Myasthenia Gravis, Generalized
Conditions
Keywords
CFZ533, Myasthenia Gravis
Brief summary
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).
Interventions
DRUGPlacebo
DRUGCFZ533
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of MG class IIa to IVa inclusive (Myasthenia Gravis Foundation of America Clinical Classification). 2. 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). 3. Documented history of acetylcholine receptor (AChR) or Muscle Specific Kinase (MuSK) antibody positive. 4. 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. 5. 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. 6. If the patient is on cholinesterase inhibitors at screening, the dose must be stable for at least 2 weeks prior to randomization. 7. 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
1. MGFA grade I, IVb, or V disease. 2. Documented presence of unresected thymoma. 3. Patients having undergone thymectomy or thymo thymectomy (resection of thymoma) within 6 months of screening. 4. Patients having received any of the following treatments prior to randomization: 1. IVIg or plasma exchange within 8 weeks; 2. oral or IV cyclosphosphamide treatment within 3 months; 3. IV corticosteroid bolus (dose higher than 1 mg/kg) within 3 months; 4. belimumab within 6 months. For patients who received belimumab earlier, B cell count should be within normal range; 5. rituximab within 12 months. For patients who received rituximab earlier, B cell count should be within normal range; 6. any other biologic or an investigational drug within 1 month or five times thehalf-life, whichever is longer. 7. Live vaccines within 4 weeks of study drug infusion. 5. Patients who are at significant risk for TE as judged by the investigator or have any one of the following: 1. History of either thrombosis or 3 or more spontaneous abortions with or without the presence of anti-cardiolipin autoantibodies; 2. Presence of prolonged partial thromboplastin time (PTT).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in the Quantitative Myastenia Gravis (QMG) Score at Week 25. Posterior Median Was Used as Measure Type. | week 25 | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients With Improvement or Worsening by ≥ 3 Points in the QMG Score | at week 49 | 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). |
| 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) | week 25 | 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. |
| Mean Changes From Baseline in the Myasthenia Gravis Composite (MGC) Score. Posterior Median Was Used as Measure Type. | From baseline to week 49 | 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. |
| Mean Change From Baseline in the Myasthenia Gravis Quality of Life (MG QOL-15) | week 25 | 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. |
| Free CD40 on B Cells | week 1, week 25 | 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. |
| Total Soluble CD40 (sCD40) in Plasma | week1, week 25 | PD |
| Plasma CFZ533 Concentration at Steady State Conditions (Week 17) | week 17 | — |
| Mean Changes From Baseline in the QMG Score at Week 49 | 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 |
Countries
Canada, Denmark, Germany, Russia, Taiwan
Participant flow
Recruitment details
A total of 44 patients were randomized to receive either IV CFZ533 or IV placebo, of which 34 patients (77%) completed the study.
Pre-assignment details
Safety analysis set, and Full analysis: 44 patients (22 treated with CFZ533 and 22 with placebo) PK analysis set : 20 patients treated with CFZ533 PD analysis set: 42 patients (20 treated with CFZ533 and 20 with placebo)
Participants by arm
| Arm | Count |
|---|---|
| CFZ533 CFZ533 10 mg/kg | 22 |
| Placebo Placebo | 22 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | abnormal lab value | 2 | 0 |
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Death | 0 | 2 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | subject / guardian decision | 1 | 3 |
Baseline characteristics
| Characteristic | CFZ533 | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 44.7 years STANDARD_DEVIATION 13.54 | 43.3 years STANDARD_DEVIATION 13.92 | 44.0 years STANDARD_DEVIATION 13.59 |
| Race/Ethnicity, Customized Asian (Chinese) | 3 Participants | 5 Participants | 8 Participants |
| Race/Ethnicity, Customized caucasian | 19 Participants | 16 Participants | 35 Participants |
| Race/Ethnicity, Customized other | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Female | 12 Participants | 16 Participants | 28 Participants |
| Sex: Female, Male Male | 10 Participants | 6 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 2 / 22 |
| other Total, other adverse events | 20 / 22 | 21 / 22 |
| serious Total, serious adverse events | 7 / 22 | 4 / 22 |
Outcome results
Primary
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).
Time frame: week 25
Population: pharmacodynamic (PD) analysis set, participants with non-detectable AChR or MuSK autoantibodies were excluded from the PD analysis set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CFZ533 | Mean Change From Baseline in the Quantitative Myastenia Gravis (QMG) Score at Week 25. Posterior Median Was Used as Measure Type. | -4.07 score |
| Placebo | Mean Change From Baseline in the Quantitative Myastenia Gravis (QMG) Score at Week 25. Posterior Median Was Used as Measure Type. | -2.93 score |
Comparison: Primary analysis was performed on the PD analysis set. Changes from baseline in QMG scores at Week 25 were analyzed using a Bayesian model. The model investigated effects for treatment (CFZ533 or placebo) and baseline QMG score. A difference of 3 points on the mean change in QMG score between CFZ533 and placebo was deemed a clinical meaningful effect.90% CI: [-3.41, 1.14]bayesian
Secondary
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.
Time frame: week 1, week 25
Population: Pharmacodynamic analysis set, participants with measure
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CFZ533 | Free CD40 on B Cells | Free CD40 on B cells week 1 predose | 34242.9 MESF | Standard Deviation 18455.8 |
| CFZ533 | Free CD40 on B Cells | Free CD40 on B cells week 25 | 5259.1 MESF | Standard Deviation 11341.57 |
| Placebo | Free CD40 on B Cells | Free CD40 on B cells week 1 predose | 31025.9 MESF | Standard Deviation 16138.97 |
| Placebo | Free CD40 on B Cells | Free CD40 on B cells week 25 | 24908.3 MESF | Standard Deviation 5022.03 |
Secondary
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.
Time frame: week 25
Population: PD analysis set, participants with measure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CFZ533 | Mean Change From Baseline in the Myasthenia Gravis Quality of Life (MG QOL-15) | -9.7 score | Standard Deviation 11 |
| Placebo | Mean Change From Baseline in the Myasthenia Gravis Quality of Life (MG QOL-15) | -6.7 score | Standard Deviation 10.86 |
Secondary
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.
Time frame: week 25
Population: PD analysis set, participants with measure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CFZ533 | Mean Change From Baseline in the Myasthenia Gravis-specific Activities of Daily Living Scale (MG-ADL) | -2.6 score | Standard Deviation 2.97 |
| Placebo | Mean Change From Baseline in the Myasthenia Gravis-specific Activities of Daily Living Scale (MG-ADL) | -1.1 score | Standard Deviation 3.23 |
Secondary
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.
Time frame: From baseline to week 49
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CFZ533 | Mean Changes From Baseline in the Myasthenia Gravis Composite (MGC) Score. Posterior Median Was Used as Measure Type. | -8.00 score |
| Placebo | Mean Changes From Baseline in the Myasthenia Gravis Composite (MGC) Score. Posterior Median Was Used as Measure Type. | -5.62 score |
Secondary
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
Time frame: week 49
Population: PD analysis set, participants with measure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CFZ533 | Mean Changes From Baseline in the QMG Score at Week 49 | -2.9 score on a scale | Standard Deviation 5.16 |
| Placebo | Mean Changes From Baseline in the QMG Score at Week 49 | -2.6 score on a scale | Standard Deviation 4.3 |
Secondary
Number of Patients Who Discontinued Due to Inefficacy or Worsening
Time frame: week 49
Population: Full analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CFZ533 | Number of Patients Who Discontinued Due to Inefficacy or Worsening | 0 Participants |
| Placebo | Number of Patients Who Discontinued Due to Inefficacy or Worsening | 0 Participants |
Secondary
Plasma CFZ533 Concentration at Steady State Conditions (Week 17)
Time frame: week 17
Population: pharmacokinetic set, participants treated with CFZ533 only, with measure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CFZ533 | Plasma CFZ533 Concentration at Steady State Conditions (Week 17) | 120 micrograms/mL | Standard Deviation 40.5 |
Secondary
Proportion of Patients Intolerant to Steroid Taper
Time frame: week 49
Population: this data was not collected. No analysis could be performed for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CFZ533 | Proportion of Patients Intolerant to Steroid Taper | NA Participants |
| Placebo | Proportion of Patients Intolerant to Steroid Taper | NA Participants |
Secondary
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).
Time frame: at week 49
Population: PD analysis set, participants with measure
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| CFZ533 | Proportion of Patients With Improvement or Worsening by ≥ 3 Points in the QMG Score | improvement by ≥ 3 points in the QMG score | 10 Participants |
| CFZ533 | Proportion of Patients With Improvement or Worsening by ≥ 3 Points in the QMG Score | worsening by ≥ 3 points in the QMG score | 2 Participants |
| Placebo | Proportion of Patients With Improvement or Worsening by ≥ 3 Points in the QMG Score | improvement by ≥ 3 points in the QMG score | 9 Participants |
| Placebo | Proportion of Patients With Improvement or Worsening by ≥ 3 Points in the QMG Score | worsening by ≥ 3 points in the QMG score | 2 Participants |
Secondary
Total Soluble CD40 (sCD40) in Plasma
PD
Time frame: week1, week 25
Population: pharmacodynamic analysis set, participants with measure
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CFZ533 | Total Soluble CD40 (sCD40) in Plasma | week 1 | 0.1778 ng/ml | Standard Deviation 0.13077 |
| CFZ533 | Total Soluble CD40 (sCD40) in Plasma | week 25 | 191.1278 ng/ml | Standard Deviation 69.67597 |
| Placebo | Total Soluble CD40 (sCD40) in Plasma | week 1 | 0.1577 ng/ml | Standard Deviation 0.17243 |
| Placebo | Total Soluble CD40 (sCD40) in Plasma | week 25 | 0.1163 ng/ml | Standard Deviation 0.18298 |