Safety,Tolerability,Pharmacokinetics and Efficacy of CFZ533 in Moderate to Severe Myasthenia Gravis

Study Overview
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Brief Summary
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The purpose of this study is to evaluate safety, tolerability, pharmacokinetics/pharmacodynamics and efficacy of CFZ533 as an add-on therapy to standard of care in patients with moderate to severe myasthenia gravis (MG).

Official Title
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A Multi-center, Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Preliminarily Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy of CFZ533 in Patients With Moderate to Severe Myasthenia Gravis

Conditions
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Myasthenia Gravis, Generalized

Intervention / Treatment
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* Drug: Placebo
* Drug: CFZ533


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of MG class IIa to IVa inclusive (Myasthenia Gravis Foundation of America Clinical Classification). Quantitative Myasthenia Gravis (QMG) score of 10 or greater. If the QMG score is < 15 no more than 4 points may be derived from items 1 or 2 (ocular motility disturbance and ptosis). Documented history of acetylcholine receptor (AChR) or Muscle Specific Kinase (MuSK) antibody positive. Only one immunosuppressant or immunomodulatory drug at a stable dose is allowed during the study (i) azathioprine and mycophenolate mofetil must be stable for at least 4 months prior to randomization (ii) cyclosporine must be stable for at least 3 months prior to randomization. If the patient is on oral corticosteroids, methotrexate or tacrolimus at screening, the dose must be stable for at least 1 month prior to randomization. If the patient is on cholinesterase inhibitors at screening, the dose must be stable for at least 2 weeks prior to randomization. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, may be included in the study if they are using highly effective methods of contraception during the study and for 12 weeks after study treatment. Exclusion Criteria: MGFA grade I, IVb, or V disease. Documented presence of unresected thymoma. Patients having undergone thymectomy or thymo thymectomy (resection of thymoma) within 6 months of screening. Patients having received any of the following treatments prior to randomization: IVIg or plasma exchange within 8 weeks; oral or IV cyclosphosphamide treatment within 3 months; IV corticosteroid bolus (dose higher than 1 mg/kg) within 3 months; belimumab within 6 months. For patients who received belimumab earlier, B cell count should be within normal range; rituximab within 12 months. For patients who received rituximab earlier, B cell count should be within normal range; any other biologic or an investigational drug within 1 month or five times thehalf-life, whichever is longer. Live vaccines within 4 weeks of study drug infusion. Patients who are at significant risk for TE as judged by the investigator or have any one of the following: History of either thrombosis or 3 or more spontaneous abortions with or without the presence of anti-cardiolipin autoantibodies; Presence of prolonged partial thromboplastin time (PTT).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: CFZ533<br>CFZ533 | Drug: Placebo<br> <br> Drug: CFZ533<br> <br> |
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in the Quantitative Myastenia Gravis (QMG) Score at Week 25. Posterior Median Was Used as Measure Type. | QMG score is an established validated measure of disease severity used in MG trials (Jaretzki et al 2000). The scoring system is based on quantitative testing of sentinel muscle groups by means of a 4 point scale ranging from 0 (no symptoms) to 3 (severe symptoms). The scale measures ocular, bulbar, respiratory, and limb function, grading each finding, and the total score ranges from 0 (no myasthenic findings) to 39 (maximal myasthenic deficits) (Sharshar et al 2000, Bedlack et al 2005). | week 25 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Changes From Baseline in the Myasthenia Gravis Composite (MGC) Score. Posterior Median Was Used as Measure Type. | The Myasthenia Gravis Composite (MGC) score is another key efficacy outcome measure, ranging from 0 to 50. It is reliable and demonstrates concurrent and longitudinal construct validity in the MG practice care setting (Burns et al 2010). The MGC scale covers 10 important functional domains most frequently involved in patients with MG. The proportion of bulbar and respiratory items reflect the clinical importance of these domains in the disease, and are appropriately weighted. The assessment of each of the 10 test items provides immediate insight into the status of that particular functional domain. A decrease in this score shows an improvement. | From baseline to week 49 | 
| Proportion of Patients With Improvement or Worsening by ≥ 3 Points in the QMG Score | QMG score is an established validated measure of disease severity used in MG trials (Jaretzki et al 2000). The scoring system is based on quantitative testing of sentinel muscle groups by means of a 4 point scale ranging from 0 (no symptoms) to 3 (severe symptoms). The scale measures ocular, bulbar, respiratory, and limb function, grading each finding, and the total score ranges from 0 (no myasthenic findings) to 39 (maximal myasthenic deficits) (Sharshar et al 2000, Bedlack et al 2005). | at week 49 | 
| Proportion of Patients Intolerant to Steroid Taper |  | week 49 | 
| Number of Patients Who Discontinued Due to Inefficacy or Worsening |  | week 49 | 
| Mean Change From Baseline in the Myasthenia Gravis-specific Activities of Daily Living Scale (MG-ADL) | The MG-ADL is an 8-item survey to assess functional performance of daily activities that are sometimes impaired by MG e.g. talking, breathing, swallowing etc. (Muppidi et al 2011). The higher score on MG-ADL scale (0-24 points) indicates worse functional performance of daily activities. | week 25 | 
| Mean Changes From Baseline in the QMG Score at Week 49 | QMG (quantitative myasthenia gravis) score is an established validated measure of disease severity used in MG trials (Jaretzki et al 2000). The scoring system is based on quantitative testing of sentinel muscle groups by means of a 4 point scale ranging from 0 (no symptoms) to 3 (severe symptoms). The scale measures ocular, bulbar, respiratory, and limb function, grading each finding, and the total score ranges from 0 (no myasthenic findings) to 39 (maximal myasthenic deficits) (Sharshar et al 2000, Bedlack et al 2005). A decrease in the QMG score indicated an improvement. Results given as a change in the score as compared from baseline | week 49 | 
| Mean Change From Baseline in the Myasthenia Gravis Quality of Life (MG QOL-15) | The MG-QOL15 is a 15-item survey, completed by MG patients and it is designed to assess some aspects of quality of life (QoL) related to MG (Burns et al 2011) e.g. assesment of mood, eating, speaking, driving a car etc.. The higher score on MG-QOL15 scale (0-60 points) indicates worse QoL. | week 25 | 
| Free CD40 on B Cells | CD40 receptor occupancy by CFZ533 in peripheral blood was assessed by flow cytometry analysis, measuring free or total CD40 receptors on whole blood B cells. Free CD40 on CD19-positive B cells, using PE-conjugated CFZ533 whose binding was prevented by bound, unconjugated CFZ533 (drug bound to CD40 on peripheral blood B cells). The more CD40 was occupied by unlabeled CFZ533, the less binding of labeled CFZ533, manifest as a lower mean fluorescence intensity (MFI) of CD40 on B cells. MFI from free CD40 on B cells was converted into Molecules of Equivalent Soluble Fluorochrome (MESF) using PE-MESF beads. | week 1, week 25 | 
| Total Soluble CD40 (sCD40) in Plasma | PD | week1, week 25 | 
| Plasma CFZ533 Concentration at Steady State Conditions (Week 17) |  | week 17 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CFZ533, Myasthenia Gravis