Beta-agonist Efficacy and Tolerability as Adjuvant Therapy in Myasthenia Gravis

Study Overview
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Brief Summary
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This study examines the effect of adjuvant therapy with the oral beta-agonist Salbutamol in patients with generalized myasthenia gravis on stable standard of care having residual symptoms.

Detailed Description
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Myasthenia Gravis (MG) causes various degrees of increased muscular fatigue and ocular, bulbar, respiratory and extremity symptoms. Residual symptoms often remain despite treatment with acetylcholinesterase inhibitors and immunosuppressive agents. Escalation of immunosuppressive treatment may provide additional benefit but is associated with potentially severe side effects, and high economic costs. Treatment with beta-agonists has been investigated in animal models of MG, and in small, randomized pilot studies of generalized MG. Adjuvant therapy with oral beta-agonists in MG may be safe and cheap and may improve symptoms. The trial will examine the tolerability and efficacy of adjuvant therapy with the oral beta-agonist Salbutamol in patients with generalized myasthenia gravis on stable standard of care having residual symptoms. Present study is an investigator-initiated, randomized, placebo-controlled, rater and subject-blinded crossover study. Study consists of Screening Period (4 weeks), Treatment Period 1 (8 weeks), Washout Period (4 weeks), Treatment Period 2 (8 weeks).

Official Title
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Beta-agonist Efficacy and Tolerability as Adjuvant Therapy in Myasthenia Gravis

Conditions
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Myasthenia Gravis

Intervention / Treatment
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* Drug: Salbutamol 4Mg Tablet
* Drug: Placebo oral capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Generalized myasthenia gravis (MGFA IIa-IVb) at screening, verified by ≥ 1 of the following: 1) AchR-antibodies in medical history, 2) Abnormal decrement on repetitive nerve stimulation in medical history Disease duration of ≥ 1 year Stable dose of antimyasthenic medications at screening Residual symptoms with a MG-QOL15 score of ≥ 10 Age ≥ 18 years Ability to understand the requirements of the trial and provide written, informed consent Exclusion Criteria: Evidence of malignancy ≤ 3 years prior to screening, unless deemed completely cured Thymectomy ≤ 6 months prior to screening Impending MG crisis or respiratory insufficiency Worsening of MG symptoms due to other diseases or medications (e.g. infection, beta-blockers, aminoglycosides, etc.) Other factor(s) or medical condition(s) that may explain residual symptoms Pregnancy or breast-feeding Treatment with beta-agonists Uncontrolled diabetes Ischemic Heart Disease, Cardiac Arrhythmia or Heart Failure (including hypertrophic cardiomyopathy) Uncontrolled Hypertension (≥ 160/110) Known hypersensitivity to any of the study drug components Treatment with tricyclic antidepressants, monoamineoxidase inhibitors, digoxine, or methylxanthines.

Ages Eligible for Study
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Minimum Age: 18 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: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active<br>Active intervention arm. Treatment for 8 weeks per treatment period. | Drug: Salbutamol 4Mg Tablet<br>* Salbutamol 4 mg, three times daily<br>|
| Placebo Comparator: Placebo<br>Placebo arm. Treatment for 8 weeks per treatment period. | Drug: Placebo oral capsule<br>* Placebo, three times daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Myasthenia Gravis Quality of Life 15-items (MG-QOL15) | Validated patient reported outcome-questionnaire consisting of 15 items and their impact on quality of life. Results are reported as change from baseline to 8 weeks of treatment in both treatment periods (Visit 4 compared to Visit 2, and Visit 7 compared to Visit 5). | 8 weeks (Treatment Period 1), 8 weeks (Treatment Period 2) | 
| Treatment Tolerability | Tolerability assessed by rate of adverse events and drug discontinuation in both treatment periods. | 8 weeks (Treatment Period 1), 8 weeks (Treatment Period 2) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Myasthenia Gravis Activity of Daily Living (MG-ADL) | Validated patient-reported outcome scale consisting of 8 disease-related items and their impact on activity of daily living. Results are reported as change from baseline to 8 weeks of treatment in both treatment periods (Visit 4 compared to Visit 2, and Visit 7 compared to Visit 5). | 8 weeks (Treatment Period 1), 8 weeks (Treatment Period 2) | 
| Neuro QOL | Patient reported fatigue-questionnaire used to rate fatigue and impact on quality of life. Results are reported as change from baseline to 8 weeks of treatment in both treatment periods (Visit 4 compared to Visit 2, and Visit 7 compared to Visit 5). | 8 weeks (Treatment Period 1), 8 weeks (Treatment Period 2) | 
| Quantitative Myasthenia Gravis (QMG) | Validated rating scale consisting of 13 items measuring muscle function and endurance. Results are reported as change from baseline to 8 weeks of treatment in both treatment periods (Visit 4 compared to Visit 2, and Visit 7 compared to Visit 5). | 8 weeks (Treatment Period 1), 8 weeks (Treatment Period 2) | 
| Myasthenia Gravis Composite (MG-Composite) | Validated scale consisting of 10 items with different weighting assessing severity of symptoms in MG. Results are reported as change from baseline to 8 weeks of treatment in both treatment periods (Visit 4 compared to Visit 2, and Visit 7 compared to Visit 5). | 8 weeks (Treatment Period 1), 8 weeks (Treatment Period 2) |