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

Primary Purpose

Myasthenia Gravis, Generalized

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Placebo
CFZ533
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Myasthenia Gravis, Generalized focused on measuring CFZ533, Myasthenia Gravis

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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).

Sites / Locations

  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

CFZ533

Placebo

Arm Description

CFZ533

Placebo

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

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.
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).
Proportion of Patients Intolerant to Steroid Taper
Number of Patients Who Discontinued Due to Inefficacy or Worsening
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.
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
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.
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.
Total Soluble CD40 (sCD40) in Plasma
PD
Plasma CFZ533 Concentration at Steady State Conditions (Week 17)

Full Information

First Posted
June 23, 2015
Last Updated
December 9, 2020
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT02565576
Brief Title
Safety,Tolerability,Pharmacokinetics and Efficacy of CFZ533 in Moderate to Severe Myasthenia Gravis
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
July 2019
Overall Recruitment Status
Completed
Study Start Date
September 29, 2015 (Actual)
Primary Completion Date
July 31, 2017 (Actual)
Study Completion Date
December 19, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myasthenia Gravis, Generalized
Keywords
CFZ533, Myasthenia Gravis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
44 (Actual)

8. Arms, Groups, and Interventions

Arm Title
CFZ533
Arm Type
Active Comparator
Arm Description
CFZ533
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Type
Drug
Intervention Name(s)
CFZ533
Primary Outcome Measure Information:
Title
Mean Change From Baseline in the Quantitative Myastenia Gravis (QMG) Score at Week 25. Posterior Median Was Used as Measure Type.
Description
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
Secondary Outcome Measure Information:
Title
Mean Changes From Baseline in the Myasthenia Gravis Composite (MGC) Score. Posterior Median Was Used as Measure Type.
Description
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
Title
Proportion of Patients With Improvement or Worsening by ≥ 3 Points in the QMG Score
Description
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
Title
Proportion of Patients Intolerant to Steroid Taper
Time Frame
week 49
Title
Number of Patients Who Discontinued Due to Inefficacy or Worsening
Time Frame
week 49
Title
Mean Change From Baseline in the Myasthenia Gravis-specific Activities of Daily Living Scale (MG-ADL)
Description
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
Title
Mean Changes From Baseline in the QMG Score at Week 49
Description
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
Title
Mean Change From Baseline in the Myasthenia Gravis Quality of Life (MG QOL-15)
Description
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
Title
Free CD40 on B Cells
Description
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
Title
Total Soluble CD40 (sCD40) in Plasma
Description
PD
Time Frame
week1, week 25
Title
Plasma CFZ533 Concentration at Steady State Conditions (Week 17)
Time Frame
week 17

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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).
Facility Information:
Facility Name
Novartis Investigative Site
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H3A 2BA
Country
Canada
Facility Name
Novartis Investigative Site
City
Quebec
ZIP/Postal Code
G1J 1Z4
Country
Canada
Facility Name
Novartis Investigative Site
City
Aarhus
ZIP/Postal Code
8000 C
Country
Denmark
Facility Name
Novartis Investigative Site
City
Copenhagen
ZIP/Postal Code
2100
Country
Denmark
Facility Name
Novartis Investigative Site
City
Berlin
ZIP/Postal Code
13353
Country
Germany
Facility Name
Novartis Investigative Site
City
Halle/S
ZIP/Postal Code
06120
Country
Germany
Facility Name
Novartis Investigative Site
City
Muenchen
ZIP/Postal Code
81377
Country
Germany
Facility Name
Novartis Investigative Site
City
Samara
State/Province
Samara Region
ZIP/Postal Code
443095
Country
Russian Federation
Facility Name
Novartis Investigative Site
City
Barnaul
ZIP/Postal Code
656024
Country
Russian Federation
Facility Name
Novartis Investigative Site
City
Kazan
ZIP/Postal Code
420021
Country
Russian Federation
Facility Name
Novartis Investigative Site
City
Novosibirsk
ZIP/Postal Code
630087
Country
Russian Federation
Facility Name
Novartis Investigative Site
City
S-Petersburg
ZIP/Postal Code
194354
Country
Russian Federation
Facility Name
Novartis Investigative Site
City
Tainan
State/Province
Taiwan ROC
ZIP/Postal Code
70403
Country
Taiwan
Facility Name
Novartis Investigative Site
City
Taipei
ZIP/Postal Code
10002
Country
Taiwan
Facility Name
Novartis Investigative Site
City
Taipei
Country
Taiwan

12. IPD Sharing Statement

Links:
URL
https://www.novctrd.com/ctrdweb/patientsummary/patientsummaries?patientSummaryId=415
Description
A Plain Language Trial Summary is available on novartisclinicatrials.com

Learn more about this trial

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

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