Cladribine for Myasthenia Gravis

Recruiting at 36 trial locations

Overseen By Communication Center

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

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)

Prior Safety Data

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

The purpose of this clinical study is to determine the efficacy and safety of a new oral cladribine formulation in participants with Generalized Myasthenia Gravis (gMG) in comparison to placebo. It will also investigate the sustained efficacy, the need for retreatment, and the long-term safety of oral cladribine in gMG. An additional component is included to characterize the Pharmacokinetics (PK) of the new cladribine formulation in gMG participants. This study is divided into 3 periods: the double-blind placebo control (DBPC) pivotal period, and 2 extensions, the blinded extension (BE) and the retreatment (RT) period.

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.

What data supports the effectiveness of the drug Cladribine for treating myasthenia gravis?

The pilot open-label study aimed to assess the effectiveness of Cladribine in patients with refractory myasthenia gravis, suggesting some level of investigation into its potential benefits for this condition. ^{1 2 3 4 5}

Is Cladribine safe for use in humans?

The available research does not provide specific safety data for Cladribine in humans, particularly for myasthenia gravis, but it has been used in other conditions, suggesting some level of safety in humans. ^{4 6 7 8 9}

How is the drug Cladribine unique in treating Myasthenia Gravis?

Cladribine is unique because it is a prodrug (a medication that is converted into an active form inside the body) that selectively targets and depletes lymphocytes, which are a type of white blood cell involved in immune responses. This mechanism is different from other treatments for Myasthenia Gravis, as it is primarily used for conditions like multiple sclerosis and certain types of leukemia, where it helps to modulate the immune system. ^{10 11 12 13 14}

Research Team

Medical Responsible

Principal Investigator

EMD Serono Research & Development Institute, Inc.

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Cladribine (Anti-metabolites)

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.

Participant Groups

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.

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

Findings from Research

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]

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]

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]

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]

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 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 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]

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]

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]

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]

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]

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]

References

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

Learning from the past: reflections on recently completed myasthenia gravis trials. [2019]

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

Myasthenia Gravis. [2019]

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

Comparative effectiveness clinical trials to advance treatment of myasthenia gravis. [2019]

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

Cladribine in myasthenia gravis: a pilot open-label study. [2021]

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

The best and worst of times in therapy development for myasthenia gravis. [2023]

6. China pubmed.ncbi.nlm.nih.gov

[Efficacy and safety of low-dose cyclophosphamide plus corticosteroids for type I/II myasthenia gravis]. [2013]

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

Oral Immunosuppressive Treatment of Myasthenia Gravis in Denmark: A Nationwide Drug Utilization Study, 1996-2013. [2018]

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

Patient registries: useful tools for clinical research in myasthenia gravis. [2012]

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

Five years experience on 3,4-diaminopyridine phosphate in Lambert-Eaton syndrome: Case reports. [2023]

10. 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]

11. New Zealand pubmed.ncbi.nlm.nih.gov

Cladribine. [2018]

12. Spain pubmed.ncbi.nlm.nih.gov

[Recommendations for the use of cladribine tablets in recurring multiple sclerosis]. [2020]

13. Poland pubmed.ncbi.nlm.nih.gov

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

14. Japan pubmed.ncbi.nlm.nih.gov

[Cladribine]. [2013]