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CLINICAL RESEARCH ARTICLE
Efficacy and safety of maintenance intravenous
immunoglobulin in generalized myasthenia gravis patients
with acetylcholine receptor antibodies: A multicenter,
double-blind, placebo-controlled trial
Vera Bril MD
1
| Tomasz Berkowicz MD
2
| Andrzej Szczudlik MD
3
|
Michael W. Nicolle MD
4
| Josef Bednarik MD
5
| Petr Hon MD
6
|
Antanas Vaitkus MD
7
| Tuan Vu MD
8
| Csilla Rozsa MD, PhD
9
|
Tim Magnus MD
10
| Gyula Panczel PhD
11
| Toomas Toomsoo MD, PhD
12
|
Mamatha Pasnoor MD
13
| Tahseen Mozaffar MD
14
| Miriam Freimer MD
15
|
Ulrike Reuner MD
16
| László Vécsei MD
17
| Nizar Souayah MD
18
|
Todd Levine MD
19
| Robert M. Pascuzzi MD
20
| Marinos C. Dalakas MD
21,22
|
Michael Rivner MD
23
| Rhonda Griffin MS
24
| Montse Querolt Coll MS
25
|
Elsa Mondou MD
24
Correspondence
Vera Bril, Toronto General Hospital,
200 Elizabeth St., 5EC, Room 309, Toronto,
ON M5G 2C4, Canada.
Email: vera.bril@utoronto.ca
Funding information
Grifols Therapeutics LLC
Abstract
Introduction/Aims: Prospective, randomized, controlled trials of intravenous immu-
noglobulin (IVIG) maintenance therapy in myasthenia gravis (MG) are lacking. In this
trial, we evaluated the safety and efficacy of caprylate/chromatography-purified
IVIG; (IGIV-C) in patients with generalized MG undergoing standard care.
Methods: Sixty-two patients enrolled in this phase 2, multicenter, international, ran-
domized trial (1:1 IGIV-C [2 g/kg loading dose; 1 g/kg every 3 weeks through week
21] or placebo). Efficacy was assessed by changes in Quantitative MG (QMG) score
at week 24 versus baseline (primary endpoint) and percentage of patients with clini-
cal improvement in QMG, MG Composite (MGC), and MG-Activities of Daily Living
(MG-ADL) scores (secondary endpoints). Safety assessments reported all adverse
events (AEs).
Abbreviations: AChR, acetylcholine receptor; AE, adverse event; CIDP, chronic inflammatory demyelinating polyneuropathy; CS, corticosteroid; gMG, generalized myasthenia gravis; IVIG,
intravenous immunoglobulin; IGIV-C, caprylate/chromatography-purified intravenous immunoglobulin; I/I, immunosuppressant/immunomodulator; ITT, intent to treat; MG, myasthenia gravis;
MG-ADL, Myasthenia Gravis Activities of Daily Living; MGC, Myasthenia Gravis Composite; MGFA, Myasthenia Gravis Foundation of America; MG-QOL, Myasthenia Gravis Quality of Life;
mITT, modified intent to treat; NA, not applicable; ND, not determined; QMG, Quantitative Myasthenia Gravis; SAE, serious adverse event; TEAE, treatment-emergent adverse event; USP, US
Pharmacopeia.
Previous presentation: The material in this manuscript has not been presented as a whole or in part at a national or international meeting.
For affiliations refer to page 52
Received: 24 October 2023 Revised: 14 October 2024 Accepted: 16 October 2024
DOI: 10.1002/mus.28289
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited and is not used for commercial purposes.
© 2024 The Author(s). Muscle & Nerve published by Wiley Periodicals LLC.
Muscle & Nerve. 2025;71:43–54. wileyonlinelibrary.com/journal/mus 43
Results: The change in QMG at 24 weeks was 5.1 for IGIV-C and 3.1 for placebo
(p=.187). Seventy percent of patients in the IGIV-C group had improvement in MG-
ADL (≥2-point decrease) versus 40.6% in the placebo group (p=.025). Patients
showing clinical improvement in QMG and MGC (≥3-point decrease) were 70.0% for
IGIV-C versus 59.4% for placebo (p=.442) and 60.0% for IGIV-C versus 53.1% for
placebo (p=.610). IGIV-C was well tolerated; serious AEs were similar between
arms. Three of four MG exacerbations requiring hospitalizations occurred in the
IGIV-C arm with one death.
Discussion: Several efficacy parameters showed numerical results greater than those
seen in the placebo group. This was a small study and may have been underpowered
to see significant differences. Additional studies may be warranted to fully determine
the efficacy of IVIG maintenance therapy in MG.
KEYWORDS
autoimmune disease, intravenous immunoglobulin, myasthenia gravis, neuromuscular disease
1|INTRODUCTION
Intravenous immunoglobulin (IVIG) has been proven safe and effective
for several conditions: primary immunodeficiency, idiopathic thrombo-
cytopenic purpura, chronic inflammatory demyelinating polyneuropa-
thy (CIDP),
1
and other indications in various countries. IVIG has also
been shown to be efficacious for short-term treatment of acute exac-
erbations of myasthenia gravis (MG).
2–5
However, IVIG maintenance
therapy for MG has not been extensively studied.
6,7
IVIG can improve strength in patients with MG and is used as res-
cue therapy for MG exacerbation and crisis,
5,8,9
but data supporting
the efficacy of IVIG as maintenance therapy for MG are lacking.
Although there have been several studies assessing the efficacy of
IVIG in MG in acute
2–4,10,11
and maintenance settings,
12–18
few have
been controlled trials with none in the maintenance setting.
6,7
These
controlled trials involved small numbers of patients (n=12 and
n=15) and have limitations (e.g., premature termination due to lack
of IVIG
7
or a crossover design with plasma exchange).
6
There is still a
need for prospective, randomized, controlled trials of IVIG as acute
and maintenance therapy in MG.
This is a prospective, randomized, double-blind, placebo-
controlled trial of IVIG maintenance therapy in MG. In the current
study, we assessed the safety and efficacy of immune globulin 10%
caprylate/chromatography purified (IGIV-C) in symptomatic patients
with generalized MG (gMG) being treated with standard-of-care
therapy.
2|METHODS
2.1 |Study design and objectives
The study consisted of screening (weeks 3–0), baseline and loading
dose (week 0), and maintenance dosing (weeks 3–21) with the primary
endpoint evaluated at week 24 (Figure S1). Patients were randomized
1:1 to IGIV-C or placebo treatment and received intravenous treat-
ment every 3 weeks (double-blind). The method for assigning patients
to treatment groups is described in the Data S1.
Randomization was stratified by the patient's MG therapy at random-
ization. The strata were as follows: (1) cholinesterase inhibitors only;
(2) corticosteroid (CS) as the only immunosuppressant/immunomodulator
(cholinesterase inhibitors allowed as concomitant medication); and (3) any
non-CS immunosuppressant/immunomodulator alone or in combination
with other MG medications (including CS and cholinesterase inhibitors).
The study protocol was approved by institutional review boards,
ethics committees, or research ethics boards at all participating insti-
tutions. The study was authorized by regulatory authorities in all
participating countries. Written informed consent was obtained from
all subjects. All local regulations, international standards of Good
Clinical Practice, and the Declaration of Helsinki were followed in
this study. The full protocol and statistical plan can be accessed at
https://clinicaltrials.gov/ct2/show/NCT02473952.
2.2 |Selection of study patients
Patients eligible for this study were recruited in 25 centers across
Europe (Belgium, Czech Republic, Estonia, France, Germany, Hungary,
Lithuania, and Poland) and North America (Canada and the
United States). Patients were male or female, 18–85 years old, posi-
tive for anti-AChR antibodies, and with confirmed diagnosis of gMG—
MG Foundation of America (MGFA) classification: Class II, III, or IVa.
19
At screening, potential participants were required to have a QMG
score ≥10 while receiving standard care for MG. Standard of care was
defined as follows: (1) cholinesterase inhibitor monotherapy (pyridos-
tigmine/equivalent) with stable dosing ≥2 weeks and no immunosup-
pressants (in Germany, patients on cholinesterase monotherapy were
not enrolled); (2) a cholinesterase inhibitor (stable dose ≥2 weeks)
44 BRIL ET AL.
and/or only one of the following (stable dosing for the indicated
period): prednisone (≤60 mg/day/equivalent) ≥2 months, azathioprine
≥6 months, mycophenolate mofetil ≥6 months, methotrexate
≥6 months, and cyclosporine or tacrolimus ≥3 months; and (3) cholin-
esterase inhibitor (≥2 weeks) and/or prednisone (≤60 mg/day/equiva-
lent, ≥1 month) and only one of the following: azathioprine,
mycophenolate mofetil, methotrexate, or cyclosporine or tacrolimus
(as described above).
Patients were excluded if they had received cyclophosphamide or
any immunosuppressant not stated in the inclusion criteria in the last
6 months. Patients with a change in their MG treatment regimen or
>2-point change in QMG score between screening (week 3) and
baseline (week 0), a myasthenic crisis in the last month, or thymec-
tomy in the last 6 months were excluded. Patients were also excluded
for any malignancy in the last 5 years other than non-melanoma skin
cancers or in situ cervical cancer. A thymoma potentially requiring
treatment during the trial was also exclusionary. Other exclusionary
treatments and conditions are listed in the Data S1.
2.3 |Investigational product
The investigational product (IGIV-C) used in this trial was Gamunex-C
®
(immune globulin injection (human) 10% caprylate/chromatography
purified; Grifols Therapeutics LLC, Research Triangle Park, NC, USA).
1
The placebo treatment was an equal volume of normal saline (sterile
0.9% sodium chloride injection, USP) or equivalent.
2.4 |Treatments
The optimal dosing of IVIG for MG has not been determined. The
dose chosen for this study, a loading dose of 2 g/kg over 2–4 days,
was based on review articles showing that 2 g/kg was commonly
used
20,21
and could be safely administered over a minimum of
2 days.
2–4
This dosing was also similar to that used for other neuroim-
munological diseases, for example, Guillain–Barre syndrome and
CIDP.
22,23
The dosing used in this study was that used in the phase
3 ICE study of IGIV-C in CIDP.
23
Patients randomized to IGIV-C received a loading dose (2 g/kg) over
2 days at the baseline visit (week 0) (Figure S1). Maintenance doses (1 g/
kg over 1 day) were administered every 3 weeks through week 21. Lon-
ger administration periods (up to 4 days for loading and 2 days for main-
tenance doses) were allowed for higher doses due to higher body weight
(maximum dose 80 g/day) and to promote tolerability. Patients random-
ized to the placebo group were administered an equivalent volume of
normal saline (0.9% sodium chloride, USP). Administration of IGIV-C and
placebo was double-blinded. IGIV-C and placebo were prepared by an
unblinded pharmacist and visually masked to prevent the unblinding of
blinded site personnel and study participants during infusions.
The patient's concurrent MG medication regimen was held con-
stant throughout the study unless there was an urgent medical need,
the patient met the criteria for a treatment failure, or the patient had
intolerable adverse effects.
The last dose of IGIV-C or placebo was administered at week
21 (visit 8), and the primary endpoint was assessed at week 24 (visit
9). The week 24 visit was also the end-of-study visit.
2.5 |Efficacy assessments
The mean change in Quantitative MG (QMG) score
24
from baseline to
week 24 was the endpoint to evaluate the primary efficacy objective
of this study. A decrease in QMG score was indicative of clinical
improvement.
Three endpoints were set to evaluate the secondary efficacy objec-
tive: (1) percentage of patients who showed clinical improvement
(defined as ≥3-point decrease
25
) in QMG score at week 24 compared to
baseline; (2) percentage of patients who showed clinical improvement
(defined as ≥3-point decrease) in MG Composite (MGC) score
26,27
at
week 24 compared to baseline; (3) percentage of patients who showed
clinical improvement (defined as ≥2 point decrease) in MG-Activities of
Daily Living (MG-ADL) score
28
at week 24 compared to baseline.
In addition, a series of exploratory efficacy endpoints were set
that included the following: the percentage of patients who experi-
enced clinical improvement in QMG or MGC scores during the main-
tenance phase of the study (weeks 6, 9, 12, 15, 18, and 21); the time
to clinical improvement in QMG score; the time to treatment failure
(based on QMG score: ≥4-point increase from baseline at 2 consecu-
tive visits at or after week 9 [following administration of loading dose
and 2 maintenance study drug doses]); the change from baseline in
QMG and MGC scores during the maintenance phase and at the final
visit (MGC only); the percentage of patients showing clinical improve-
ment in MG-ADL at weeks 9 and 15; the change from baseline in
MG-ADL at weeks 9, 15, and 24; the MG Foundation of America
(MGFA) post-interventional change status at week 24 related to base-
line; and the change from baseline in the 15-item MG Quality-of-Life
(MG-QOL 15) score at weeks 9, 15, and 24.
2.6 |Safety assessments
Safety variables included reporting of all AEs. In addition, vital signs,
physical examinations, and blood hematology and chemistry were
recorded. An additional description of safety assessments is included
in the Data S1.
2.7 |Determination of sample size
Sample size determination is described in Data S1.
2.8 |Statistical analyses
A detailed description of the statistical analyses is included in the
Data S1. There was no adjustment for multiple comparisons/
multiplicity in this phase 2 proof-of-concept study.
BRIL ET AL.45
3|RESULTS
3.1 |Trial registration
The trial was registered on clinicaltrialsregister.eu (2014–003997-18)
and clinicaltrials.gov (identifier NCT02473952).
3.2 |Patient disposition
The first patient was enrolled on August 14, 2015, and the last patient
completed the study on January 26, 2018. Enrollment was ended
when the target was reached, and the study ended when the last
enrolled patient completed the study. A total of 79 patients were
screened, and 62 were randomized (intent-to-treat population—
Figure 1). The modified ITT (mITT) population (n=62) included all
randomized patients that received at least one dose of study medica-
tion (active or placebo). These 62 patients were included in efficacy
and AE analyses. Fifty-two (52) of these patients (83.9%) completed
all study visits: 28 (93.3%) in the IGIV-C group and 24 (75.0%) in the
placebo group. Two patients in the IGIV-C group withdrew due to MG
exacerbations. Eight patients in the placebo group discontinued from the
study (six withdrew consent, and two had MG exacerbations).
3.3 |Baseline characteristics of the treatment and
placebo groups
The baseline characteristics of both study groups are shown in
Table 1. The treatment groups were similar in terms of demographics,
MG status, and prior and present MG treatment (Table 1). The
placebo group had a higher percentage of female patients and those
less <65 years old than the IGIV-C group. In addition, the time since
diagnosis was longer in the placebo group than in the IGIV-C group.
MG assessments were comparable between the groups. A similar
proportion of patients had previously undergone thymectomy (56.7%
and 59.4%, for active and control arms, respectively).
3.4 |Primary and secondary efficacy endpoints
The change in QMG score from baseline at week 24, the primary end-
point, was not significantly different for the IGIV-C group and for the
placebo group (Table 2). For the secondary endpoints, there was no
evidence of a difference in the percentage of patients who showed
improvement (≥3-point decrease) in QMG or MGC scores at week
24 versus baseline for the IGIV-C group compared with the placebo
group (Table 2).
An apparent difference in the percentage of patients with a
clinically meaningful improvement (≥2-point decrease) in MG-ADL
score was observed in the IGIV-C group compared to the placebo
group.
3.5 |Exploratory efficacy endpoints
The percentage of patients showing clinical improvement in QMG
scores was higher, the change from baseline was larger in the IGIV-C
treatment group at all measured time points, and there was evidence
of a greater difference at weeks 9 and 21 (Figure 2A,B).
FIGURE 1 Disposition of subjects in a multicenter, randomized, double-blind, placebo-controlled study of the efficacy and safety of
intravenous immunoglobulin (10%, caprylate/chromatography-purified; IGIV-C) in patients with symptomatic myasthenia gravis. ITT, intent to
treat; mITT, modified intent to treat; PP, per protocol.
46 BRIL ET AL.
There was no evidence of a difference in the time to first clinical
improvement in the IGIV-C group versus the placebo group (see
Table 2). The percentage of patients with clinical improvement in
MGC scores and change from baseline were relatively constant over
time (Figure 3A). Similar results were seen in change from baseline in
MGC scores, with evidence of a larger difference between the treat-
ment groups at 9 weeks (Figure 3B).
The percentage of patients who showed improvement in MG-
ADL scores showed no apparent difference between the IGIV-C treat-
ment group and the placebo group.
TABLE 1 Demographics and baseline characteristics of the modified intent-to-treat study population.
Demographics IGIV-C (n=30) Placebo (n=32) Total (n=62)
Age (years)—mean (SD) 54.6 (17.1) 48.0 (13.7) 51.2 (15.6)
Age category (years)—n(%)
<65 20 (66.7) 29 (90.6) 49 (79.0)
≥65 10 (33.3) 3 (9.4) 13 (21.0)
Sex—n(%)
Female 14 (46.7) 19 (59.3) 33 (53.2)
Male 16 (53.3) 13 (40.6) 29 (46.8)
Race—n(%)
White (Caucasian) 29 (96.7) 30 (93.8) 59 (95.2)
Black (African American) 1 (3.3) 0 1 (1.6)
Asian 0 1 (3.1) 1 (1.6)
American Indian or Alaskan Native 0 0 0
Native Hawaiian or other Pacific Islander 0 1 (3.1) 1 (1.6)
Ethnicity—n(%)
Hispanic or Latino 2 (6.7) 3 (9.4) 5 (8.1)
Non-Hispanic or Latino 28 (93.3) 29 (90.6) 57 (91.9)
Geographic region—n(%)
North America 11 (36.7) 12 (37.5) 23 (37.1)
Europe 19 (63.3) 20 (62.5) 39 (62.9)
Screening weight (kg) - mean (SD) 86.4 (21.6) 81.1 (20.3) 83.7 (20.9)
Height (cm) - mean (SD) 172.1 (8.6) 170.0 (8.8) 171.0 (8.7)
Screening BMI (kg/m
2
) - M 29.1 (6.5) 27.9 (6.1) 28.5 (6.3)
Baseline
Time since MG diagnosis (years) - mean (SD) 8.1 (7.0) 11.3 (10.1) 9.8 (8.9)
MGFA classification—n(%)
Class IIa 11 (36.7) 9 (28.1) 20 (32.3)
Class IIb 5 (16.7) 5 (15.6) 10 (16.1)
Class IIIa 12 (40.0) 14 (43.8) 26 (41.9)
Class IIIb 1 (3.3) 3 (9.4) 4 (6.5)
Class Iva 1 (3.3) 1 (3.1) 2 (3.2)
Baseline QMG total score - mean (SD) 14.6 (2.8) 16.2 (4.5)
Baseline MG Composite total score - mean (SD) 14.3 (6.9) 16.8 (7.3)
Baseline MG-ADL total score - mean (SD) 7.4 (3.2) 7.8 (3.4)
Baseline MG-QOL 15 total score - mean (SD) 27.9 (14.4) 30.8 (15.0)
Stratification based on MG Regimen at screening - n(%)
Only ChEI 8 (26.7%) 10 (31.3%) 18 (29.0%)
CS only I/I 6 (20%) 4 (12.5%) 10 (16.1%)
Any non-CS I/I 16 (53.3%) 18 (56.3%) 34 (54.8%)
Abbreviations: ADL, Activities of Daily Living; ChEI, cholinesterase inhibitor; CS, corticosteroid; I/I, immunosuppressant/immunomodulator; IGIV-C,
caprylate/chromatography-purified IVIG; MG, myasthenia gravis; MGFA, Myasthenia Gravis Foundation of America; QMG, Quantitative Myasthenia
Gravis; QOL, Quality of Life; SD, standard deviation.
BRIL ET AL.47
There was no evidence of a difference between the treatment
groups in the mean decrease from baseline in MG-ADL score at
weeks 9, 15, and 24.
There was evidence of a larger change from baseline in the MG-
QOL 15 score (measured at weeks 9, 15, and 24) at week 24 (7.1
vs. 1.6; p=.032).
The analysis of MGFA post-interventional change in status at
week 24 compared to baseline showed that a higher percentage of
patients in the IGIV-C group were classified as improved compared to
the placebo group (Table 2).
3.6 |Subgroup analyses
Subgroup analysis of change from baseline QMG scores, stratified by
median overall baseline (entry) QMG score (<15 or ≥15), at week
24, showed no evidence of a difference between the IGIV-C group
(≥15 QMG =4.7; <15 QMG =4.6) and the placebo
group (≥15 =2.8; <15 QMG =2.6).
Subgroup analysis of the baseline MG treatment regimen showed
that for the regimen containing a non-corticosteroid immunosuppressant/
immunomodulator, there was no evidence of a change from baseline in
QMG score for this subgroup between the IGIV-C and placebo groups
(Figure 4). The other 2 strata were not of sufficient size for analysis.
3.7 |Safety endpoints
IGIV-C was well tolerated. A similar percentage of patients in the
IGIV-C treatment group experienced at least one treatment-emergent
AE (TEAE) as in the placebo group. The two most frequently reported
TEAEs were headache and nasopharyngitis (Table 3). Most TEAEs
were mild or moderate in both treatment groups. Few TEAEs were
reported as severe for IGIV-C or placebo (Table 3).
TEAEs considered by the investigator to be potentially related to
treatment were more common in the IGIV-C group (53.3% of patients)
than in the placebo group (25.0% of patients). The perceived relation-
ship of TEAEs to the study medications is shown in Table 3.
The percentage of patients experiencing serious AEs (SAEs) was
similar in the IGIV-C group (16.7%; n=5/30) and the placebo group
(12.5%; n=4/32). MG exacerbation/relapse/worsening occurred in
three patients in the IGIV-C group (one evolving to MG crisis) and one
patient in the placebo group. Three of the four MG exacerbations
requiring hospitalization and intensive management occurred in sub-
jects in the IGIV-C arm and one in the placebo arm.
Two patients in each treatment group experienced MG AEs that
led to discontinuation from the study. One death occurred in the
IGIV-C treatment group. At the week 24 visit, the patient was hospi-
talized for a myasthenic crisis requiring mechanical ventilation. The
patient developed pneumonia and Staphylococcus aureus septicemia
and died due to cardiopulmonary failure 15 days later.
No clinically significant overall changes in laboratory values were
seen in either treatment group, but shifts from normal baseline values
to low values for hemoglobin, hematocrit, and erythrocyte count were
more common in the IGIV-C group than in the placebo group; these
effects were usually transient.
Six patients in the IGIV-C treatment group and four patients in the
placebo group had laboratory TEAEs. None were considered SAEs.
In the IGIV-C treatment group, 10 patients met the predefined
parameters in the algorithm for hemolysis. Seven were not overtly
TABLE 2 Primary, secondary, and exploratory endpoints for the effects of IGIV-C.
L
IGIV-C
(n=30)
Placebo
(n=32) Mean difference pvalue
Primary endpoint
QMG score—Δfrom baseline (least squares mean ± SE; last observation carried
forward)
5.1 ± 1.1 3.1 ± 1.1 2.0 ± 1.5 .187
Secondary endpoints Risk ratio
(95% CI)
QMG score—n(%) Pt with clinical improvement 21/30 (70.0) 19/32 (59.4) 1.16 (0.80, 1.68) .442
MG composite—n(%) Pt with clinical improvement 18/30 (60.0) 17/32 (53.1) 1.12 (0.73, 1.73) .610
MG-ADL—n(%) Pt with clinical improvement 21/30 (70.0) 13/32 (40.6) 1.70 (1.06, 2.73) .025
Exploratory endpoints
Time to first clinical improvement (weeks: median, IQR) 6.1 (3.1, 15.1) 9.3 (6.0, 24.1) ND .195
Time to treatment failure (weeks) NA NA NA NA
MGFA post-interventional Δin status - n (%)
Improved 20 (71.4) 13 (54.2) NA
Unchanged 7 (25.0) 9 (37.5) ND NA
Worse 1 (3.6) 2 (8.3) ND NA
Abbreviations: ADL, Activities of Daily Living; IGIV-C, caprylate/chromatography-purified IVIG; MG, myasthenia gravis; MGFA, Myasthenia Gravis
Foundation of America; NA, not applicable; ND, not determined; QMG, Quantitative Myasthenia Gravis.
48 BRIL ET AL.
anemic (hemoglobin values within normal limits), and three had
treatment-emergent anemia. One case was reported as an AE. In the
placebo group, no incidence of a positive direct antiglobulin test was
accompanied by other markers of hemolysis.
4|DISCUSSION
In this study, the effect of IGIV-C on the primary efficacy endpoint
was not statistically significant. The absolute change in QMG score in
the placebo group in this study (3.1) was larger than the placebo-
induced change in similar studies investigating treatments for MG
(1.6 and 2.37),
29,30
but similar to the placebo group in a study of
tacrolimus in MG (3.3).
31
These differences in QMG score changes
may be due to dissimilarities in the study populations in terms of
demographics, disease severity at baseline, baseline regimen, and
other factors.
It should also be pointed out that the clinical significance of the
QMG score change depends on MG severity at baseline. According to
Katzberg et al., a 3-point change is clinically significant for severe MG
FIGURE 2 (A) Percentage of patients showing improvement in Quantitative Myasthenia Gravis (QMG) score in patients treated with
caprylate/chromatography-purified IVIG (IGIV-C) or placebo (LOCF). Improvement was defined as at least a three-point decrease in QMG total
score. For IGIV-C, n=30 patients, and for placebo, n=32 patients.*p< .05 ( p=.029 at week 9 and p=.005 at week 21). (B) Change from
baseline in Quantitative Myasthenia Gravis (QMG) score in patients treated with caprylate/chromatography-purified IVIG (IGIV-C) or placebo. For
IGIV-C, n=30 patients, and for placebo, n=32 patients. Data shown are mean ± standard deviation. Treatment group comparisons showed
significant differences between the groups at week 9 and week 21 ( p< .05: p=.023 at week 9 and p=.025 at week 21).
BRIL ET AL.49
(QMG >16).
24,25
Since baseline QMG score in our patient population
was on the threshold of severe MG (14.6 in the IGIV-C group and
16.2 in the placebo group), we cannot discount the clinical relevance
of the observed 2-point change in the IVG-C group compared to the
placebo group (5.1 improvement vs. 3.1, respectively).
There was an apparent difference in the percentage of patients
with a two-point decrease in MG-ADL between the IGIV-C group and
the placebo group, although there was no adjustment for multiple
comparisons. MGL-ADL is a robust and validated tool for use in MG
clinical trials.
32
Subgroup analysis showed that the change in QMG from baseline
in the subgroup with a non-corticosteroid immunosuppressant/
immunomodulator in their baseline regimen was greater in the IGIV-C
group than in the placebo group—a clinically meaningful difference.
The observation warrants consideration for further research.
In summary, there were several efficacy parameters in this study
that showed numerical results greater than those seen in the placebo
group. Since this was a relatively small study, it is possible that it may
have been underpowered to see a significant difference between
arms in QMG change from baseline. However, what is more likely is
FIGURE 3 (A) Percentage of patients showing improvement in myasthenia gravis (MG) composite score in patients treated with caprylate/
chromatography-purified IVIG (IGIV-C) or placebo (LOCF). Improvement was defined as at least a three-point decrease in MG Composite score.
For IGIV-C, n=30 patients, and for placebo, n=32 patients. (B) Change from baseline in Myasthenia Gravis (MG) Composite score in patients
treated with caprylate/chromatography-purified IVIG (IGIV-C) or placebo. For IGIV-C, n=30 patients, and for placebo, n=32 patients. Data
shown are mean ± standard deviation. Treatment group comparisons showed a significant difference only at week 9 ( p=.042).
50 BRIL ET AL.
FIGURE 4 Change from baseline in Quantitative Myasthenia Gravis (QMG) score in patients treated with caprylate/chromatography-purified
IVIG (IGIV-C) or placebo (LOCF). For this analysis, patients were analyzed as a priori stratified by baseline treatment regimen: cholinesterase
inhibitor (ChEI) only, corticosteroid (CS) as the only immunosuppressant/immunomodulator (I/I), or non-CS I/I. For the ChEI-only subgroup:
IGIV-C n=8 and placebo n=10; for the CS-only I/I subgroup: IGIV-C n=6 and placebo n=4; and for the non-CS I/I subgroup: IGIV-C n=16
and placebo n=18.
TABLE 3 Summary of treatment emergent adverse events (TEAEs).
IGIV-C (n=30) Placebo (n=32)
Patients with any TEAE—n(%) 22 (73.3) 22 (68.8)
Total number of TEAEs—n142 71
Patients with any SAE—n(%) 5 (16.7) 4 (12.5)
Total number of SAEs—n95
Patients with AE leading to withdrawal—n(%) 2 (6.7) 2 (6.3)
Total number of AEs leading to withdrawal—n22
Severity of TEAEs—n(%)
Mild 79 (55.6) 49 (69.0)
Moderate 46 (32.4) 17 (23.9)
Severe 17 (12.0) 5 (7.0)
TEAEs reported in >10% of treatment group—n(%)
Headache 9 (30.0) 4 (12.5)
Nasopharyngitis 3 (10.0) 4 (12.5)
Myasthenia gravis 3 (10.0) 3 (9.4)
Diarrhea 3 (10.0) 2 (6.3)
Hypertension 3 (10.0) 2 (6.3)
Nausea 3 (10.0) 1 (3.1)
Cough 3 (10.0) 0 (0)
Causal relationship of TEAE to study medication—n(%)
Unrelated 67 (47.2) 48 (67.6)
Doubtful/unlikely 19 (13.4) 5 (7.0)
Possible 20 (14.1) 11 (15.5)
Probable 22 (15.5) 5 (7.0)
Definite 14 (9.9) 2 (2.8)
BRIL ET AL.51
that the assumed effect size for IGIV-C may have been overestimated
in the MG maintenance treatment setting.
It should also be noted that there were some differences in base-
line demographics. The placebo group had a higher percentage of
females and younger patients than the IGIV-C treatment group. The
time since diagnosis of MG was also longer in the placebo group.
These factors may have affected the study outcomes. Further studies
may be warranted to fully elucidate the efficacy of IVIG as mainte-
nance therapy in MG while carefully monitoring all patients for MG
exacerbations.
AUTHOR CONTRIBUTIONS
All authors met the authorship criteria established by the International
Committee of Medical Journal Editors (ICMJE). Conceptualization:
RG, MQC, and EM. Methodology: RG, MQC, and EM. Formal analysis:
RG, MQC, and EM. Investigation: VB, TB, AS, MWN, JB, PH, AV, TV,
CR, TM, GP, TT, MP, TM. MF, UR, LV, NS, TL, RMP, MCD, MR, RG,
MQC, and EM. Resources: RG, MQC, and EM. Data curation:
RG, MQC, and EM. Writing—original draft: VB, RG, and EM. Writing—
review and editing: VB, TB, AS, MWN, JB, PH, AV, TV, CR, TM, GP,
TT, MP, TM. MF, UR, LV, NS, TL, RMP, MCD, MR, RG, MQC, and EM.
AFFILIATIONS
1
Toronto General Hospital, Toronto, Ontario, Canada
2
III Miejskie Centrum Medyczne im, Dr Karola Jonschera w Łodzi,
Lodz, Poland
3
Centrum Neurologii Klinicznej, Krakow, Poland
4
London Health Sciences Centre and Western University, London,
Ontario, Canada
5
Department of Neurology, University Hospital Brno and Faculty of
Medicine, Masaryk University, Brno, Czech Republic
6
Fakultni Nemocnice Ostrava, Neurologicka Klinika, Ostrava-Poruba,
Czech Republic
7
Department of Neurology, Hospital of Lithuanian University of
Health Sciences, Kaunas Clinics, Kaunas, Lithuania
8
Department of Neurology, University of South Florida Morsani
College of Medicine, Tampa, Florida, USA
9
Jahn Ferenc Del-pesti Korhaz es Rendelointezet Neurologiai Osztaly,
Budapest, Hungary
10
Universitaetsklinikum Hamburg Eppendorf, Klinik und Poliklinik fuer
Neurologie, Neurologische Studienzentrale, Hamburg, Germany
11
Department of Neurology, Flór Ferenc County Hospital, Kistarcsa,
Hungary
12
East Tallinn Central Hospital, Tallinn, Estonia
13
Department of Neurology, University of Kansas Medical Center,
Kansas City, Kansas, USA
14
University of California, Irvine, Orange, California, USA
15
Department of Neurology, The Ohio State University, Columbus,
Ohio, USA
16
Department of Neurology, University Clinic Dresden, Technische
Universität Dresden, Dresden, Germany
17
Department of Neurology, Albert Szent-Györgyi Clinical Center,
University of Szeged, Szeged, Hungary
18
Department of Neurology, Rutgers-New Jersey Medical School,
Newark, New Jersey, USA
19
Honor Health Neurology, Scottsdale, Arizona, USA
20
Indiana School of Medicine, Indianapolis, Indiana, USA
21
Department of Neurology, Thomas Jefferson University,
Philadelphia, Pennsylvania, USA
22
National and Kapodistrian University of Athens, Athens, Greece
23
Neurology/EMG Laboratory, Augusta University, Augusta,
Georgia, USA
24
Grifols Bioscience Research Group, Research Triangle Park, North
Carolina, USA
25
Grifols Bioscience Research Group, Sant Cugat, Spain
ACKNOWLEDGMENTS
Michael K. James, Ph.D., and Jordi Bozzo, Ph.D., are acknowledged for
writing and editorial assistance and Michelle McCrory for biostatistical
review. Furthermore, the authors acknowledge the internal Grifols
team members and vendors that collaborated in conducting the study.
Specifically, the authors would like to thank the following individuals
for their collaborations: Donna Babiar (Grifols), Kim Hanna (Grifols),
and Junliang Chen (Grifols).
FUNDING INFORMATION
This work was sponsored by Grifols Therapeutics LLC.
CONFLICT OF INTEREST STATEMENT
V. Bril, T. Berkowicz, A. Szczudlik, J. Bednarik, M.W. Nicolle, P. Hon,
A. Vaitkus, C. Rozsa, T. Magnus, G. Panczel, T. Toomsoo, M. Pasnoor,
T. Mozaffar, M. Freimer, U. Reuner, L. Vécsei, N. Souayah, T. Levine,
and R.M. Pascuzzi report no potential conflicts of interest. M. Querolt
Coll, R. Griffin, and E. Mondou are employees of Grifols, which finan-
cially supported this study and manufactures human immune globulin
10%, caprylate/chromatography purified (Gamunex-C
®
). T. Vu served
as a site principal investigator for myasthenia gravis trials sponsored
by Alexion, argenx, Ra Pharma/UCB, Horizon/Viela Bio, Janssen/
Momenta, Regeneron, and Cartesian Therapeutics and as a consultant
and/or speaker for UCB, Alexion, and argenx. M. Dalakas is an Associ-
ate Editor for Neurology: Neuroimmunology & Neuroinflammation,Neu-
rodiem, and Therapeutic Advances in Neurology; is on the editorial
board for Acta Myologica,Acta Neurologica Scandinavica,and Neuro-
Therapeutics; is a commentator for Clinical Practice Elsevier; serves on
the CIPD DSMB for Octapharma; has consulted for Grifols, Octa-
pharma, Dysimmune Diseases Foundation, Takeda, Alexion, and
argenx; and has received institutional support for Thomas Jefferson
University Neurology Department or for the Neuroimmunology Unit,
University of Athens Medical School for research and education from
Merck-Serono, Novartis, Guillain–Barre/CIDP Foundation, Dysim-
mune Diseases Foundation, InfuCare, and Nufactor. M. Rivner has
served as a consultant and received research support from Alexion,
argenx, and Allergan and received research support from UCB,
Momenta, Shire Takeda, Orion, Biohaven, Catalyst, Seikagaku, Viela
Bio, Apellis Pharmaceuticals, MediciNova, Millennium Pharmaceuti-
cals, Anelixis Therapeutics, and RA Pharmaceutical.
52 BRIL ET AL.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on
request from the corresponding author. The data are not publicly
available due to privacy or ethical restrictions.
ETHICS STATEMENT
We confirm that we have read the Journal's position on issues
involved in ethical publication and affirm that this report is consistent
with those guidelines.
PERMISSION TO REPRODUCE MATERIAL FROM OTHER
SOURCES
No material from other published sources was included in this
manuscript.
ORCID
Vera Bril https://orcid.org/0000-0002-5805-4883
Tuan Vu https://orcid.org/0000-0003-0724-0210
Tahseen Mozaffar https://orcid.org/0000-0002-1230-0188
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SUPPORTING INFORMATION
Additional supporting information can be found online in the Support-
ing Information section at the end of this article.
How to cite this article: Bril V, Berkowicz T, Szczudlik A, et al.
Efficacy and safety of maintenance intravenous
immunoglobulin in generalized myasthenia gravis patients with
acetylcholine receptor antibodies: A multicenter, double-blind,
placebo-controlled trial. Muscle & Nerve. 2025;71(1):43‐54.
doi:10.1002/mus.28289
54 BRIL ET AL.
