Cladribine Tablets for Multiple Sclerosis

Overseen By Judy Button

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Keith Edwards, M.D.

Must be taking: Cladribine tablets

Must not be taking: Alemtuzumab, Ocrelizumab, Rituximab, others

Disqualifiers: Diabetes, Obesity, Liver conditions, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

Duration: 96 weeks

30 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to explore the concept that biomarker sensitivity will detect activity in Multiple Sclerosis (MS) subjects and allow appropriate change in treatment to prevent dysfunction.

Will I have to stop taking my current medications?

The trial requires that certain medications be stopped before participation. Specifically, treatments like ocrelizumab, rituximab, natalizumab, fingolimod, teriflunomide, dimethyl fumarate, interferon, glatiramer acetate, and systemic corticosteroids must be stopped for specified periods before the trial. However, medications for spasticity or neuropathic pain can be continued if they have been stable for at least 30 days before screening.

What data supports the effectiveness of the drug Cladribine Tablets for treating multiple sclerosis?

Research shows that Cladribine Tablets, marketed as Mavenclad, are effective in treating relapsing multiple sclerosis, with studies indicating that 75% of patients experienced benefits for up to 4 years with a specific dosing schedule. ^{1 2 3 4 5}

Is cladribine safe for humans?

Cladribine tablets, used for treating multiple sclerosis, have been studied for their long-term safety. They are generally considered safe, but they can temporarily lower the number of immune cells, which might affect how well vaccines work. ^{2 3 4 6 7}

What makes the drug Cladribine Tablets unique for treating multiple sclerosis?

Cladribine Tablets are unique because they are taken orally and work by selectively targeting and reducing certain immune cells, which helps manage multiple sclerosis. This is different from many other treatments that require injections or infusions. ^{8 9 10 11 12}

Research Team

Keith R Edwards, M.D.

Principal Investigator

MS Center of Northeastern New York, P.C.

Eligibility Criteria

This trial is for adults aged 21-65 with clinically definite Secondary Progressive Multiple Sclerosis (SPMS) who are neurologically stable and have chosen Cladribine Tablets as their treatment. Participants must be healthy otherwise, not pregnant or breastfeeding, agree to use effective contraception, and commit to follow-ups for two years post-study.

Inclusion Criteria

I am between 21 and 65 years old.

If female: must have a negative serum pregnancy test at screen and week 48 and a negative urine pregnancy test at baseline. All females must agree to notify us immediately if they have concern of possible pregnancy

My neurological condition has been stable for more than 30 days.

Exclusion Criteria

I have a liver condition or history of heavy drinking.

Any other significant medical condition that in the opinion of the investigator that could potentially cause interference of complications of subject taking study Investigational Product (IP)

I do not have conditions like TBI, meningitis, stroke, or recent drug abuse that could affect brain tests.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

6 weeks

Run-in

Subjects will have a 28 day run-in period consisting of 2 visits at week -4 and week -2

4 weeks

2 visits (in-person)

Treatment

Participants receive cladribine tablets according to the current FDA package guidelines

96 weeks

Visits at week 4, 8, 12, 16, 24, 36, 48, 52, 56, 60, 72, 84, 96

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Cladribine Tablets

Trial Overview The study tests if biomarkers can detect MS activity in patients taking Cladribine Tablets, potentially guiding treatment changes to prevent dysfunction. It involves routine clinic visits and assessments over a two-year period following FDA guidelines.

Participant Groups

Group I: Cladribine Tablets Experimental Treatment 1 Intervention

All participants will receive cladribine tablets according to the current United States Federal Food and Drug Administration (FDA) package guidelines.

Cladribine Tablets is already approved in European Union, United States for the following indications:

Approved in European Union as Mavenclad for:

• Relapsing-remitting multiple sclerosis

Approved in United States as Mavenclad for:

• Relapsing forms of multiple sclerosis, including relapsing-remitting disease and active secondary progressive disease

Approved in United States as Leustatin for:

• Hairy cell leukemia

Who Is Running the Clinical Trial?

Keith Edwards, M.D.

Lead Sponsor

Trials

1

Recruited

30+

EMD Serono

Industry Sponsor

Trials

147

Recruited

27,800+

Dr. Shepard

EMD Serono

Chief Medical Officer since 2021

MD from University of Cincinnati Medical School, Fellowships in Hematology and Oncology at University of Chicago Hospitals and Clinics

Miguel Fernández Alcalde

EMD Serono

Chief Executive Officer

Bachelor's Degree in Pharmacy from the University Complutense in Madrid, MBA from the University of Alcalá de Henares, Master's Degree in Management from IESE Business School

Findings from Research

In a 96-week phase 3 trial involving 1326 patients with relapsing-remitting multiple sclerosis, cladribine tablets significantly reduced the annualized relapse rate compared to placebo (0.14 and 0.15 vs. 0.33), indicating strong efficacy in preventing disease relapses.

Cladribine treatment also lowered the risk of sustained disability progression and reduced brain lesions on MRI, but it was associated with higher rates of lymphocytopenia and herpes zoster, highlighting the need to balance benefits against potential risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. Giovannoni, G., Comi, G., Cook, S., et al.[2022]

Cladribine tablets (Mavenclad) have been shown to be effective in treating relapsing multiple sclerosis (MS) for up to 4 years in 75% of patients, based on a multicenter, 6-year observational study that monitors various biomarkers.

This study will be the first to evaluate the long-term efficacy of cladribine and the potential for reinitiating therapy after the initial treatment, providing insights into the safety and effectiveness of this oral therapy in MS management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Cladribine Tablets as a Treatment for People With Multiple Sclerosis: Protocol for the CLOBAS Study (Cladribine, a Multicenter, Long-term Efficacy and Biomarker Australian Study). Maltby, VE., Lea, RA., Monif, M., et al.[2021]

In a study of 320 people with highly active relapsing multiple sclerosis treated with cladribine, over 90% did not experience worsening of disability or relapses in the first two years, indicating strong efficacy of the treatment.

The safety profile of cladribine was consistent with previous studies, with common side effects including infections and lymphopenia, but no new safety concerns were identified, suggesting it is a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cladribine tablets in people with relapsing multiple sclerosis: A real-world multicentric study from southeast European MS centers. Adamec, I., Brecl Jakob, G., Rajda, C., et al.[2023]

In a study involving 208 multiple sclerosis patients, subcutaneous cladribine (Litak®) was generally well tolerated, with only a few serious adverse events reported, indicating a favorable safety profile.

The treatment showed promising effectiveness, with 64% of patients with relapsing MS and 62% of those with progressive MS achieving no evidence of disease activity (NEDA) or no evidence of progression or active disease (NEPAD) after treatment, suggesting cladribine's potential benefits across different stages of MS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subcutaneous cladribine to treat multiple sclerosis: experience in 208 patients. Allen-Philbey, K., De Trane, S., Mao, Z., et al.[2022]

In a 96-week phase III study involving 1,326 patients with relapsing-remitting multiple sclerosis, cladribine tablets demonstrated a safety profile with a high treatment completion rate (88.6% for cladribine vs. 86.3% for placebo).

The most common adverse event was lymphopenia, which aligns with cladribine's mechanism of action, and while infections were more frequent in the cladribine group (48.3% vs. 42.5% for placebo), they were mostly mild-to-moderate, indicating a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of cladribine tablets in multiple sclerosis: the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study. Cook, S., Vermersch, P., Comi, G., et al.[2022]

In a comprehensive safety analysis involving 923 patients treated with cladribine tablets 3.5 mg/kg, the overall incidence of serious adverse events (SAEs) was higher compared to the placebo group, with notable occurrences of lymphopenia and herpes zoster in the treatment group.

Despite a higher reported number of SAEs and a numerical imbalance in malignancy incidence, the rate of malignancies in patients taking cladribine was not significantly different from the expected rate in the general population, indicating a consistent safety profile over time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term safety data from the cladribine tablets clinical development program in multiple sclerosis. Leist, T., Cook, S., Comi, G., et al.[2022]

Cladribine tablets (MAVENCLAD®) are an effective oral treatment for relapsing forms of multiple sclerosis, administered for a maximum of 10 days per year over 2 years, which temporarily reduces lymphocyte levels.

The MAGNIFY-MS study found that cladribine tablets do not interfere with the body's response to flu and chickenpox vaccines, allowing people with MS to remain protected against these diseases while on treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A plain language summary of the impact of vaccines against flu and chickenpox in people with multiple sclerosis treated with cladribine tablets. Schmierer, K., Wiendl, H., Oreja-Guevara, C., et al.[2023]

A new fixed-dose combination (FDC) tablet containing lamivudine and stavudine has been shown to have similar pharmacokinetic profiles to individual formulations, indicating equivalent exposure levels in the bloodstream.

The FDC is expected to improve treatment adherence and provide cost savings for HIV treatment in children, while maintaining a comparable safety and efficacy profile to the individual drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A single-dose, randomized, open-label, two-period crossover bioequivalence study comparing a fixed-dose pediatric combination of lamivudine and stavudine tablet for oral suspension with individual liquid formulations in healthy adult male volunteers. Monif, T., Reyar, S., Tiwari, HK., et al.[2013]

Novel prodrugs of the HIV drug d4T were developed using phosphorochloridate chemistry, but they showed almost no anti-HIV activity in vitro, being significantly less potent than related compounds.

The lack of efficacy is likely due to poor enzyme-mediated hydrolysis, which prevents the prodrugs from converting into their active forms effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthesis and anti-HIV activity of some novel chain-extended phosphoramidate derivatives of d4T (stavudine): esterase hydrolysis as a rapid predictive test for antiviral potency. McGuigan, C., Tsang, HW., Sutton, PW., et al.[2017]

Stavudine is an effective treatment for HIV-1 infection, particularly in developing countries due to its low cost and inclusion in generic combinations, but it is associated with mitochondrial toxicities like lipoatrophy and peripheral neuropathy.

Research suggests that a lower dose of 30 mg b.i.d. may provide similar antiviral efficacy to the approved 40 mg b.i.d. dose, with potentially reduced side effects, highlighting the importance of dose optimization for safer use in resource-limited settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic review of clinical trials evaluating low doses of stavudine as part of antiretroviral treatment. Hill, A., Ruxrungtham, K., Hanvanich, M., et al.[2019]

Lipophilic masked aryloxyaminoacylphosphoramidate derivatives of 2',3'-dideoxynucleoside analogues showed significantly enhanced anti-visna virus activity compared to their free counterparts, with d4A and ddA derivatives being particularly effective at very low concentrations (EC50 ≤ 0.003 microM).

The study suggests that the specific amino acid linked to the prodrug's structure influences its antiviral potency, indicating that these prodrugs could be promising candidates for further investigation in vivo, especially in lamb models for their potential antiretroviral efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Marked inhibitory activity of masked aryloxy aminoacyl phosphoramidate derivatives of dideoxynucleoside analogues against visna virus infection. Balzarini, J., Cahard, D., Wedgwood, O., et al.[2019]

Stavudine is an effective and well-tolerated treatment for HIV-1, typically administered at a dose of 40mg twice daily, with infrequent hematological toxicity and reversible peripheral neuropathy as the main side effect.

When combined with other antiviral drugs, stavudine can significantly reduce viral load, but it is recommended to avoid using it with zidovudine due to potential increased side effects and reduced effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stavudine: A Review. Fuchs, JE., Pollard, RB.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. [2022]

2. Canada pubmed.ncbi.nlm.nih.gov

Efficacy of Cladribine Tablets as a Treatment for People With Multiple Sclerosis: Protocol for the CLOBAS Study (Cladribine, a Multicenter, Long-term Efficacy and Biomarker Australian Study). [2021]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Cladribine tablets in people with relapsing multiple sclerosis: A real-world multicentric study from southeast European MS centers. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Subcutaneous cladribine to treat multiple sclerosis: experience in 208 patients. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Safety and tolerability of cladribine tablets in multiple sclerosis: the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study. [2022]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Long-term safety data from the cladribine tablets clinical development program in multiple sclerosis. [2022]

7. England pubmed.ncbi.nlm.nih.gov

A plain language summary of the impact of vaccines against flu and chickenpox in people with multiple sclerosis treated with cladribine tablets. [2023]

8. Germany pubmed.ncbi.nlm.nih.gov

A single-dose, randomized, open-label, two-period crossover bioequivalence study comparing a fixed-dose pediatric combination of lamivudine and stavudine tablet for oral suspension with individual liquid formulations in healthy adult male volunteers. [2013]

9. England pubmed.ncbi.nlm.nih.gov

Synthesis and anti-HIV activity of some novel chain-extended phosphoramidate derivatives of d4T (stavudine): esterase hydrolysis as a rapid predictive test for antiviral potency. [2017]

10. England pubmed.ncbi.nlm.nih.gov

Systematic review of clinical trials evaluating low doses of stavudine as part of antiretroviral treatment. [2019]

11. United States pubmed.ncbi.nlm.nih.gov

Marked inhibitory activity of masked aryloxy aminoacyl phosphoramidate derivatives of dideoxynucleoside analogues against visna virus infection. [2019]

12. Brazil pubmed.ncbi.nlm.nih.gov

Stavudine: A Review. [2019]