Myasthenia gravis MedDRA version: 21.1 Level: PT Classification code 10028417 Term: Myasthenia gravis System Organ Class: 10029205 - Nervous system disorders
Conditions
Interventions
Product Name: Cladrybine
Pharmaceutical Form: Solution for injection
INN or Proposed INN: CLADRIBINE
CAS Number: 4291-63-8
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Sponsors
Medical University of Lublin
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: GENERAL CRITERIA: 1. Age > 18 years (no border). 2. Obtaining informed consent for the patient's participation in the entry. 3. The characteristic clinical picture of myasthenia gravis with non-painful movement of typical striated muscle groups with the intensity of professional development changing throughout the day. 4. 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). 5. 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. 6. 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). 7.AChEI dose stabilised = 4 weeks prior to randomisation (W1D1). 8. 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). 9. 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. - complementary cohort: no immunoactive treatment (acceptable symptomatic treatment with acetylcholinesterase inhibitors) and non-acceptance of the patient's side for the sick steroid therapy dictated by the disease before side effects. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 180 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 20
Exclusion criteria
Exclusion criteria: 1. Unusual distribution of muscle weakness or lack of apocamnosis effect with other diagnosis (such as LEMS, OPMD). 2. 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). 3. Electrophysiological exponents of presynaptic disorders of neuromuscular conduction (facilitation phenomenon in electromyographic myasthenia gravis test). 4. 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). 5. 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. 6. Tumour disease active at the time of the qualifying visit (W0) for the study, or completed non-deferred temporal ( 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). 8. 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. 9. 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. 10. 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. 11. Other contraindications which, in the opinion of the Investigator, exclude the patient from participating in the study.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary end point(s): Changes in the evaluation of the effects of intensified myasthenia symptoms on the daily living activities according to the Myasthenia Gravis Activities of Daily Living (MG-ADL) scale. SIMPLIFIED TRIAL DESIGN (compatible with text documents without graphics) BLINDED PHASE (BASIC TRIAL PERIOD): In the blinded phase, the following will be assessed: 1.the clinical effect of cladribine in patients treated immunoactively with oral steroids (the primary cohort), 2.the clinical effect of cladribine in patients with newly diagnosed myasthenia / previously untreated immunoactively (the complementary cohort of the clinical trial). W0 (week 0) – preliminary evaluation The duration of immunoactive therapy with the use of the therapeutic product studied W1 (week 4) – administration of the therapeutic product in question W2 (week 6) – search for the symptoms of early adverse side effects W3 (week 16) –administration of the therapeutic product studied W4 (week 18), W5 (week 28), W6 (week 34), W7 (week 40), W8 (week 48) – neurological exams with the evaluation of increased symptoms of myasthenia, revision of steroid demands with the dose correction in the primary cohort/ emergency therapy, if required. OPEN PHASE (additional trial time): Patients who completed the blinded phase of the study as scheduled or as a result of a significant intensification of the symptoms of myasthenia gravis defined in 2 points exclusion criteria after the use of IVIG salvage therapy and a 4-week grace period eliminating the impact of IVIG on the assessment of the effects of cladribine they can begin the open-label phase with cladribine (visits W9 and W11 / weeks 54 and 66, respectively) and follow-up with a simplified follow-up (visits W10 and W12 - W15 / weeks 56 and 68 - 96). The visits will be carried out in the same way as in the double-blind phase, according to the schedule. The duration of immunoacive therapy with the use of the therapeutic product studied W9 (week 54) – ad | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Reduction in the requirement for simultaneous oral corticosteroids used in immunotherapy (steroid-sparing effect). Stabilized = 4 weeks prior to study entry, systematically revised and adjusted to the need at follow-up visits. The endpoint will only be assessed in the core cohort. Evaluation of W4-W8 during the primary study duration and W12-W15 during the additional study duration. Frequency of occurrence of the need for salvage therapy due to An exacerbation of myasthenia gravis with respiratory failure at any time observation time during the study, separately in the primary and secondary duration research. Changed antibodies to acetylcholine receptors (anti-AChR-ab) and specific muscle tyrosine kinase (anti-MUSK-ab) in serum baseline result (on W1 at baseline and 18 on W9 during the additional study duration). Grade for W3 and W6 in basic study duration, and W11 and W15 in the additional study duration. Change in the concentration of complement components (C3, C4) relative to the result baseline time (on W1 at the base time of the study and on W9 at the additional time the duration of the study). Assessment of W3 and W6 in the basic duration of the study and W11 i W15 during the additional study duration. Change in cytokine concentrations from baseline (to W1 at baseline time study and on W9 in an additional study duration). Grade on W3 and W6 in baseline study duration and W11 and W15 in additional study duration research. Change in the percentage of individual lymphocyte populations in immunophenotyping lymphocytes from baseline (on W1 at baseline and on W9 during the additional study duration). Assessment for W3 and W6 at the basic time the duration of the study and W11 and W15 in the additional study duration. Regarding treatment safety: The frequency of adverse events. Change in safety parameters (complete blood count, creatinine, urea, bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gammaglutamyltranspept | — |
Countries
Poland
Contacts
Public ContactCountry Clinical Trial Coordinator
Medical University of Lublin,Konrad Rejdak
Outcome results
None listed