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

• Sponsor: Grifols Therapeutics LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02473965
• Collaborator: (none)
• Enrollment: 60
• Locations: 39
• Arms: 2
• Duration (Months): 44.1
• Patients Per Site: 1.5
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Myasthenia Gravis	Drug: IGIV-C; Drug: Placebo	Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Jun 1, 2015
• Actual Primary Completion Date: Feb 1, 2019
• Actual Study Completion Date: Feb 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: IGIV-C 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; 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
Placebo Comparator: Placebo 0.9% sodium chloride injection, USP or equivalent	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Percent of Subjects Achieving a 50% or Greater Reduction in CS Dose (Prednisone or Equivalent) From Baseline to Week 39 [Baseline/Week 0 (Visit 1) and Week 39 (Visit 14).]

   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.

Secondary Outcome Measures

1. Mean Percent Change in Daily CS Dose (Prednisone or Equivalent) From Baseline to Week 39 [Baseline/Week 0 (Visit 1) and Week 39 (Visit 14).]

   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.

2. Median Time to First Episode of MG Worsening [From Baseline/Week 0 (Visit 1) to Week 39 (Visit 14).]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California-Irvine	Orange	California	United States	92868
2	Yale University School of Medicine, Department of Neurology	New Haven	Connecticut	United States	06510
3	University of Florida at Shands Jacksonville	Jacksonville	Florida	United States	32209
4	University of South Florida	Tampa	Florida	United States	33612
5	Georgia Regents University	Augusta	Georgia	United States	30912
6	Indiana University	Indianapolis	Indiana	United States	46202
7	University of Kansas Medical Center Research Institute, Inc.	Kansas City	Kansas	United States	66160
8	Rutgers New Jersey Medical School	Newark	New Jersey	United States	07103
9	Columbia University Medical Center	New York	New York	United States	10032
10	Ohio State University Wexner Medical Center, Neurology Department	Columbus	Ohio	United States	43220
11	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania	United States	19107
12	Houston Methodist Neurological Institute	Houston	Texas	United States	77030
13	University of Vermont Medical Center	Burlington	Vermont	United States	05405
14	University of Washington Medical Center	Seattle	Washington	United States	98105
15	UZ Leuven	Leuven		Belgium	3000
16	London Health Sciences Centre- University Hospital	London	Ontario	Canada	N6A 5A5
17	University Health Network (UHN) - Toronto General Hospital	Toronto	Ontario	Canada	M5G 2C4
18	Fakultni nemocnice Brno, Dept of Neurologicka klinika	Brno		Czechia	625 00
19	Fakultni nemocnice Ostrava	Ostrava - Poruba		Czechia	708 52
20	Vseobecna fakultni nemocnice v Praze, Dept of Neurologicka klinika	Praha 2		Czechia	128 21
21	East Tallinn Central Hospital	Tallinn		Estonia	10138
22	CHU Strasbourg - Nouvel Hôpital Civil, Clinique Neurologique	Strasbourg cedex	Bas Rhin	France	67091
23	CHU de Toulouse - Hôpital Purpan, Service de Neurologie Générale	Toulouse cedex 9	Haute Garonne	France	31059
24	Universitaetsklinikum Regensburg, Parent	Regensburg	Bayern	Germany	93053
25	Universitaetsklinikum Giessen und Marburg GmbH Standort Marburg	Marburg	Hessen	Germany	35043
26	Universitaetsmedizin Goettingen, Parent	Göttingen	Niedersachsen	Germany	37075
27	Krankenhaus Martha-Maria Halle-Doelau, Klinik fuer Neurologie	Halle	Sachsen Anhalt	Germany	6120
28	Fachkrankenhaus Hubertusburg gGmbH, Klinik f. Neurologie	Wermsdorf	Sachsen	Germany	4779
29	Universitaetsklinikum Jena, Klinik fuer Neurologie	Jena	Thueringen	Germany	7747
30	Charité Universitaetsmedizin Berlin, Klinik für Neurologie	Berlin		Germany	10117
31	Universitaetsklinikum Hamburg-Eppendorf, Klinik und Poliklinik	Hamburg		Germany	20246
32	Jahn Ferenc Del-pesti Korhaz es Rendelointezet, Neurologiai Osztaly	Budapest		Hungary	1204
33	Pest Megyei Flor Ferenc Korhaz, Neurologia es Stroke Osztaly	Kistarcsa		Hungary	2143
34	Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kozpont	Szeged		Hungary	6725
35	Hospital of Lithuanian University of Health Sciences Kaunas Clinics	Kaunas		Lithuania	50161
36	Uniwersyteckie Centrum Kliniczne, Dept of Neurology	Gdansk		Poland	80-952
37	Krakowska Akademia Neurologii Sp z o.o. Centrum Neurologii Klinicznej	Krakow		Poland	31-505
38	III Szpital Miejski w Lodzi im. Dr K. Jonschera	Lodz		Poland	93-113
39	Samodzielny Publiczny Centralny Szpital Kliniczny	Warszawa		Poland	02-097

Sponsors and Collaborators

• Grifols Therapeutics LLC

Investigators

None specified.

Study Documents (Full-Text)

• Statistical Analysis Plan - Apr 12, 2019
• Study Protocol - Dec 23, 2016

More Information

Publications

None provided.

• Responsible Party: Grifols Therapeutics LLC
• ClinicalTrials.gov Identifier: NCT02473965
• Other Study ID Numbers: GTI1306
• First Posted: Jun 17, 2015
• Last Update Posted: Mar 30, 2020
• Last Verified: Mar 1, 2020

• Additional relevant MeSH terms: Myasthenia Gravis; Muscle Weakness

Study Results

Participant Flow

Recruitment Details	Sixty subjects with a confirmed diagnosis of generalized myasthenia gravis (MG) historically meeting the clinical criteria for MG diagnosis Class II, III, IV or V of the Myasthenia Gravis Foundation of America were randomized. The study was conducted in 8 countries from November 2015 to February 2019.
Pre-assignment Detail	Subjects had symptoms at screening controlled by corticosteroids (CS), had been dependent on systemic CS for at least the preceding 3 months and had received a stable dose of CS for at least 1 month immediately prior to the screening visit.

Arm/Group Title	IGIV-C	Placebo
Arm/Group Description	Investigational Product (IP) Run-in Maintenance Phase (Weeks 0-9): Subjects randomized to receive Immune Globulin (Human), 10% Caprylate/Chromatography Purified (IGIV-C) were given a loading dose of 2 grams per kilogram (g/kg) by intravenous (IV) infusion at Baseline/Week 0 (Visit 1) and 2 maintenance doses of 1 g/kg at Weeks 3 and 6 (Visits 2 and 3). The CS dose remained stable in this phase. CS Tapering/IP Maintenance Phase (Weeks 9-36): Subjects continued to receive maintenance doses (1 g/kg) every third week from Week 9 (Visit 4) up to Week 36 (Visit 13). Prescribed CS tapering began at Week 9 (Visit 4) after the third maintenance dose of IGIV-C was given. The last CS dose reduction was at Week 36 (Visit 13). Safety/Follow-up Phase: Follow-up visits were at Weeks 39, 42 and 45 (Visits 14, 15 and 16). If considered medically indicated, the investigator could increase the CS dose after the Week 39 (Visit 14) assessments.	IP Run-in Maintenance Phase (Weeks 0-9): Subjects randomized to receive placebo were given 3 doses of placebo matching IGIV-C by IV infusion at Baseline/Week 0 (Visit 1) and at Weeks 3 and 6 (Visits 2 and 3). The CS dose remained stable in this phase. CS Tapering/IP Maintenance Phase (Weeks 9-36): Subjects continued to receive maintenance doses of placebo matching IGIV-C every third week from Week 9 (Visit 4) up to Week 36 (Visit 13). Prescribed CS tapering began at Week 9 (Visit 4) after the third maintenance dose of placebo was given. The last CS dose reduction was at Week 36 (Visit 13). Safety/Follow-up Phase: Follow-up visits were at Weeks 39, 42 and 45 (Visits 14, 15 and 16). If considered medically indicated, the investigator could increase the CS dose after the Week 39 (Visit 14) assessments.
Period Title: Overall Study
STARTED	30	30
COMPLETED	18	20
NOT COMPLETED	12	10

Baseline Characteristics

Arm/Group Title	IGIV-C	Placebo	Total Title
Arm/Group Description	IP Run-in Maintenance Phase (Weeks 0-9): Subjects randomized to receive IGIV-C were given a loading dose of 2 g/kg by IV infusion at Baseline/Week 0 (Visit 1) and 2 maintenance doses of 1 g/kg at Weeks 3 and 6 (Visits 2 and 3). The CS dose remained stable in this phase. CS Tapering/IP Maintenance Phase (Weeks 9-36): Subjects continued to receive maintenance doses (1 g/kg) every third week from Week 9 (Visit 4) up to Week 36 (Visit 13). Prescribed CS tapering began at Week 9 (Visit 4) after the third maintenance dose of IGIV-C was given. The last CS dose reduction was at Week 36 (Visit 13). Safety/Follow-up Phase: Follow-up visits were at Weeks 39, 42 and 45 (Visits 14, 15 and 16). If considered medically indicated, the investigator could increase the CS dose after the Week 39 (Visit 14) assessments.	IP Run-in Maintenance Phase (Weeks 0-9): Subjects randomized to receive placebo were given 3 doses of placebo matching IGIV-C by IV infusion at Baseline/Week 0 (Visit 1) and at Weeks 3 and 6 (Visits 2 and 3). The CS dose remained stable in this phase. CS Tapering/IP Maintenance Phase (Weeks 9-36): Subjects continued to receive maintenance doses of placebo matching IGIV-C every third week from Week 9 (Visit 4) up to Week 36 (Visit 13). Prescribed CS tapering began at Week 9 (Visit 4) after the third maintenance dose of placebo was given. The last CS dose reduction was at Week 36 (Visit 13). Safety/Follow-up Phase: Follow-up visits were at Weeks 39, 42 and 45 (Visits 14, 15 and 16). If considered medically indicated, the investigator could increase the CS dose after the Week 39 (Visit 14) assessments.
Overall Participants	30	30	60
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47.6 (16.99)	48.5 (14.51)	48.1 (15.67)
Sex: Female, Male (Count of Participants)
Female	16 53.3%	18 60%	34 56.7%
Male	14 46.7%	12 40%	26 43.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	2 6.7%	2 3.3%
Not Hispanic or Latino	30 100%	28 93.3%	58 96.7%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	3 10%	2 6.7%	5 8.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	1 3.3%	1 1.7%
White	27 90%	27 90%	54 90%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Baseline Daily Prednisone Equivalent Dose Level Stratification Categories (Count of Participants)
15 mg to 40 mg/day	29 96.7%	28 93.3%	57 95%
41 to 60 mg/day	1 3.3%	2 6.7%	3 5%
Baseline QMG Total Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	12.1 (6.98)	11.2 (6.48)	11.6 (6.69)

Outcome Measures

1. Primary Outcome

Title	Percent of Subjects Achieving a 50% or Greater Reduction in CS Dose (Prednisone or Equivalent) From Baseline to Week 39
Description	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.
Time Frame	Baseline/Week 0 (Visit 1) and Week 39 (Visit 14).

Outcome Measure Data

Analysis Population Description

The mITT population included all randomized subjects who received at least 1 dose of study medication. Subjects were classified according to randomized treatment.

Arm/Group Title	IGIV-C	Placebo
Arm/Group Description	IP Run-in Maintenance Phase (Weeks 0-9): Subjects randomized to receive IGIV-C were given a loading dose of 2 g/kg by IV infusion at Baseline/Week 0 (Visit 1) and 2 maintenance doses of 1 g/kg at Weeks 3 and 6 (Visits 2 and 3). The CS dose remained stable in this phase. CS Tapering/IP Maintenance Phase (Weeks 9-36): Subjects continued to receive maintenance doses (1 g/kg) every third week from Week 9 (Visit 4) up to Week 36 (Visit 13). Prescribed CS tapering began at Week 9 (Visit 4) after the third maintenance dose of IGIV-C was given. The last CS dose reduction was at Week 36 (Visit 13). Safety/Follow-up Phase: Follow-up visits were at Weeks 39, 42 and 45 (Visits 14, 15 and 16). If considered medically indicated, the investigator could increase the CS dose after the Week 39 (Visit 14) assessments.	IP Run-in Maintenance Phase (Weeks 0-9): Subjects randomized to receive placebo were given 3 doses of placebo matching IGIV-C by IV infusion at Baseline/Week 0 (Visit 1) and at Weeks 3 and 6 (Visits 2 and 3). The CS dose remained stable in this phase. CS Tapering/IP Maintenance Phase (Weeks 9-36): Subjects continued to receive maintenance doses of placebo matching IGIV-C every third week from Week 9 (Visit 4) up to Week 36 (Visit 13). Prescribed CS tapering began at Week 9 (Visit 4) after the third maintenance dose of placebo was given. The last CS dose reduction was at Week 36 (Visit 13). Safety/Follow-up Phase: Follow-up visits were at Weeks 39, 42 and 45 (Visits 14, 15 and 16). If considered medically indicated, the investigator could increase the CS dose after the Week 39 (Visit 14) assessments.
Measure Participants	30	30
All subjects	60.0	63.3
15 mg to 40 mg/day	58.6	60.7
41 mg to 60 mg/day	100.0	100.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IGIV-C, Placebo
	Comments	An unstratified analysis using Fisher's exact test was used for treatment comparison without adjustment for stratified baseline prednisone equivalent dose level due to the small cell size. The odds ratio and confidence intervals are calculated overall (i.e. all mITT subjects).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=1.00
	Comments	The statistical inference was tested as 2-sided with alpha=0.05.
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.868
	Confidence Interval	(2-Sided) 95%; 0.270 to 2.787
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Mean Percent Change in Daily CS Dose (Prednisone or Equivalent) From Baseline to Week 39
Description	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.
Time Frame	Baseline/Week 0 (Visit 1) and Week 39 (Visit 14).

Outcome Measure Data

Analysis Population Description

The mITT population included all randomized subjects who received at least 1 dose of study medication. Subjects were classified according to randomized treatment.

Arm/Group Title	IGIV-C	Placebo
Arm/Group Description	IP Run-in Maintenance Phase (Weeks 0-9): Subjects randomized to receive IGIV-C were given a loading dose of 2 g/kg by IV infusion at Baseline/Week 0 (Visit 1) and 2 maintenance doses of 1 g/kg at Weeks 3 and 6 (Visits 2 and 3). The CS dose remained stable in this phase. CS Tapering/IP Maintenance Phase (Weeks 9-36): Subjects continued to receive maintenance doses (1 g/kg) every third week from Week 9 (Visit 4) up to Week 36 (Visit 13). Prescribed CS tapering began at Week 9 (Visit 4) after the third maintenance dose of IGIV-C was given. The last CS dose reduction was at Week 36 (Visit 13). Safety/Follow-up Phase: Follow-up visits were at Weeks 39, 42 and 45 (Visits 14, 15 and 16). If considered medically indicated, the investigator could increase the CS dose after the Week 39 (Visit 14) assessments.	IP Run-in Maintenance Phase (Weeks 0-9): Subjects randomized to receive placebo were given 3 doses of placebo matching IGIV-C by IV infusion at Baseline/Week 0 (Visit 1) and at Weeks 3 and 6 (Visits 2 and 3). The CS dose remained stable in this phase. CS Tapering/IP Maintenance Phase (Weeks 9-36): Subjects continued to receive maintenance doses of placebo matching IGIV-C every third week from Week 9 (Visit 4) up to Week 36 (Visit 13). Prescribed CS tapering began at Week 9 (Visit 4) after the third maintenance dose of placebo was given. The last CS dose reduction was at Week 36 (Visit 13). Safety/Follow-up Phase: Follow-up visits were at Weeks 39, 42 and 45 (Visits 14, 15 and 16). If considered medically indicated, the investigator could increase the CS dose after the Week 39 (Visit 14) assessments.
Measure Participants	30	30
Least Squares Mean (Standard Error) [percent change]	-52.57 (8.835)	-54.15 (8.835)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IGIV-C, Placebo
	Comments	Treatment comparison of percent change in daily CS dose from baseline to Week 39. The Analysis of Covariance model included the percent change from baseline in daily CS dose as the dependent variable, treatment as a fixed effect and baseline daily CS dose as covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=0.900
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	1.58
	Confidence Interval	(2-Sided) 95%; -23.52 to 26.68
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 12.536
	Estimation Comments

3. Secondary Outcome

Title	Median Time to First Episode of MG Worsening
Description	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.
Time Frame	From Baseline/Week 0 (Visit 1) to Week 39 (Visit 14).

Outcome Measure Data

Analysis Population Description

The mITT population included all randomized subjects who received at least 1 dose of study medication. Subjects were classified according to randomized treatment.

Arm/Group Title	IGIV-C	Placebo
Arm/Group Description	IP Run-in Maintenance Phase (Weeks 0-9): Subjects randomized to receive IGIV-C were given a loading dose of 2 g/kg by IV infusion at Baseline/Week 0 (Visit 1) and 2 maintenance doses of 1 g/kg at Weeks 3 and 6 (Visits 2 and 3). The CS dose remained stable in this phase. CS Tapering/IP Maintenance Phase (Weeks 9-36): Subjects continued to receive maintenance doses (1 g/kg) every third week from Week 9 (Visit 4) up to Week 36 (Visit 13). Prescribed CS tapering began at Week 9 (Visit 4) after the third maintenance dose of IGIV-C was given. The last CS dose reduction was at Week 36 (Visit 13). Safety/Follow-up Phase: Follow-up visits were at Weeks 39, 42 and 45 (Visits 14, 15 and 16). If considered medically indicated, the investigator could increase the CS dose after the Week 39 (Visit 14) assessments.	IP Run-in Maintenance Phase (Weeks 0-9): Subjects randomized to receive placebo were given 3 doses of placebo matching IGIV-C by IV infusion at Baseline/Week 0 (Visit 1) and at Weeks 3 and 6 (Visits 2 and 3). The CS dose remained stable in this phase. CS Tapering/IP Maintenance Phase (Weeks 9-36): Subjects continued to receive maintenance doses of placebo matching IGIV-C every third week from Week 9 (Visit 4) up to Week 36 (Visit 13). Prescribed CS tapering began at Week 9 (Visit 4) after the third maintenance dose of placebo was given. The last CS dose reduction was at Week 36 (Visit 13). Safety/Follow-up Phase: Follow-up visits were at Weeks 39, 42 and 45 (Visits 14, 15 and 16). If considered medically indicated, the investigator could increase the CS dose after the Week 39 (Visit 14) assessments.
Measure Participants	30	30
Median (Inter-Quartile Range) [weeks]	NA	NA

Adverse Events

Time Frame	Treatment emergent adverse events (TEAEs) were collected from Baseline/Week 0 to Week 39 (approximately 9 months).
Adverse Event Reporting Description	TEAEs are presented for the Safety population which consisted of all randomized subjects who received any amount of study medication. Subjects were classified according to the treatment received.
Arm/Group Title	IGIV-C		Placebo
Arm/Group Description	IP Run-in Maintenance Phase (Weeks 0-9): Subjects randomized to receive IGIV-C were given a loading dose of 2 g/kg by IV infusion at Baseline/Week 0 (Visit 1) and 2 maintenance doses of 1 g/kg at Weeks 3 and 6 (Visits 2 and 3). The CS dose remained stable in this phase. CS Tapering/IP Maintenance Phase (Weeks 9-36): Subjects continued to receive maintenance doses (1 g/kg) every third week from Week 9 (Visit 4) up to Week 36 (Visit 13). Prescribed CS tapering began at Week 9 (Visit 4) after the third maintenance dose of IGIV-C was given. The last CS dose reduction was at Week 36 (Visit 13). Safety/Follow-up Phase: Follow-up visits were at Weeks 39, 42 and 45 (Visits 14, 15 and 16). If considered medically indicated, the investigator could increase the CS dose after the Week 39 (Visit 14) assessments.		IP Run-in Maintenance Phase (Weeks 0-9): Subjects randomized to receive placebo were given 3 doses of placebo matching IGIV-C by IV infusion at Baseline/Week 0 (Visit 1) and at Weeks 3 and 6 (Visits 2 and 3). The CS dose remained stable in this phase. CS Tapering/IP Maintenance Phase (Weeks 9-36): Subjects continued to receive maintenance doses of placebo matching IGIV-C every third week from Week 9 (Visit 4) up to Week 36 (Visit 13). Prescribed CS tapering began at Week 9 (Visit 4) after the third maintenance dose of placebo was given. The last CS dose reduction was at Week 36 (Visit 13). Safety/Follow-up Phase: Follow-up visits were at Weeks 39, 42 and 45 (Visits 14, 15 and 16). If considered medically indicated, the investigator could increase the CS dose after the Week 39 (Visit 14) assessments.
All Cause Mortality
	IGIV-C		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/30 (3.3%)		2/30 (6.7%)
Serious Adverse Events
	IGIV-C		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/30 (13.3%)		6/30 (20%)
Cardiac disorders
Cardiac arrest	0/30 (0%)	0	1/30 (3.3%)	1
Infections and infestations
Pneumonia	0/30 (0%)	0	1/30 (3.3%)	1
Sepsis	0/30 (0%)	0	1/30 (3.3%)	1
Subcutaneous abscess	0/30 (0%)	0	1/30 (3.3%)	1
Pneumonia staphylococcal	0/30 (0%)	0	1/30 (3.3%)	1
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain	0/30 (0%)	0	1/30 (3.3%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Renal cell carcinoma	0/30 (0%)	0	1/30 (3.3%)	1
Nervous system disorders
Myasthenia gravis	4/30 (13.3%)	4	1/30 (3.3%)	1
Myasthenia gravis crisis	1/30 (3.3%)	1	2/30 (6.7%)	2
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	0/30 (0%)	0	1/30 (3.3%)	1
Other (Not Including Serious) Adverse Events
	IGIV-C		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/30 (70%)		24/30 (80%)
Gastrointestinal disorders
Nausea	5/30 (16.7%)	6	1/30 (3.3%)	1
Vomiting	2/30 (6.7%)	3	0/30 (0%)	0
Diarrhoea	1/30 (3.3%)	1	3/30 (10%)	3
General disorders
Asthenia	2/30 (6.7%)	2	1/30 (3.3%)	1
Fatigue	2/30 (6.7%)	2	2/30 (6.7%)	3
Non-cardiac chest pain	2/30 (6.7%)	2	0/30 (0%)	0
Oedema peripheral	2/30 (6.7%)	2	3/30 (10%)	4
Infections and infestations
Upper respiratory tract infection	6/30 (20%)	7	3/30 (10%)	3
Influenza	2/30 (6.7%)	2	2/30 (6.7%)	2
Nasopharyngitis	2/30 (6.7%)	2	5/30 (16.7%)	6
Pneumonia	2/30 (6.7%)	2	1/30 (3.3%)	1
Viral infection	2/30 (6.7%)	2	1/30 (3.3%)	1
Bronchitis	1/30 (3.3%)	1	2/30 (6.7%)	2
Urinary tract infection	1/30 (3.3%)	1	3/30 (10%)	4
Investigations
Blood pressure increased	2/30 (6.7%)	5	0/30 (0%)	0
Red blood cell count decreased	2/30 (6.7%)	3	0/30 (0%)	0
White blood cell count decreased	2/30 (6.7%)	2	0/30 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	4/30 (13.3%)	4	6/30 (20%)	7
Arthritis	2/30 (6.7%)	2	0/30 (0%)	0
Musculoskeletal pain	2/30 (6.7%)	2	1/30 (3.3%)	2
Myalgia	2/30 (6.7%)	2	2/30 (6.7%)	2
Back pain	0/30 (0%)	0	5/30 (16.7%)	6
Nervous system disorders
Headache	10/30 (33.3%)	15	3/30 (10%)	3
Myasthenia gravis	7/30 (23.3%)	7	2/30 (6.7%)	2
Psychiatric disorders
Depression	2/30 (6.7%)	2	0/30 (0%)	0
Reproductive system and breast disorders
Benign prostatic hyperplasia	2/30 (6.7%)	2	1/30 (3.3%)	1
Respiratory, thoracic and mediastinal disorders
Cough	3/30 (10%)	3	2/30 (6.7%)	2
Skin and subcutaneous tissue disorders
Urticaria	3/30 (10%)	3	0/30 (0%)	0
Rash	0/30 (0%)	0	2/30 (6.7%)	2
Vascular disorders
Hypertension	2/30 (6.7%)	2	1/30 (3.3%)	1

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.