Cladribine for Myasthenia Gravis

Recruiting at 44 trial locations

Overseen By Communication Center

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Must be taking: Corticosteroids, Acetylcholinesterase inhibitors

Must not be taking: Nonsteroidal immunosuppressants, Eculizumab

Disqualifiers: Immunologic disorder, Active infection, Cancer, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

264 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial evaluates the effectiveness and safety of an oral form of cladribine for individuals with Generalized Myasthenia Gravis (gMG), a condition that causes muscle weakness. Participants will receive varying doses of cladribine or a placebo to determine the most effective dose and identify any side effects. The trial will also assess the duration of treatment effects and the need for retreatment. Individuals who have experienced generalized muscle weakness due to gMG and have been stable on their current medication may be suitable candidates for this trial. As a Phase 3 trial, this study represents the final step before FDA approval, allowing participants to contribute to the potential availability of a new treatment.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before joining. If you're on nonsteroidal immunosuppressants, you need to stop them 4 weeks before starting, and if you're on specific treatments like eculizumab or similar, you need to stop them 8 weeks before starting. However, if you're on oral corticosteroids or acetylcholinesterase inhibitors, you can continue as long as the dose is stable for at least 4 weeks before joining.

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

Research has shown that cladribine is a safe treatment for people with myasthenia gravis, a condition affecting muscle strength. One study found cladribine to be safe and effective for patients who struggled with standard treatments.

Although information on the new oral form of cladribine may be limited, the FDA has already approved it for other conditions, which supports its safety. Generally, previous patients tolerated the treatment well, and studies found no major safety issues.

However, like any medication, monitoring for side effects is important, and discussing any concerns with a doctor is advised. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for myasthenia gravis, which often involve immunosuppressants and acetylcholinesterase inhibitors, Cladribine is unique because it targets the disease through a different mechanism. Cladribine is an oral medication that selectively reduces certain immune cells, potentially offering a more targeted approach to managing the condition. This could mean fewer side effects and a more convenient dosing schedule compared to traditional treatments. Researchers are excited about Cladribine because it represents a promising new direction in treating myasthenia gravis, with the potential for improved outcomes for patients.

What evidence suggests that cladribine might be an effective treatment for Myasthenia Gravis?

Research has shown that cladribine can significantly reduce symptoms of generalized myasthenia gravis (gMG), a condition that causes muscle weakness. In an initial study, patients' average Myasthenia Gravis Composite (MGC) score dropped from 15.1 to 6.3 points over four months, indicating reduced muscle weakness and fatigue. Additionally, patients required less prednisolone, a steroid often used to manage symptoms, as their dosage decreased from 9.5 to 1.9 mg. In this trial, participants will receive either a high dose or low dose of cladribine, or a placebo. Cladribine is already approved for treating multiple sclerosis, suggesting it might also be effective for gMG because both conditions involve the immune system. ^{1 2 6 7 8}

Who Is on the Research Team?

Medical Responsible

Principal Investigator

EMD Serono Research & Development Institute, Inc.

Are You a Good Fit for This Trial?

This trial is for individuals with Generalized Myasthenia Gravis, a condition causing muscle weakness. Participants should not have taken certain other medications recently and must meet specific health criteria to ensure safety during the trial.

Inclusion Criteria

I have Myasthenia Gravis with moderate to severe muscle weakness.

Has a Screening and Baseline MG-ADL score more than or equal to (>=) 6 with at least 50 percentage (%) of the total score due to non-ocular symptoms

I tested positive for anti-AChR or anti-MuSK antibodies.

Exclusion Criteria

Other protocol defined exclusion criteria could apply

I do not have antibodies for chickenpox.

I haven't taken any nonsteroidal immunosuppressants for my gMG in the last 4 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Double-blind Placebo Control (DBPC) Period

Participants receive either cladribine or placebo in two separate treatment courses starting on Day 1 and at the beginning of Week 5

8 weeks

Blinded Extension (BE) Period

Participants receive either placebo or cladribine in two separate treatment courses starting at the beginning of Week 25 and at the beginning of Week 29

8 weeks

Retreatment (RT) Period

Participants requiring retreatment receive cladribine or placebo as clinically justified

Variable

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cladribine

Trial Overview The study tests a new oral formulation of Cladribine at two different doses against a placebo to evaluate its effectiveness and safety in treating gMG. The trial includes initial treatment, follow-up extensions, and possible retreatment phases.

How Is the Trial Designed?

Group I: Cladribine Low Dose Experimental Treatment 1 Intervention

DBPC Period: Participants will be administered with cladribine Low Dose, orally as 2 separate treatment courses starting on Day 1 and at the beginning of Week 5. BE Period: Participants initially randomized to cladribine Low Dose in DBPC period will receive placebo matched to cladribine as 2 separate treatment courses starting at the beginning of Week 25 and at the beginning of Week 29 and retreated with cladribine supplemental dose if clinically justified. RT Period: Participants requiring retreatment with cladribine Low Dose regimen and/or supplemental dose will receive the selected dose of cladribine if clinically justified.

Group II: Cladribine High Dose Experimental Treatment 1 Intervention

DBPC Period: Participants will be administered cladribine High Dose, orally as 2 separate treatment courses starting on Day 1 and at the beginning of Week 5. BE Period: Participants initially randomized to cladribine High Dose in DBPC period will receive placebo matched to cladribine as 2 separate treatment courses starting at the beginning of Week 25 and at the beginning of Week 29 and retreated with cladribine supplemental dose if clinically justified. RT Period: Participants requiring retreatment with cladribine High Dose regimen and/or supplemental dose will receive the selected dose of cladribine if clinically justified.

Group III: Placebo Placebo Group 3 Interventions

DBPC Period: Participants will be administered with Placebo, orally as 2 separate treatment courses starting on Day 1 and at the beginning of Week 5. BE Period: Participants initially randomized to placebo matched to cladribine in DBPC period will receive cladribine Low Dose or High Dose, orally as 2 separate treatment courses starting at the beginning of Week 25 and at the beginning of Week 29 and retreated if clinically justified with placebo matched to cladribine. RT Period: Participants requiring retreatment with cladribine Low Dose or High Dose or retreated with cladribine supplemental dose if clinically justified.

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

Approved in United States as Leustatin for:

• Hairy cell leukemia
• Chronic lymphocytic leukemia (CLL)
• Non-Hodgkin's lymphoma
• Multiple sclerosis

Approved in European Union as Litak for:

• Hairy cell leukemia
• Chronic lymphocytic leukemia (CLL)
• Non-Hodgkin's lymphoma

Who Is Running the Clinical Trial?

Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Lead Sponsor

Trials

60

Recruited

7,900+

Danny Bar-Zohar

Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Chief Executive Officer

MD

Danny Bar-Zohar

Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Chief Medical Officer since 2022

MD

EMD Serono Research & Development Institute, Inc.

Industry Sponsor

Trials

86

Recruited

22,700+

Miguel Fernández Alcalde

EMD Serono Research & Development Institute, Inc.

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

Danny Bar-Zohar

EMD Serono Research & Development Institute, Inc.

Chief Medical Officer since 2022

MD

Published Research Related to This Trial

Clinical trials for myasthenia gravis have varied widely in design, which can significantly impact patient recruitment and the ability to detect therapeutic effects, especially if trials focus on patients with milder disease.

Narrow eligibility criteria may limit the generalizability of results and affect recruitment, while design elements like treatment duration and outcome measures can influence the sensitivity of trials to demonstrate true therapeutic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Learning from the past: reflections on recently completed myasthenia gravis trials. Benatar, M., Howard, JF., Barohn, R., et al.[2019]

The FDA has recently approved new therapies, including complement and Fc receptor inhibitors, for treating generalized myasthenia gravis, highlighting advancements in treatment options for this condition.

There is ongoing uncertainty regarding which patients will benefit most from these expensive therapies, prompting discussions on the need for better clinical trial readiness and biomarker development to guide future research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The best and worst of times in therapy development for myasthenia gravis. Benatar, M., Cutter, G., Kaminski, HJ.[2023]

In a study of 928 myasthenia patients in Denmark from 1996 to 2013, 69% were treated with prednisolone and 55% with azathioprine, indicating a high utilization of oral immunosuppressants for managing the condition.

Most patients initiated treatment with prednisolone and azathioprine within two years of diagnosis, with azathioprine often continued long-term, reflecting a treatment approach aligned with the expected clinical course of myasthenia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral Immunosuppressive Treatment of Myasthenia Gravis in Denmark: A Nationwide Drug Utilization Study, 1996-2013. Pedersen, EG., Hallas, J., Pottegård, A., et al.[2018]

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 study of 160 patients with steroid-insensitive myasthenia gravis, the combination of low-dose cyclophosphamide and corticosteroids was found to be effective, with 69.9% of type I patients and 64.8% of type II patients achieving significant clinical improvement after 30 weeks.

The treatment was generally safe, with only minor side effects reported, and the sensitivity to cyclophosphamide varied between types, showing higher effectiveness in type I patients compared to type II.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy and safety of low-dose cyclophosphamide plus corticosteroids for type I/II myasthenia gravis]. Feng, HY., Liu, WB., Huang, X., et al.[2013]

In a study involving 13 patients with refractory myasthenia gravis, cladribine treatment led to significant clinical improvement, with the Myasthenia Gravis Composite (MGC) score decreasing from 15.1 to 6.3 points over 4 months.

Cladribine was found to be a safe treatment option, as none of the patients experienced adverse events, and the need for additional treatments like intravenous immunoglobulin or plasma exchange was eliminated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cladribine in myasthenia gravis: a pilot open-label study. Rejdak, K., Szklener, S., Korchut, A., et al.[2021]

In a study of 7 patients with nonparaneoplastic Lambert-Eaton myasthenic syndrome, treatment with 3,4-diaminopyridine phosphate (3,4-DAPP) led to clinical improvement in 5 patients over a 5-year follow-up, although the improvement was not statistically significant.

The combination of 3,4-DAPP with prednisone showed a notable association with better clinical outcomes, particularly in muscle strength, while no severe adverse events were reported, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Five years experience on 3,4-diaminopyridine phosphate in Lambert-Eaton syndrome: Case reports. Portaro, S., Brizzi, T., Sinicropi, S., et al.[2023]

Cladribine (2-CdA) is an effective treatment for indolent lymphoid malignancies, such as hairy cell leukemia and indolent B-cell lymphoma, due to its ability to induce DNA strand breaks and cell death in lymphocytes, regardless of cell division.

The drug has been extensively studied and was approved by the FDA in 1993 and in Japan in 2002, demonstrating its established efficacy and clinical usefulness based on data from multiple clinical trials across the United States, Europe, and Japan.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Cladribine]. Ogura, M.[2013]

Myasthenia gravis (MG) is primarily caused by a reduction in acetylcholine receptors at neuromuscular junctions due to autoantibodies, leading to muscle weakness and fatigue, which can be diagnosed through clinical symptoms and autoantibody testing.

Treatment for MG focuses on enhancing neuromuscular transmission with anticholinesterase drugs and immunotherapy, with options like intravenous immunoglobulin for rapid improvement and long-term therapies including corticosteroids and B-cell inhibitors, allowing most patients to lead normal lives with ongoing management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Myasthenia Gravis. Drachman, DB.[2019]

The study analyzed demographic data from two large physician-derived registries for myasthenia gravis (MG), which can provide valuable insights into patient characteristics and treatment outcomes.

These registries, the Duke MG Patient Registry and the INNCB MG Registry, utilize a common data structure that aligns with national standards, enhancing the reliability and comparability of the data collected for future research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient registries: useful tools for clinical research in myasthenia gravis. Baggi, F., Mantegazza, R., Antozzi, C., et al.[2012]

Observational comparative effectiveness research (CER) offers a promising alternative to randomized controlled trials (RCTs) for evaluating treatments in myasthenia gravis (MG), addressing challenges like disease rarity and variability by using real-life clinical data from routine care.

Recent advancements, including the creation of common data elements for MG and a standardized web-based database, enhance the feasibility of conducting multisite CER studies, allowing for better comparisons of therapies and improved understanding of treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative effectiveness clinical trials to advance treatment of myasthenia gravis. Guptill, JT., Raja, S., Sanders, DB., et al.[2019]

Cladribine shows a temporary but beneficial effect on neurological performance in patients with chronic progressive multiple sclerosis, with peak improvements observed at 14 months for a 2.8 mg/kg dose and 7 months for a 1.4 mg/kg dose.

While cladribine effectively reduces MRI lesions associated with multiple sclerosis, higher doses are linked to mild side effects like herpes zoster and transient marrow suppression, whereas lower doses appear safer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cladribine. Romine, JS., Sipe, JC., Koziol, JA., et al.[2018]

Cladribine is an effective oral treatment for very active recurring multiple sclerosis, requiring only two short courses of administration over two years to maintain efficacy for up to four years, significantly reducing flare-ups and disability progression compared to placebo.

While cladribine is generally safe, it can cause lymphopenia and increase the risk of herpes zoster infections; however, long-term follow-up (up to eight years) indicates no greater risk of serious events like cancers or opportunistic infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Recommendations for the use of cladribine tablets in recurring multiple sclerosis]. Oreja-Guevara, C., García-Merino, JA., Saiz, A., et al.[2020]

Cladribine, an antileukaemic drug, shows strong immunosuppressive activity and is being tested for its effectiveness in treating multiple sclerosis (MS).

Preliminary results from two independent randomized, placebo-controlled trials suggest that cladribine may halt the progression of chronic progressive MS, reduce relapse frequency, and improve neurological status in patients with the remitting-relapsing form of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment of multiple sclerosis with cladribine (2-CDA), a new immunosuppressant agent. Theoretical basis and preliminary results]. Grieb, P., Stelmasiak, Z.[2015]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06463587

NCT06463587 | Efficacy and Safety of a New Formulation ... The purpose of this clinical study is to determine the efficacy and safety of a new oral cladribine formulation in participants with Generalized Myasthenia ...

2. emdserono.com emdserono.com/us-en/company/news/press-releases/oral-cladribine-in-generalized-myasthenia-gravis-29-08-2024.html

2024-08-29 MyClad Phase III Update Cladribine capsules have the potential to be the first oral treatment for gMG patients. gMG is a rare, neuromuscular disorder causing muscle ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/31705552/

Cladribine in myasthenia gravis: a pilot open-label study The mean MGC score declined from 15.1 to 6.3 points within 4 months of observation. The dosage of prednisolone declined from 9.5 to 1.9 mg. None of the patients ...

4. neurologylive.com neurologylive.com/view/details-behind-phase-3-myclad-study-cladribine-myasthenia-gravis

Details Behind the Phase 3 MyClad Study of Cladribine in ... A unique trial assessing the efficacy and safety of oral cladribine tablets, an FDA-approved medication for multiple sclerosis, in patients with myasthenia ...

5. neurology.org neurology.org/doi/10.1212/WNL.0000000000208638

Oral Cladribine Capsules for Generalized Myasthenia Gravis Objective: To evaluate the efficacy and safety of a new oral formulation of cladribine versus placebo in generalized myasthenia gravis (gMG).

6. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2211034824006837

146. Post-Approval Safety of Cladribine Tablets in the ... While data are currently scant, there is no evidence for an increased risk of adverse pregnancy outcomes in patients receiving cladribine tablets. Recommended ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8672452/

Efficacy and Safety of Immunotherapies in Refractory ... The efficacy and safety of rituximab and eculizumab have been approved in patients with refractory MG. Rituximab had a superior safety profile than eculizumab.

8. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/pdf/10.1111/ene.14124

Cladribine in myasthenia gravis This is the first study to demonstrate that Cladribine proved to be a safe and effective treatment, in dealing with difficult to treat MG patients. The patients ...