Cladribine therapy in Myasthenia

• Register: EUCTR
• Last refreshed on: 7 January 2025
• Main ID: EUCTR2020-005762-34-PL
• Date of registration: 04/03/2021
• Prospective Registration: Yes
• Primary sponsor: Medical University of Lublin
• Public title: Cladribine therapy in Myasthenia
• Scientific title: A phase 2 clinical trial assessing the efficacy and safety of adding cladribine for treatment modifying course of seropositive myasthenia gravis
• Date of first enrolment: 15/07/2021
• Target sample size: 200
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2020-005762-34
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Poland

Contacts

• Name: Country Clinical Trial Coordinator
• Affiliation: Medical University of Lublin,Konrad Rejdak

• Name: Country Clinical Trial Coordinator
• Affiliation: Medical University of Lublin,Konrad Rejdak

Key inclusion & exclusion 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:
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.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Immune System Diseases [C20]

Myasthenia gravis
MedDRA version: 21.1 Level: PT Classification code 10028417 Term: Myasthenia gravis System Organ Class: 10029205 - Nervous system disorders

Intervention(s)

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
Concentration number: 1-
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Subcutaneous use

Primary Outcome(s)

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) – administration of the therapeutic product studied,
W10 (week 56) – search for the symptoms of early adverse side effects,
W11 (week 66) – administration of the therapeutic product studied.
W12 (week 68), W13 (week 78), W14 (week 84), W15 (week 96) –
neurological exams with the evaluation of increased symptoms of myasthenia, emergency therapy, if required.

Timepoint(s) of evaluation of this end point: Assessment of plasma cladribine pharmacokinetics at visits W1 and W2 according to the procedure schedule.
During visits evaluating the efficacy of treatment:
-W2 – W8 during the basic trial period and
-W10 – W15 during the additional trial period in relations to the baseline result (W1 during the basic period and W9 during the additional period of the trial).

Secondary Objective: Not applicable

Main Objective: 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 Outcome(s)

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),
gammaglutamyltranspeptidase (GGTP), C-reactive protein (CRP), PCT
procalcitonin, urinalysis) relative to baseline (W1 at baseline
study and on W9 in an additional study duration). Grade on W3-W8
during the primary study duration and W11-W15 during the additional
study duration
research.

Timepoint(s) of evaluation of this end point: Effectiveness of treatment:
Change in the demand for oral glucocorticosteroids: Evaluation of W4-
W8 plus W12-W15. Relevant to baseline (W1 or W9 respectively).
The need for rescue therapy for exacerbations of myasthenia gravis: The
endpoint will be assessed at any time during the study.
Change in the titre of antibodies to acetylcholine receptors; Change in
the concentration of complement components (C3, C4); Change in
cytokine concentrations; Change in the percentage of specific
lymphocyte populations: The endpoint will be assessed as W3 and W6
plus W11 and W15. Relevant to baseline (W1 or W9 respectively).
Incidence of adverse events: The endpoint will be assessed at any time
during the study.
Change in safety parameters: The endpoint will be assessed at W3-W8
plus W11-W15.

Secondary ID(s)

MGCDB001

Source(s) of Monetary Support

Medical University of Lublin

Ethics review

Status: Approved
Approval date: 28/01/2021
Contact: