Evaluation of Corticosteroids and Rituximab in Preventing Generalization in Ocular Myasthenia Gravis: A Multicenter Randomized Controlled Trial

The primary objective of this study is to evaluate the effect of a standardized proactive strategy in patients with **ocular myasthenia gravis**. This strategy involves immediate treatment with corticosteroids at the time of diagnosis and the addition of rituximab if ocular symptoms recur during corticosteroid tapering. The primary focus is on preventing the generalization of symptoms over a 2-year period. This is clinically relevant as it aims to mitigate the progression of the disease, potentially improving patient outcomes and reducing the burden of systemic myasthenia gravis.

Secondary objectives include:

• Evaluating the effect of the treatment strategy on generalization at 1 year.
• Assessing the severity of symptoms at the time of generalization.
• Determining the number of myasthenia-related hospitalizations and ICU admissions over 2 years.
• Evaluating the administration of intravenous immunoglobulin (Ig-IV) or plasma exchange therapy during 2 years of follow-up.
• Assessing remission of ocular symptoms at 3 months, 6 months, 1 year, and 2 years.
• Evaluating the occurrence of at least one ocular relapse during 2 years of follow-up.
• Assessing changes in myasthenia-related quality of life at 3-month, 6-month, and 2-year follow-up.
• Evaluating the total dose of corticosteroids prescribed during 2 years of follow-up.
• Describing the evolution of patients in the two arms, 6 and 12 months after the end of the randomized period of the trial.

The clinical trial involves participants diagnosed with **myasthenia gravis**, specifically focusing on those with ocular-onset symptoms. The study population includes both male and female subjects over the age of 18, with no vulnerable populations selected. Participants are required to have been diagnosed with ocular myasthenia within the last six months, with symptoms limited to ocular and/or orbicular muscles, and must be immunosuppressive therapy-naive. The trial does not provide information on the total number of participants, as this data was not disclosed by the sponsor. Participants must have received information about the study, signed consent to participate, and be affiliated with a social security system. The selection criteria ensure that individuals have myasthenic symptoms for at least one month to exclude generalized myasthenia at the outset. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the effect of a standardized proactive strategy in patients with **ocular myasthenia gravis**. This trial is a multicenter, open-label, randomized controlled study, categorized as low intervention. The primary objective is to assess the impact of immediate corticosteroid therapy at diagnosis and the addition of **rituximab** in case of recurrence of ocular symptoms during corticosteroid tapering, on the generalization of symptoms over a two-year period. The trial is expected to commence recruitment on March 4, 2024, and conclude by March 3, 2029.

Participants will undergo a series of study visits, beginning with an inclusion visit to confirm eligibility based on criteria such as age over 18 years, recent diagnosis of ocular myasthenia gravis, and absence of non-ocular symptoms. The inclusion visit will involve a comprehensive clinical examination and confirmation of diagnosis through clinical or laboratory criteria. Follow-up visits will be scheduled at regular intervals to monitor the progression of symptoms and the response to treatment. These visits will include assessments using the Myasthenic Muscle Score (MMS), Myasthenia Gravis Composite Scale (MGC), and MG Activities of Daily Living (MG-ADL) score. The end-of-study visit will evaluate the primary endpoint, which is the proportion of patients who progressed to generalized myasthenia within two years.

The expected duration of participant involvement is up to two years, with conditions for early termination including significant adverse events or withdrawal of consent. Participants will be randomly assigned to either the experimental group receiving the standardized treatment strategy or the control group. The trial will also compare secondary endpoints such as the severity of generalization symptoms, number of hospitalizations, and quality of life measures. The study aims to provide valuable insights into the management of ocular myasthenia gravis and the potential benefits of combining corticosteroids with rituximab in preventing symptom generalization.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Rituximab**, marketed as Rixathon 500 mg concentrate for solution for infusion, is utilized as an experimental treatment. It is a **protein**-based medication administered via **intravenous infusion**. The maximum daily dose is 500 mg, with a total maximum dose of 2000 mg over a treatment period of up to 12 weeks. This medication is provided by SANDOZ GMBH and is not a pediatric formulation.

**Prednisone**, under the brand name CORTANCYL 20 mg, is used as a non-experimental treatment. It is available in tablet form and administered orally. The dosing is weight-based, with a maximum daily dose of 0.75 mg/kg and a total maximum dose of 504 mg/kg over a 24-week period. This chemical-based medication is supplied by CHEPLAPHARM ARZNEIMITTEL GMBH.

**Methylprednisolone hemisuccinate**, marketed as SOLUMEDROL 40 mg, is another non-experimental treatment. It is a chemical-based medication available as a powder for solution for injection, administered either intravenously or subcutaneously. The maximum daily dose is 100 mg, with a total maximum dose of 500 mg over a 5-day period. This product is provided by PFIZER HOLDING FRANCE.

**Azathioprine**, known as IMUREL 50 mg, is administered as a film-coated tablet. It is a chemical-based medication taken orally, with a maximum daily dose of 150 mg and a total maximum dose of 23800 mg over a 6-week period. This medication is supplied by ASPEN PHARMA TRADING LIMITED.

**Paracetamol**, marketed as PARACETAMOL PANPHARMA 10 mg/ml, is used as a solution for infusion. It is a chemical-based medication administered intravenously, with a maximum daily dose of 1 g and a total maximum dose of 5 g over a 5-day period. This product is provided by PANMEDICA.

**Dexchlorpheniramine maleate**, under the brand name POLARAMINE 5 mg/1 ml, is available as a solution for injection. It is a chemical-based medication administered intravenously, with a maximum daily dose of 5 mg and a total maximum dose of 25 mg over a 5-day period. This medication is supplied by LABORATORIOS FARMACÉUTICOS ROVI, S.A.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint involves the comparison of the proportion of patients who progress to generalized **myasthenia gravis** within two 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 include several comparative analyses between the experimental and control groups. These analyses will evaluate the proportion of patients progressing to generalized myasthenia gravis in the first year, the severity of generalization symptoms using the Myasthenic Muscle Score (MMS), Myasthenia Gravis Composite Scale (MGC), and MG Activities of Daily Living (MG-ADL) score. Additional comparisons will assess the number of hospitalizations and ICU admissions due to myasthenia exacerbation or adverse events, the proportion of patients treated with Ig-IV or plasma exchange, and the proportion of patients achieving remission of ocular symptoms. Ocular relapse will be defined by a loss of 5 points or more on the sub-score comprising the two ocular items (diplopia and ptosis) of the MMS, without generalization of symptoms.

Further assessments will include quality of life measurements using the Myasthenia Gravis Quality of Life score (MG-QoL15) and the National Eye Institute Visual Functioning Questionnaire with neuro-ophthalmological supplement (NEI VFQ 25 + supplement). The cumulative dose of prednisone equivalent prescribed and changes in clinical scores such as MMS, MGC, MG-ADL, and MGFA-PIS will also be compared between the groups. These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial duration.