Cladribine therapy in Myasthenia

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Uniwersytet Medyczny W Lublinie

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

17 Dec 2021 → ongoing

Decision date (initial)

2024-10-13

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Medical University of Lublin, Poland · Medical Research Agency, Poland

External identifiers

EU CT number

2024-517083-32-00

EudraCT number

2020-005762-34

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Therapy, Safety, Efficacy

The aim of the trial is to evaluate the efficacy and safety of cladribine added to the treatment modifying the course of seropositive pseudoparalytic myasthenia gravis.

Secondary objectives 1

1. Not applicable

Conditions and MedDRA coding

Myasthenia gravis

Study design 3 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

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 nonpainful 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).
10. 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.
11. 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 11

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 (< 6 months) oncological treatment.
7. 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).
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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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 during visits assessing efficacy: W2 – W8 during the basic examination time and W10 – W15 during additional testing time, comparing to the baseline result (W1 in the basic study period and W9 in the additional study time).

Secondary endpoints 9

1. Reduction in the requirement for simultaneous oral corticosteroids used in immunotherapy (steroid-sparing effect). The endpoint will only be assessed in the core cohort. Assessment for W4-W8 during the basic duration of the study and W12-W15 during the additional duration of the study.
2. Incidence of the need for rescue therapy due to exacerbation of myasthenia gravis with respiratory failure at any time during the study period, separately in the primary and secondary study periods.
3. Change in antibodies against acetylcholine receptors (anti-AChR-ab) and specific muscle tyrosine kinase (anti-MUSK-ab) in blood serum compared to the baseline result (on W1 during the basic study period and on W9 during the additional study period). Score for W3 and W6 during the basic study period and W11 and W15 during the additional study period.
4. Change in the concentration of complement system components (C3, C4) compared to the baseline result (on W1 during the basic test period and on W9 during the additional test period). Score for W3 and W6 during the basic study period and W11 and W15 during the additional study period.
5. Change in cytokine concentration relative to the baseline result (on W1 during the basic study period and on W9 during the additional study period). Score for W3 and W6 during the basic study period and W11 and W15 during the additional study period.
6. Change in the percentage of individual lymphocyte populations in lymphocyte immunophenotyping compared to the baseline result (on W1 during the basic study period and on W9 during the additional study period). Score for W3 and W6 during the basic study period and W11 and W15 during the additional study period.
7. Frequency of adverse events.
8. Change in safety parameters (blood count, creatinine, urea, bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGTP), C-reactive protein (CRP), procalcitonin PCT, urinalysis) compared to the baseline result (on W1 during the basic test period and on W9 during the additional test period). Assessment for W3-W8 during the basic study period and W11-W15 during the additional study period.
9. Assessment of cladribine pharmacokinetics in plasma at visits W1 (on days D1, D3 and D4) and W2.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Uniwersytet Medyczny W Lublinie

Sponsor organisation

Uniwersytet Medyczny W Lublinie

Address

Ul. Aleje Raclawickie 1

City

Lublin

Postcode

20-059

Country

Poland

Scientific contact point

Organisation

Uniwersytet Medyczny W Lublinie

Contact name

Country Clinical Trial Coordinator

Public contact point

Organisation

Uniwersytet Medyczny W Lublinie

Contact name

Biuro Rektora

Third parties 6

Locations

1 EU/EEA country · 6 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications