Myasthenia Gravis
Conditions
Keywords
MG, Hizentra, autoimmune neuromuscular disorder
Brief summary
The purpose of this study is to determine whether Hizentra is a safe and effective treatment for people with myasthenia gravis (MG).
Detailed description
Myasthenia gravis (MG) is a rare autoimmune disorder which causes the muscles to become weak because the immune system attacks the connection between the nerves and the muscles. Hizentra is a subcutaneous (under the skin) immunoglobin (SCIg). An immunoglobin is a blood protein. Hizentra is being studied for the treatment of patients with MG. Hizentra is administered by an injection into the skin through a portable infusion pump, which may be easier for patients to administer than the current treatments. Participants will be asked to complete 9 clinic visits and 3 telephone calls. It could take up to 30 weeks to complete all study visits.
Interventions
DRUGHIZENTRA ®
Patients must fulfill inclusion criteria and remain stable at week 0, which means QMG does not increase by 3 points, will enter receive Hizentra for 12 weeks.
Sponsors
CSL Behring
Mazen Dimachkie, MD
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients 18 and older * Patients must have prior or current documentation of MGFA MG grades 2, 3, or 4 generalized MG, according to the MGFA classification system.48 These grades correspond to mild (2), moderate (3), and severe (4) * Elevated AChR or MuSK Ab. These tests will have been performed at some time prior to entry into the study. Double seronegative MG patients with prior documentation of an abnormal decrement (\>10%) on slow repetitive nerve stimulation or an abnormal single fiber EMG will also be allowed to participate * Patient's signs and symptoms should not be better explained by another disease process. * IVIg maintenance dose of 0.2 to 2 gm/kg/4 weeks or equivalent dose administered Q 2-4 weeks±3days * Stable IVIg for at least 3 cycles (definition of stability: no change in prescribed dosage or frequency by the treating physician) * Patient must be receiving no more than 200g/4weeks of IVIg. * Patients must be willing to complete the study and return for follow-up visits. * Patients must be willing to give written informed consent before participating in this study. A copy of the signed consent must be kept in the patient's medical record. * Patients can be on the following drugs as long as there has been no dose change for 60 days: azathioprine, cyclosporine, cyclophosphamide, mycophenolate mofetil, tacrolimus, methotrexate or other immunosuppressive drugs. * Patients can be on prednisone as long as there has been no dose change for 30 days.
Exclusion criteria
* MGFA grade V within 6 months of screening. * A history of chronic degenerative, psychiatric, or neurologic disorder other than MG that can produce weakness or fatigue. * Other major chronic or debilitating illnesses within six months prior to study entry. * Female patients who are premenopausal and are: (a) pregnant on the basis of a serum pregnancy test, (b) breast-feeding, or (c) not using an effective method of double barrier (1 hormonal plus 1 barrier method or 2 simultaneous barrier methods) birth control (birth control pills, male condom, female condom, intrauterine device, Norplant, tubal ligation, or other sterilization procedures). * Altered levels of consciousness, dementia, or abnormal mental status. * Thymectomy in the previous three months. * Evidence of renal insufficiency (Cr\>1.5 x elevated) or liver disease (transaminases \> 2.5 x elevation) at screening. * Skin disease that would interfere with assessment of injection site reaction * History of severe reactions to IVIg or SCIg. * Participation in a research study within the last 3 months * Treatment with rituximab or other biologics within 12 months of study entry * Inability to provide informed consent. * History of thrombotic episodes within the last year prior to enrollment * Known allergic or other severe reactions to blood products including intolerability to previous normal human immunoglobulin for intravenous administration (IVIG) and/or subcutaneous immunoglobulin (SCIG), such as history of clinically relevant hemolysis after IVIG infusion, aseptic meningitis, recurrent severe headache, hypersensitivity, severe generalized or severe local skin reaction. * History of IgA deficiency or evidence of IgA deficiency at screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients Whose Quantitative Myasthenia Gravis Scores Are Increased by no More Than 3 Points at the End of the SCIg Treatment Phase | Change from Baseline to Week 12 | The QMG is a 13 item ordinal scale which measures ocular, bulbar, extremity fatigue and strength, along with respiratory function. The scale is from 0 - 3 for each item, with 0 meaning normal and 3 is severe. Total score can range from 0 to 39. Change in MG severity will be measured using the Quantitative Myasthenia Gravis (QMG) Score for Disease severity. The QMG is a validated clinical composite scale. As mentioned in the protocol, our hypotheses are: H0: Proportion of patients whose QMG scores are increased by more than 3 points at the end of the SCIg treatment phase ≤ 0.65 HA: Proportion of patients whose QMG scores are increased by no more than 3 points at the end of the SCIg treatment phase \> 0.65 Thus, analysis of the primary outcome is done as a one-sample Z test of proportions. That is, the QMG is a continuous outcome, but analyses results are reported as proportions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Myasthenia Gravis Quality of Life (MG QOL-15) Scores | Change from Baseline to Week 12 | MG Quality of Life (QOL)-15: Composite measure of scores from measurement scales. The MG QOL-15 is a questionnaire answered by the patient that asked about different symptoms of MG. The questionnaire consists of 15 questions that are graded on a scale of 0 - 4. The total score has a range of 0 - 60 with a higher score meaning more severe symptoms or a worse outcome. |
| Myasthenia Gravis Composite (MGC) Score | Change from Baseline to Week 12 | The MGC takes scores from the MG-ADL, the QMG, and combines them will manual muscle testing scores to create the MGC. The scale of this score ranges from 0 - 50 with higher scores meaning a worse outcome or more sever symptoms. |
| Treatment Satisfaction Questionnaire for Medication (TSQM) - Convenience Score | Change from Baseline to Week 12 | Treatment Satisfaction Questionnaire for Medication (TSQM) - Convenience Score measured on a scale of 0 to 100. 0 indicates no treatment convenience satisfaction and 100 indicates highest treatment convenience satisfaction. |
| Myasthenia Gravis-specific Activities of Daily Living Scale (MG-ADL) Scores | Change from Baseline to Week 12 | Myasthenia Gravis-specific Activities of Daily Living scale (MG-ADL): Composite measure of scores from measurement scales. The MG-ADL has a scale of 0 - 24 with 0 being the lowest (no symptoms) and 24 being the highest (most severe symptoms. The MG-ADL is a staff-administered, patient-reported questionnaire that measures 8 commons symptoms of myasthenia gravis and grades them on a scale of 0 - 3. |
| Treatment Satisfaction Questionnaire for Medication (TSQM) - Satisfaction Score | Change from Baseline to Week 12 | Treatment Satisfaction Questionnaire for Medication (TSQM) - Satisfaction Score measured on a scale of 0 to 100. 0 indicates no treatment satisfaction and 100 indicates highest treatment satisfaction. |
| Immunoglobulin G (IgG) Antibody Levels | Change from Week -10 to Week 0 versus Week 1 to Week 12 | Measure IgG level (mg/dL) between intravenous and subcutaneous study phases. Normal range equals 762-1488 mg/dL. |
| Tolerabililty | 12 weeks from start of SCIg | Tolerability is assessed as the number of subjects who completed the study and/or did not withdraw due to worsening. |
| Treatment Satisfaction Questionnaire for Medication (TSQM) - Effectiveness Score | Change from Baseline to Week 12 | Treatment Satisfaction Questionnaire for Medication (TSQM) - Effectiveness Score measured on a scale of 0 to 100. 0 indicates no treatment effectiveness satisfaction and 100 indicates highest treatment effectiveness satisfaction. |
Countries
Canada, United States
Participant flow
Recruitment details
North American study involving 5 sites (4 in the US and 1 in Canada). Subjects were recruited through clinical practice and advertisement through the Myasthenia Gravis Foundation of America.
Participants by arm
| Arm | Count |
|---|---|
| Hizentra Hizentra is a subcutaneous (under the skin) immunoglobin (SCIg). Participants will receive weekly Hizentra. Dose and rate depend on the visit and how each participant tolerates the drug. Max flow rate not to exceed 100 mL per hour.
HIZENTRA ® | 23 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Did not pass screening phase | 1 |
Baseline characteristics
| Characteristic | Hizentra |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 7 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants |
| Age, Continuous | 51.36 years STANDARD_DEVIATION 17.001 |
| Quantitative Myasthenia Gravis test at Baseline | 10 points |
| Race/Ethnicity, Customized Race African American | 2 Participants |
| Race/Ethnicity, Customized Race Asian | 1 Participants |
| Race/Ethnicity, Customized Race Other | 1 Participants |
| Race/Ethnicity, Customized Race Unknown | 1 Participants |
| Race/Ethnicity, Customized Race White | 18 Participants |
| Region of Enrollment Canada | 11 participants |
| Region of Enrollment United States | 12 participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 23 |
| other Total, other adverse events | 17 / 23 |
| serious Total, serious adverse events | 6 / 23 |
Outcome results
Primary
Proportion of Patients Whose Quantitative Myasthenia Gravis Scores Are Increased by no More Than 3 Points at the End of the SCIg Treatment Phase
The QMG is a 13 item ordinal scale which measures ocular, bulbar, extremity fatigue and strength, along with respiratory function. The scale is from 0 - 3 for each item, with 0 meaning normal and 3 is severe. Total score can range from 0 to 39. Change in MG severity will be measured using the Quantitative Myasthenia Gravis (QMG) Score for Disease severity. The QMG is a validated clinical composite scale. As mentioned in the protocol, our hypotheses are: H0: Proportion of patients whose QMG scores are increased by more than 3 points at the end of the SCIg treatment phase ≤ 0.65 HA: Proportion of patients whose QMG scores are increased by no more than 3 points at the end of the SCIg treatment phase \> 0.65 Thus, analysis of the primary outcome is done as a one-sample Z test of proportions. That is, the QMG is a continuous outcome, but analyses results are reported as proportions.
Time frame: Change from Baseline to Week 12
Population: 23 patients were enrolled in the study. The protocol mentions that only those subjects who have stable QMG in the screening phase will be considered eligible for analyses. In our case 22 out of 23 patients are eligible for the final analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hizentra | Proportion of Patients Whose Quantitative Myasthenia Gravis Scores Are Increased by no More Than 3 Points at the End of the SCIg Treatment Phase | 0.864 proportion of participants |
Comparison: Sample size/power calculations are mentioned in the study protocol.~The study hypotheses are as follows:~H0: Proportion of patients whose QMG scores are increased by no more than 3 points at the end of the SCIg treatment phase ≤ 0.65 HA: Proportion of patients whose QMG scores are increased by no more than 3 points at the end of the SCIg treatment phase \> 0.65p-value: 0.017995% CI: [0.72, 1]One sample Z test of proportions
Secondary
Immunoglobulin G (IgG) Antibody Levels
Measure IgG level (mg/dL) between intravenous and subcutaneous study phases. Normal range equals 762-1488 mg/dL.
Time frame: Change from Week -10 to Week 0 versus Week 1 to Week 12
Population: Note: Change in IgG from Week -10 to Week 0 can be assessed for 20 participants. Change in IgG from Week 1 to Week 12 can be assessed for 19 participants.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Hizentra | Immunoglobulin G (IgG) Antibody Levels | Change: Week -10 to Week 0 | 661 mg/dL |
| Hizentra | Immunoglobulin G (IgG) Antibody Levels | Change: Week 1 to Week 12 | -54 mg/dL |
p-value: 0.0028Wilcoxon Signed Rank for paired data
Secondary
Myasthenia Gravis Composite (MGC) Score
The MGC takes scores from the MG-ADL, the QMG, and combines them will manual muscle testing scores to create the MGC. The scale of this score ranges from 0 - 50 with higher scores meaning a worse outcome or more sever symptoms.
Time frame: Change from Baseline to Week 12
Population: Here we consider the 21 participants on whom the MG-Composite scores are available for analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Hizentra | Myasthenia Gravis Composite (MGC) Score | Week 12 | 4 score on a scale |
| Hizentra | Myasthenia Gravis Composite (MGC) Score | Baseline | 6 score on a scale |
p-value: 0.047Wilcoxon Signed Rank for paired data
Secondary
Myasthenia Gravis Quality of Life (MG QOL-15) Scores
MG Quality of Life (QOL)-15: Composite measure of scores from measurement scales. The MG QOL-15 is a questionnaire answered by the patient that asked about different symptoms of MG. The questionnaire consists of 15 questions that are graded on a scale of 0 - 4. The total score has a range of 0 - 60 with a higher score meaning more severe symptoms or a worse outcome.
Time frame: Change from Baseline to Week 12
Population: Here we consider the 22 participants on whom the MG-ADL scores at either baseline or Week 12 are available for analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Hizentra | Myasthenia Gravis Quality of Life (MG QOL-15) Scores | Week 12 | 16 score on a scale |
| Hizentra | Myasthenia Gravis Quality of Life (MG QOL-15) Scores | Baseline | 22 score on a scale |
p-value: 0.612Wilcoxon Signed Rank for paired data
Secondary
Myasthenia Gravis-specific Activities of Daily Living Scale (MG-ADL) Scores
Myasthenia Gravis-specific Activities of Daily Living scale (MG-ADL): Composite measure of scores from measurement scales. The MG-ADL has a scale of 0 - 24 with 0 being the lowest (no symptoms) and 24 being the highest (most severe symptoms. The MG-ADL is a staff-administered, patient-reported questionnaire that measures 8 commons symptoms of myasthenia gravis and grades them on a scale of 0 - 3.
Time frame: Change from Baseline to Week 12
Population: Here we consider the 22 participants on whom the MG-ADL scores at either baseline or Week 12 are available for analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Hizentra | Myasthenia Gravis-specific Activities of Daily Living Scale (MG-ADL) Scores | Week 12 | 3 score on a scale |
| Hizentra | Myasthenia Gravis-specific Activities of Daily Living Scale (MG-ADL) Scores | Baseline | 3 score on a scale |
p-value: 0.113Wilcoxon Signed Rank for paired data
Secondary
Tolerabililty
Tolerability is assessed as the number of subjects who completed the study and/or did not withdraw due to worsening.
Time frame: 12 weeks from start of SCIg
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Hizentra | Tolerabililty | 20 Participants |
Secondary
Treatment Satisfaction Questionnaire for Medication (TSQM) - Convenience Score
Treatment Satisfaction Questionnaire for Medication (TSQM) - Convenience Score measured on a scale of 0 to 100. 0 indicates no treatment convenience satisfaction and 100 indicates highest treatment convenience satisfaction.
Time frame: Change from Baseline to Week 12
Population: This secondary outcome was recorded for 18 patients. Analysis is done as per the protocol.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Hizentra | Treatment Satisfaction Questionnaire for Medication (TSQM) - Convenience Score | Week 12 | 75 score on a scale |
| Hizentra | Treatment Satisfaction Questionnaire for Medication (TSQM) - Convenience Score | Baseline | 69.40 score on a scale |
p-value: 0.901Wilcoxon Signed Rank for paired data
Secondary
Treatment Satisfaction Questionnaire for Medication (TSQM) - Effectiveness Score
Treatment Satisfaction Questionnaire for Medication (TSQM) - Effectiveness Score measured on a scale of 0 to 100. 0 indicates no treatment effectiveness satisfaction and 100 indicates highest treatment effectiveness satisfaction.
Time frame: Change from Baseline to Week 12
Population: This secondary outcome was recorded for 20 patients. Analysis is done as per the protocol.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Hizentra | Treatment Satisfaction Questionnaire for Medication (TSQM) - Effectiveness Score | Week 12 | 79.20 score on a scale |
| Hizentra | Treatment Satisfaction Questionnaire for Medication (TSQM) - Effectiveness Score | Baseline | 75 score on a scale |
p-value: 0.51Wilcoxon Signed Rank for paired data
Secondary
Treatment Satisfaction Questionnaire for Medication (TSQM) - Satisfaction Score
Treatment Satisfaction Questionnaire for Medication (TSQM) - Satisfaction Score measured on a scale of 0 to 100. 0 indicates no treatment satisfaction and 100 indicates highest treatment satisfaction.
Time frame: Change from Baseline to Week 12
Population: This secondary outcome was recorded for 18 patients. Analysis is done as per the protocol.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Hizentra | Treatment Satisfaction Questionnaire for Medication (TSQM) - Satisfaction Score | Week 12 | 83.30 score on a scale |
| Hizentra | Treatment Satisfaction Questionnaire for Medication (TSQM) - Satisfaction Score | Baseline | 75 score on a scale |
p-value: 0.289Wilcoxon Signed Rank for paired data