Phase 2 Evaluation of Cladribine Efficacy and Safety in Seropositive Myasthenia Gravis Treatment Modification
- Trial ID
- 2024-517083-32-00
- Protocol
- MGCDB001
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this phase 2 clinical trial is to evaluate the **efficacy** and **safety** of adding **cladribine** to the treatment regimen for patients with seropositive **myasthenia gravis**. This study aims to determine whether cladribine can effectively modify the course of this autoimmune neuromuscular disorder, which is characterized by muscle weakness and fatigue. The clinical relevance of this objective lies in the potential to improve therapeutic outcomes for patients with this condition, offering a novel approach to management that could enhance quality of life and reduce disease burden.
Participants
The clinical trial focuses on evaluating the efficacy and safety of cladribine in the treatment of **myasthenia gravis**, specifically targeting seropositive pseudoparalytic cases. The study population includes both male and female participants, aged 18 years and older, with no upper age limit specified. Participants are selected based on their failure to achieve pharmacological remission despite optimal treatment with acetylcholinesterase inhibitors and chronic oral steroid therapy. The trial includes individuals with a characteristic clinical presentation of myasthenia gravis, confirmed by increased titers of anti-acetylcholine receptor or muscle tyrosine kinase antibodies. Participants must have a known status of thymus pathology and stabilized doses of corticosteroids and acetylcholinesterase inhibitors prior to randomization. The trial also considers vulnerable populations. However, the sponsor has not provided information regarding the total number of participants involved in the study.
Plans and Procedures
The clinical trial is designed to evaluate the **efficacy** and safety of adding **cladribine** to the treatment regimen for patients with seropositive **myasthenia gravis**. This is a phase 2, randomized, double-blind, controlled trial. The trial is expected to run from December 17, 2021, to October 31, 2026. Participants will be involved in the study for a maximum of 12 months, with the possibility of early termination if they experience significant adverse events or fail to comply with the study protocol.
The trial will include several study visits, starting with a screening visit to confirm eligibility based on criteria such as age, clinical presentation, and previous treatment history. Participants must have a stable corticosteroid dose and meet specific electrophysiological and radiological criteria. Following the screening, eligible participants will be randomized to receive either cladribine or a placebo. The primary endpoint is the change in the Myasthenia Gravis Activities of Daily Living (MG-ADL) scale score, assessed at multiple visits throughout the study.
Follow-up visits will occur at regular intervals to monitor efficacy and safety, including assessments of corticosteroid use, antibody levels, and safety parameters such as blood count and liver function tests. The end-of-study visit will evaluate the overall impact of the treatment on disease symptoms and any long-term safety concerns. Participants may be withdrawn from the study if they require rescue therapy for respiratory failure or if they do not adhere to the study requirements. The trial aims to provide valuable insights into the potential benefits of cladribine in modifying the course of myasthenia gravis.
Treatment
The clinical trial involves the administration of **CLADRIBINE**, a chemical-origin medication, as the experimental treatment. **CLADRIBINE** is administered in a subcutaneous form, with a pharmaceutical form code of PHF00230MIG. The active substance, **CLADRIBINE**, is also known by the synonym 2-chlorodeoxyadenosine. The maximum daily dose of **CLADRIBINE** is 10 mg, with a total maximum dose of 60 mg over the treatment period. The treatment duration is set for a maximum of 12 weeks. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.
In addition to the experimental treatment, the trial includes the use of **sodium chloride** (0.9% NaCl) as a non-experimental treatment. **Sodium chloride** serves as a placebo in this study. The pharmaceutical form and route of administration for **sodium chloride** are not specified in the trial data. The use of **sodium chloride** is intended to provide a control for evaluating the efficacy and safety of the experimental treatment, **CLADRIBINE**. Compliance with the administration of the placebo is also monitored throughout the trial to maintain the integrity of the study results.
Efficacy
The efficacy of the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint involves evaluating changes in the effects of intensified myasthenia symptoms on daily living activities, as measured by the Myasthenia Gravis Activities of Daily Living (MG-ADL) scale. This assessment will occur during specific visits: Weeks 2 to 8 during the basic examination period and Weeks 10 to 15 during the additional testing period, with comparisons made to baseline results at Week 1 and Week 9, respectively.
Secondary endpoints include several parameters: reduction in the requirement for oral corticosteroids, incidence of rescue therapy due to exacerbation of myasthenia gravis, changes in antibodies against acetylcholine receptors and muscle tyrosine kinase, changes in complement system components (C3, C4), cytokine concentrations, and lymphocyte populations. These will be measured at various timepoints, including Weeks 3, 6, 11, and 15, compared to baseline results. Additionally, safety parameters such as blood count, creatinine, urea, bilirubin, and liver enzymes will be monitored, alongside the frequency of adverse events. Cladribine pharmacokinetics in plasma will also be assessed at specific visits.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age > 18 years (no border).
- Obtaining informed consent for the patient's participation in the entry.
- The characteristic clinical picture of myasthenia gravis with nonpainful movement of typical striated muscle groups with the intensity of professional development changing throughout the day.
- Increased cut-off titer of anti-acetylcholine receptor (anti-AchR-ab) or muscle tyrosine kinase (anti-MUSK-ab) involved in the pathogenesis of myasthenia gravis (historical result: untimed).
- The known status of thymus pathology based on the chest radiological examination (CT) (historical up to 5 years prior to qualifying visit or performed at qualifying visit) and / or the hist-path results of the removed thymus if the patient underwent a thymectomy.
- Corticosteroid dose stabilised ≥ 4 weeks prior to randomisation and a minimum 4-week withdrawal period from other immunosuppressive agents (cytostatic or biological) in the absence of lymphopenia and drug-induced parenchymal organ damage (liver, kidney).
- AChEI dose stabilised ≥ 4 weeks prior to randomisation (W1D1).
- Electrophysiological test result of the myasthenia test (historical up to 5 years before the qualifying visit) or the test can be performed at the qualifying visit (W0).
- MRI result of head with contrast (archived up to 5 years prior to qualifying visit or performed at qualifying visit).
- DETAILED CRITERIA - the main cohort: validity of second-line immunoactive treatment indicated by failure to achieve pharmacological remission according to MGFA post-interventional status despite symptomatic acetylcholinesterase inhibitor treatment at optimal doses combined with chronic oral steroid therapy with achievement of stable 4 weeks prior to the randomisation visit (W1D1) prednisone equivalent dose.
- DETAILED CRITERIA - complementary cohort: no immunoactive treatment (acceptable symptomatic treatment with acetylcholinesterase inhibitors) and nonacceptance of the patient's side for the sick steroid therapy dictated by the disease before side effects.
Exclusion Criteria
- Unusual distribution of muscle weakness or lack of apocamnosis effect with other diagnosis (such as LEMS, OPMD).
- Negative results (below the cut-off threshold) of determinations of acetylcholine receptor auto-aggressive antibodies (anti-AChR-ab) or muscle tyrosine kinase (anti-MUSK-ab).
- Electrophysiological exponents of presynaptic disorders of neuromuscular conduction (facilitation phenomenon in electromyographic myasthenia gravis test).
- Coexistence of diseases that make it impossible to assess the disease state in the context of the severity of myasthenia gravis (e.g. cardiovascular or respiratory diseases clinically manifested by fatigue).
- Coexistence of diseases that reduce resistance to opportunistic infection, which may be the cause of complications of immunoactive treatment of myasthenia gravis (e.g. HIV, hepatitis B or C, tuberculosis) or recurrent herpes zoster in treatment.
- Tumour disease active at the time of the qualifying visit (W0) for the study, or completed non-deferred temporal (< 6 months) oncological treatment.
- Significant deviation in basic research: - peripheral blood count: leukopenia < 1.5 x 109/l; - neck functions: creatinine > 1.4 mg/dl in women and > 1.5 mg/dl in men; - liver function: AST or ALT > 3x ggn; - anti-IgA infection in people with IgA deficiency (in case emergency treatment is needed due to intravenous administration of human immunoglobulins *IVIG). If there is improvement in follow-up, deviations from the above criteria are acceptable based on the patient's clinical presentation (to be at the decision of the Investigator).
- Hypersensitivity to cladribine or to any of them has been helpful: - mechanical obstruction of the urinary tract (with attention to AChEI); - pregnancy (patients of childbearing age will be required to declare use of an effective method of contraception [Pearl index ≤2 ] from the qualifying visit (W0) during the trial and 6 months after its completion); - breastfeeding.
- No use of an effective method of contraception [Pearl index ≤ 2] by patients of childbearing age at the time of eligibility (visit W0) for the study until 6 months after the last dose of study medicinal product.
- No use of barrier contraception by patients at the time of study eligibility (W0 visit) until 6 months after the last dose of study medicinal product.
- Other contraindications which, in the opinion of the Investigator, exclude the patient from participating in the study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Poland | Not Recruiting | 17 Dec 2021 | 200 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
sodium chloride, sól fizjologiczna0,9%NaCl | Placebo | N/A | — | — | — | N/A |
CLADRIBINE | Test | PHF00230MIG | SUBCUTANEOUS USE | 10 | 12 | SCP112617484 |