Immediate corticosteroid therapy and rituximab to prevent generalization in ocular myasthenia gravis: a PROBE-type multicenter, open-label, randomized controlled trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Hopital Fondation Adolphe De Rothschild

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

12 Feb 2025 → ongoing

Decision date (initial)

2024-03-21

Transition trial

No

Low-intervention

Yes

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy

To evaluate, in patients with ocular-onset myasthenia gravis, the effect of a standardized proactive strategy combining immediate treatment with corticosteroids at the time of diagnosis and the addition of rituximab in the event of recurrence of ocular symptoms during corticosteroid taper, on generalization at 2 years.

Secondary objectives 9

1. To evaluate, in patients with ocular myasthenia gravis, the effect of a standardized proactive strategy combining immediate corticosteroid treatment at diagnosis and the addition of rituximab in the event of recurrence of ocular symptoms during corticosteroid tapering, on generalization at 1 year.
2. To evaluate, in patients with ocular myasthenia gravis, the effect of a standardized proactive strategy combining immediate treatment with corticosteroids at the time of diagnosis and the addition of rituximab in the event of recurrence of ocular symptoms as corticosteroids taper off, on the severity of symptoms at the time of generalization.
3. To evaluate, in patients with ocular myasthenia, the effect of a standardized proactive strategy combining immediate corticosteroid treatment at diagnosis and the addition of rituximab in the event of recurrence of ocular symptoms during corticosteroid taper, on the number of myasthenia-related hospitalizations and ICU admissions during 2 years of follow-up.
4. To evaluate, in patients with ocular myasthenia, the effect of a standardized proactive strategy combining immediate corticosteroid treatment at diagnosis and the addition of rituximab in the event of recurrence of ocular symptoms during corticosteroid taper, on the administration of Ig-IV or plasma exchange therapy during 2 years of follow-up
5. To evaluate, in patients with ocular myasthenia gravis, the effect of a standardized proactive strategy combining immediate corticosteroid treatment at diagnosis and the addition of rituximab in the event of recurrence of ocular symptoms during corticosteroid taper, on remission of ocular symptoms at 3 months, 6 months, 1 year and 2 years.
6. To evaluate, in patients with ocular myasthenia gravis, the effect of a standardized proactive strategy combining immediate treatment with corticosteroids at the time of diagnosis and the addition of rituximab in the event of recurrence of ocular symptoms during corticosteroid taper, on the occurrence of at least one ocular relapse during 2 years of follow-up.
7. To evaluate, in patients with ocular myasthenia gravis, the effect of a standardized proactive strategy combining immediate corticosteroid treatment at diagnosis and the addition of rituximab in the event of recurrence of ocular symptoms during corticosteroid taper, on changes in myasthenia-related quality of life at 3-month, 6-month and 2-year follow-up.
8. To evaluate, in patients with ocular myasthenia gravis, the effect of a standardized proactive strategy combining immediate corticosteroid treatment at diagnosis and the addition of rituximab in the event of recurrence of ocular symptoms during corticosteroid taper, on the total dose of corticosteroids prescribed during 2 years of follow-up
9. Describe the evolution of patients in the two arms, 6 and 12 months after the end of the randomized period of the trial.

Conditions and MedDRA coding

Myasthenia gravis

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Patients over 18 years old
2. Diagnosis of ocular myasthenia within the last 6 months, defined : either by a typical clinical examination objectified by an expert clinician: ptosis and/or binocular diplopia, with a variable and fluctuating character (either spontaneous or provoked by effort or rest) ; or by positive anti-AChR antibodies or the presence of a decrement on repetitive nerve stimulation or a positive edrophonium test
3. Myasthenic symptoms limited to ocular and/or orbicular muscles muscles (no non-ocular symptoms on MMS, MGC and MG-ADL).
4. Myasthenic symptoms for at least one month (to rule out generalized myasthenia at the outset)
5. Immunosuppressive therapy-naive management of ocular myasthenia gravis
6. Having received information about the study and having signed a consent to participate in the study
7. Affiliated to a social security system

Exclusion criteria 22

1. Thymoma
2. Hypersensitivity to paracetamol
3. Hypersensitivity to dexchlorpheniramine
4. Any infectious condition (including hepatitis b)
5. Patients with severe immune deficiency
6. Severe heart failure (New York Heart Association (NYHA) Class IV) or severe uncontrolled heart disease
7. Severe liver failure
8. Psychotic state not yet controlled by treatment
9. Hyperuricemia on xanthine oxidase inhibitors (allopurinol and febuxostat)
10. Risk of angle-closure glaucoma
11. Risk of urinary retention due to urethro-prostatic disorders
12. Alternative diagnosis to ocular involvement (pupillary abnormality other than that resulting from previous local disease or surgery abduction myopathy due to dysthyroid ophthalmopathy or dysimmune orbitopathy)
13. Vaccination with live attenuated vaccine required during study and up to 6 months after rituximab discontinuation
14. Women of childbearing age* who do not wish to use effective contraception (effective contraception includes oral contraception, intrauterine devices and other forms of contraception with a failure rate <1%) during their participation and at least 12 months after the last dose (oral commitment by the patient recorded in the file by the investigator)
15. Pregnant or breast-feeding women
16. Persons deprived of their liberty by judicial or administrative administrative decision, persons under psychiatric care by virtue of articles L.3212-1 and L.3213-1 and persons admitted to a health or social establishment for purposes purposes other than research (L.1121-6)
17. Adults under legal protection (L.1121-8)
18. History of immunosuppressive treatment or current immunosuppressive therapy for the management of a chronic pathology
19. Onset of ocular symptoms more than one year prior to diagnosis
20. Hypersensitivity to rituximab or murine proteins
21. Hypersensitivity to prednisone and/or methylprednisone
22. Hypersensitivity to aziathioprine or 6-mercaptopurine

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Comparison of the proportion of patients who progressed to generalized myasthenia within 2 years of follow-up between the standardized experimental group and the control group. Generalization is defined by a loss of 5 points or more on any Myasthenic Muscle Score (MMS) item, excluding "eyelid occlusion" and "extrinsic ocular musculature".

Secondary endpoints 9

1. Comparison of the proportion of patients who progressed to generalized myasthenia gravis in the first year of follow-up between the standardized experimental group and the control group. Generalization is defined as for the primary endpoint.
2. Comparison between the standardized experimental group and the control group of the severity of generalization symptoms according to: a. Myasthenic Muscle Score (MMS), b. Myasthenia Gravis Composite Scale (MGC), c. MG Activities of Daily Living (MG-ADL) score.
3. Comparison between standardized experimental group and control group of number of hospitalizations and ICU admissions due to myasthenia exacerbation or adverse event
4. Comparison of the proportion of patients treated with Ig-IV or plasma exchange between the standardized experimental group and the control group.
5. Comparison between the standardized experimental group and the control group of the proportion of patients achieving remission of ocular symptoms, as defined by the first three items of the MGC equal to zero
6. Comparison between the standardized experimental group and the control group of the proportion of patients presenting an ocular relapse, defined by a loss of 5 points or more on the sub-score comprising the 2 ocular items (diplopia and ptosis) of the MMS, without generalization of symptoms.
7. Comparison between standardized experimental group and control group of quality of life measured by: a. Myasthenia gravis quality of life score (MG-QoL15), b. National Eye Institute Visual Functioning Questionnaire with neuro-ophthalmological supplement (NEI VFQ 25 + supplement)
8. Comparison between standardized experimental group and control group, of cumulative dose of prednisone equivalent prescribed
9. Comparison between the standardized experimental group and the control group of changes in the following clinical scores: MMS, MGC, MG-ADL, MGFA-PIS.

Investigational products

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

Test 2

Auxiliary 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Hopital Fondation Adolphe De Rothschild

Sponsor organisation

Hopital Fondation Adolphe De Rothschild

Address

29 Rue Manin

City

Paris

Postcode

75019

Country

France

Scientific contact point

Organisation

Hopital Fondation Adolphe De Rothschild

Contact name

Clinical research department

Public contact point

Organisation

Hopital Fondation Adolphe De Rothschild

Contact name

Clinical research department

Locations

1 EU/EEA country · 11 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 12 files

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

Application history

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