer. Chihara, Y., Yoshimura, A., Date, K., et al.[2020]

A new regimen combining doxorubicin and paclitaxel has been developed that is both well-tolerated and highly effective, utilizing bolus administration of doxorubicin and a 3-hour infusion of paclitaxel, overcoming previous schedule-dependent toxicity issues.

Paclitaxel has shown promising results when combined with fluorouracil and folinic acid in patients with extensive prior chemotherapy, and adding mitoxantrone to this combination appears to enhance its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel-based combination chemotherapy for breast cancer. Hortobagyi, GN.[2015]

In a study of 201 patients with hormone-refractory prostate cancer, the combination of vinblastine and estramustine (EM-V) showed a significantly longer time to disease progression compared to vinblastine alone, with median times of 3.7 months versus 2.2 months, respectively.

While overall survival was not significantly different between the two treatments, EM-V resulted in a higher percentage of patients achieving a significant decline in prostate-specific antigen (PSA) levels (25.2% vs. 3.2%), indicating better efficacy in managing the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vinblastine versus vinblastine plus oral estramustine phosphate for patients with hormone-refractory prostate cancer: A Hoosier Oncology Group and Fox Chase Network phase III trial. Hudes, G., Einhorn, L., Ross, E., et al.[2017]

Combining paclitaxel with doxorubicin has shown impressive remission rates for metastatic breast cancer, with overall rates exceeding 90% and nearly 50% achieving complete remission, especially when administered in a specific sequence.

While other combinations of paclitaxel with drugs like cisplatin and vinorelbine have shown variable results, the doxorubicin/paclitaxel combination remains the most effective and tolerable treatment option currently available.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel-containing combination chemotherapy for metastatic breast cancer. Hortobagyi, GN., Ibrahim, N.[2018]

Paclitaxel has shown single-agent activity in breast cancer, leading to ongoing trials exploring its effectiveness in various combinations with other drugs like doxorubicin, cisplatin, and cyclophosphamide.

Despite numerous studies, no optimal combination regimen for paclitaxel has been established yet, highlighting the need for well-designed trials to safely explore these combinations due to the unpredictable nature of drug interactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel combination therapy in the treatment of metastatic breast cancer. Holmes, FA.[2015]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40371642/

Clemastine fumarate accelerates accumulation of disability in ... Clemastine fumarate, the over-the-counter antihistamine and muscarinic receptor blocker, has remyelinating potential in MS.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT02040298

NCT02040298 | Assessment of Clemastine Fumarate as a ... The main purpose of this study is to assess clemastine as a remyelinating agent in patients with relapsing forms of multiple sclerosis.

3. neurologylive.com neurologylive.com/view/clemastine-arm-trap-ms-trial-halted-following-increased-disability-accumulation-progressive-ms

Clemastine Arm of TRAP-MS Trial Halted Following ... New data from the TRAP-MS trial showed clemastine fumarate's association with increased disability accumulation in cases of non-lesional multiple sclerosis.

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0140673617323462

Articles Clemastine fumarate as a remyelinating therapy for ... The primary efficacy endpoint was met with clemastine fumarate treatment, which reduced the latency delay by 1·7 ms/eye (95% CI 0·5–2·9; p=0·0048) when ...

5. rarediseaseadvisor.com rarediseaseadvisor.com/news/clemastine-fumarate-drives-disease-progression-progressive-ms/

Clemastine Fumarate Drives Disease Progression in ... Clemastine fumarate amplifies disease progression in progressive MS by amplifying innate immune responses.

6. practicalneurology.com practicalneurology.com/news/otc-antihistamine-clemastine-may-accelerate-disability-in-those-with-progressive-ms/2470414/

OTC Antihistamine Clemastine May Accelerate Disability in ... In terms of results, 3 patients increased disability 5-times faster compared to their 18-months “baseline” progression slopes. This outcome ...

7. mdedge.com mdedge.com/neurologyreviews/article/268320/multiple-sclerosis/unexpected-finding-clemastine-fumarate-linked

In Unexpected Finding, Clemastine Fumarate Linked to ... Researchers halted an arm of a clinical trial of clemastine fumarate for MS after a fivefold increase in disease progression was reported in ...