Study Comparing Two Tapering Strategies of Prednisone in Myasthenia Gravis

Study Overview
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Brief Summary
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Pathology - Generalized myasthenia gravis (MG) is cause of muscle weakness that can have a significant impact on daily life activity but can also be, when respiratory or bulbar muscles are involved, life-threatening. Rationale - Additionally to thymectomy, which indication of is still debated in absence of thymoma, the long-term treatment of generalized myasthenia gravis includes usually prednisone and azathioprine. However, the most used scheme for prescribing and tapering corticosteroid in MG resulted in a very important cumulative dose of prednisone. Indeed, at twelve month, more than 50 percent of patients are still daily treated with at least 18 mg of prednisone and the proportion of patients who are in remission and no longer taking prednisone is very low (Palace and NEWSOM Davis, Neurology 1998). Prolonged corticosteroid therapy is accompanied with various and major side effects, hypertension, osteoporosis, weight gain, glaucoma. Therefore, tapering, eventually discontinuing, prednisone earlier is a relevant therapeutic goal. For this reason, the investigators will compare to the standard one, a strategy consisting of a rapid decrease in corticosteroid. Objective - To assess whether, in patients with generalized MG requiring a long-term treatment with corticosteroids and azathioprine, that the strategy of rapid tapering allows discontinuing more rapidly the prednisone for equivalent efficacy than the classical strategy.

Detailed Description
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Rapid strategy consists of decreasing the prednisone dose if at each monthly consultation the patient fulfils the criteria for improvement or minimal manifestation state, in order to discontinue it before twelve months. The starting dose is 0.75 mg/kg/day. Classical strategy consists of decreasing the prednisone dose if at each monthly consultation the patient fulfils the criteria for minimal manifestation state, in order to discontinue it before twelve months. The starting dose is 1.5 mg/kg/2days. Duration of follow-up is 15 months. In both arms, Myasthenia Muscular Score (MMS), activities of Daily Living Scale (ADLS), MGFA Clinical Classification and MGFA Post-Intervention Status as well as prednisone and azathioprine side effects will be monthly assessed by a senior neurologist who will be blind for treatment group. A second physician, who is aware of the patient's therapeutic group, will then prescribe prednisone dose and tapering for a month, according to MGFA Post-Intervention Status. In case of worsening, prednisone dose will be increased. In case of exacerbation, the patients will be hospitalised for eventually IvIg infusion or plasma exchange. In case of a severe side effect, prednisone will be reduced irrespectively of MGFA Post-Intervention Status. In case of side effect, azathioprine will be replaced by mycophenolate mofetil.

Official Title
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Comparison of Two Tapering Strategies of Prednisone in Patients With Generalised Myasthenia Gravis Treated With Prednisone and Azathioprine: a Single-blind Randomised Controlled Multicenter Study

Conditions
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Myasthenia Gravis

Intervention / Treatment
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* Drug: Prednisone - Azathioprine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written consent of the patient, after informing Generalized MG of grade III, IV or V - Classification MGFA Follow-up on 15 months possible and accepted by patients Exclusion Criteria: Age<18 or >80 years Pregnancy Myasthenia of grade I or II of MGFA Patients already treated with prednisone or azathioprine Contraindication for prednisone or azathioprine Other associated disease requiring a treatment with prednisone or azathioprine Weight >100kg Invasive thymoma

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Starting dose Prednisone Azathioprine<br>Classical Strategy | Drug: Prednisone - Azathioprine<br>* Rapid strategy consists of decreasing the prednisone dose if at each monthly consultation the patient fulfils the criteria for improvement or minimal manifestation state, in order to discontinue it before twelve months. The starting dose is 0.75 mg/kg/day. Classical strategy consists of decreasing the prednisone dose if at each monthly consultation the patient fulfils the criteria for minimal manifestation state, in order to discontinue it before twelve months. The starting dose is 1.5 mg/kg/2days.<br>|
| Active Comparator: Starting dose Prednisone - Azathioprine<br>Rapid strategy | Drug: Prednisone - Azathioprine<br>* Rapid strategy consists of decreasing the prednisone dose if at each monthly consultation the patient fulfils the criteria for improvement or minimal manifestation state, in order to discontinue it before twelve months. The starting dose is 0.75 mg/kg/day. Classical strategy consists of decreasing the prednisone dose if at each monthly consultation the patient fulfils the criteria for minimal manifestation state, in order to discontinue it before twelve months. The starting dose is 1.5 mg/kg/2days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients who have reach minimal manifestation state (according to MGFA criteria) and are not treated with prednisone after 12 months of treatment and have not relapsed during the next 3 months. |  | 15 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative dose of prednisone at twelve months |  | 15 MONTHS | 
| Proportion of patients having reached minimal manifestation state 12 months |  | 15 MONTHS | 
| Time for reaching the improvement or minimal manifestation state (MGFA criteria) |  | 15 MONTHS | 
| Frequency of exacerbations within the first 15 months after randomization |  | 15 MONTHS | 
| Frequency of treatment by IvIg or plasma exchange within the first 15 months after randomization |  | 15 MONTHS | 
| Frequency and type of complications related to prednisone. |  | 15 MONTHS | 
| Frequency and type of complications of azathioprine |  | 15 MONTHS | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myasthenia gravis, Steroids side effects, Comparison of strategies for tapering steroids, Generalized MG corresponding to grade III, IV or V of MGFA