Open Label Study of Subcutaneous Immunoglobulin (SCIg) in Myasthenia Gravis

Study Overview
=================
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.

Official Title
-----------------
Open Label Study of Subcutaneous Immunoglobulin (SCIg) in Myasthenia Gravis

Conditions
-----------------
Myasthenia Gravis

Intervention / Treatment
-----------------
* Drug: HIZENTRA ®


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HIZENTRA ®<br>Hizentra is a subcutaneous (under the skin) immunoglobin (SCIg). Participants will receive Hizentra in a minimum of one infusion per week and a maximum of 4 infusions per week. Dose and rate depend on the visit and how each participant tolerates the drug. Max cc per site is 50 cc per site per hour. | Drug: HIZENTRA ®<br>* 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.<br>* Other names: Immune Globulin Subcutaneous (Human), 20% Liquid;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Change from Baseline to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Change from Baseline to Week 12 | 
| 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. | Change from Baseline to Week 12 | 
| 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. | Change from Baseline to Week 12 | 
| 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. | Change from Baseline to Week 12 | 
| 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. | Change from Baseline to Week 12 | 
| 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. | Change from Baseline to Week 12 | 
| Immunoglobulin G (IgG) Antibody Levels | Measure IgG level (mg/dL) between intravenous and subcutaneous study phases. Normal range equals 762-1488 mg/dL. | Change from Week -10 to Week 0 versus Week 1 to Week 12 | 
| Tolerabililty | Tolerability is assessed as the number of subjects who completed the study and/or did not withdraw due to worsening. | 12 weeks from start of SCIg | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
MG, Hizentra, autoimmune neuromuscular disorder