Efficacy and Safety of IGIV-C in Corticosteroid Dependent Patients With Generalized Myasthenia Gravis

Study Overview
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Brief Summary
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This is a multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of Immune Globulin (Human), 10% Caprylate/Chromatography Purified (IGIV-C) as a corticosteroid (CS)-sparing agent in subjects with CS-dependent Myasthenia Gravis (MG).

Detailed Description
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This study consists of 2 phases: IGIV-C Run-in Phase and Corticosteroid Tapering/IGIV-C Maintenance Phase. In the Run-in Phase, subjects will receive a total of 3 doses of IGIV-C (1 loading dose of 2 g/kg and 2 maintenance doses of 1 g/kg) while maintaining a stable dose of corticosteroids. In the CS Tapering/IGIV-C Maintenance Phase, subjects will continue 1 g/kg IGIV-C and begin a prescribed CS tapering regimen where the CS dose is decreased every 3 weeks. Approximately 60 subjects are planned to be enrolled in the study across multiple centers in North America and Europe. The total duration of study participation for each subject is up to 45 weeks.

Official Title
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A Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of lGIV-C as a Corticosteroid Sparing Agent in Corticosteroid Dependent Patients With Generalized Myasthenia Gravis

Conditions
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Myasthenia Gravis

Intervention / Treatment
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* Drug: IGIV-C
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Anti-acetylcholine receptor antibody positive Confirmed diagnosis of generalized MG historically meeting the clinical criteria for diagnosis of MG defined by the Myasthenia Gravis Foundation of America (MGFA) classification of Class II, III, IV, or V historically At Screening, subjects may have symptoms controlled by CS or were MGFA Class II-IVa inclusive (Class IVb and Class V excluded). Subjects who only have a history of ocular MG may not enroll. On systemic CS for a minimum period of at least 3 months and on a stable CS dose of >=15 mg/day and <=60 mg/day (prednisone equivalent) for the month prior to Screening. Had a tapering CS dose that the study investigator considered to be appropriate. At least 1 previous completed attempt to taper CS in order to minimize CS dose (lowest feasible dose based on observed MG signs and symptoms) Exclusion Criteria: Any dose change in concomitant immunosuppressant therapy, other than CS, in the prior 6 months Any change in CS dose or acetylcholinesterase inhibitor (e.g., pyridostigmine) dose in the 1 month prior to Screening A 3-point change in Quantitative Myasthenia Gravis score, increased or decreased, between the Screening/Week -3 (Visit 0) and Baseline (Week 0 [Visit 1]) Any episode of myasthenic crisis (MC) in the 1 month prior to Screening, or (at any time in the past) MC or hospitalization for MG exacerbation associated with a previous CS taper attempt Evidence of malignancy within the past 5 years (non-melanoma skin cancer, carcinoma in situ of cervix is allowed) or thymoma potentially requiring surgical intervention during the course of the trial (intent to perform thymectomy) Thymectomy within the preceding 6 months prior to Screening Rituximab, belimumab, eculizumab or any monoclonal antibody used for immunomodulation within the past 12 months prior to Screening Have received immune globulin treatment given by IV, subcutaneous, or intramuscular route within the last 3 months prior to Screening Received plasma exchange performed within the last 3 months prior to Screening History of anaphylactic reactions or severe reactions to any blood-derived product History of recent (within the last year) myocardial infarction or stroke Uncontrolled congestive heart failure; embolism; or historically documented (within the last year) electrocardiogram changes indicative of myocardial ischemia or atrial fibrillation Current known hyperviscosity or hypercoagulable state Currently receiving anti-coagulation therapy. Oral anti-platelet agents are allowed (e.g., aspirin, clopidogrel, ticlopidine) Females of child-bearing potential who are pregnant, have a positive serum pregnancy test, breastfeeding, or are unwilling to practice a highly effective method of contraception throughout the study. Renal impairment Aspartate aminotransferase or alanine aminotransferase levels exceeding more than 2.5 times the upper limit of normal for the expected normal range for the testing laboratory. Hemoglobin (Hb) levels <9 g/dL

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IGIV-C<br>An IGIV-C loading dose of 2 g/kg and maintenance dose of 1 g/kg will be administered in CS dependent subjects with MG. | Drug: IGIV-C<br>* Run-Phase: 1 loading dose of 2 g/kg IGIV-C and 2 maintenance doses of 1 g/kg IGIV-C Corticosteroid Tapering/IGIV-C Maintenance Phase: 1 g/kg IGIV-C every 3 weeks for up to 36 weeks<br>|
| Placebo Comparator: Placebo<br>0.9% sodium chloride injection, USP or equivalent | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Subjects Achieving a 50% or Greater Reduction in CS Dose (Prednisone or Equivalent) From Baseline to Week 39 | The average daily CS dose was derived for each subject at each scheduled visit based on the prescribed dose and the time interval taking into account any prescribed dose changes between routinely scheduled visits. Subjects who discontinued the study early with adverse outcomes related to MG were considered as not achieving a 50% or greater reduction. The missing dose reduction at Week 39 was imputed using the worst observation carried forward (WOCF) method. For subjects who did not have CS dose prescribed at Week 39 due to other reasons, the last observation carried forward (LOCF) method was used to impute the prescribed CS dose at Week 39. Baseline was defined as the last non-missing measurement taken prior to first dose of study medication. The percent of subjects achieving ≥50% reduction in CS dose from baseline to Week 39 is presented for each treatment group overall and for the baseline daily prednisone equivalent dose level stratification categories. | Baseline/Week 0 (Visit 1) and Week 39 (Visit 14). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Percent Change in Daily CS Dose (Prednisone or Equivalent) From Baseline to Week 39 | The average daily CS dose was derived for each subject at each scheduled visit based on the prescribed dose and the time interval taking into account any prescribed dose changes between routinely scheduled visits. For subjects who discontinued the study early with adverse outcomes related to MG, the missing dose reduction at Week 39 was imputed using the WOCF method. For subjects who had missing CS dose reduction at Week 39 due to other reasons, the missing CS dose was imputed using the LOCF method. Baseline was defined as the last non-missing measurement taken prior to first dose of study medication. The least squares (LS) mean percent change from baseline in daily CS dose to Week 39 is presented for each treatment group. | Baseline/Week 0 (Visit 1) and Week 39 (Visit 14). | 
| Median Time to First Episode of MG Worsening | The time to the first episode of MG worsening was defined as the time between baseline and the first instance of QMG total score increase by ≥4 points relative to Baseline/Week 0. The QMG total score is the sum of all 13 items and ranges from 0 to 39. Higher values represent greater severity of illness. If one or more items were missing at a given assessment, the total score was set to missing. The median time to MG worsening was calculated based on Kaplan-Meier methodology. Baseline was defined as the last non-missing measurement taken prior to the first dose of study medication. | From Baseline/Week 0 (Visit 1) to Week 39 (Visit 14). |