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IGIV-C MG Exacerbation Study

A Phase 3 Multicenter, Prospective, Open-Label Efficacy and Safety Study of Immune Globulin (Human) 10% Caprylate/Chromatography Purified in Patients with Myasthenia Gravis Exacerbations

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Year of Publication: 2019

Authors: Guntis Karelis, Rodica Balasa, Jan L. De Bleecker, ..., Jaume Ayguasanosa

Journal: European Neurology

Citation: Eur Neurol 2019;81:223-230. doi:10.1159/000502818

Link: https://clinicaltrials.gov/ct2/show/NCT02413580

Clinical Question

Is IGIV-C (2 g/kg administered over 2 consecutive days) effective and safe for treating myasthenia gravis exacerbations with significant disability (MGFA Class IVb or V)?

Bottom Line

IGIV-C 2 g/kg was effective, safe, and well-tolerated in treating severe MG exacerbations, with significant improvement in QMG scores at Day 14 (-6.4 points) and high response rates across all efficacy measures (77-88%). No serious adverse events occurred.

        Major Points
        Primary endpoint met: Significant decrease in QMG from baseline to Day 14 (-6.4 ± 5.15 points, p < 0.001)
High responder rates at Day 14: QMG 76.7%, MG Composite 86.0%, MG-ADL 88.4%
Improvement was evident by Day 7 and sustained through Day 28
MG Composite and MG-ADL scores reduced to approximately 50-60% of baseline by Day 14
No serious adverse events and no thromboembolic events
Most common adverse events were headache (38.8%) and pyrexia (16.3%)
AChR antibody levels decreased following IGIV-C administration
Results consistent with prior randomized controlled trials of IVIG in MG

      

Design

Study Type: Phase 3, multicenter, prospective, open-label, non-controlled, single-arm clinical trial

Randomization:

Blinding: Open-label, no blinding

Enrollment Period: June 1, 2015 through April 17, 2018

Follow-up Duration: 28 days

Centers: 15

Countries: Latvia, Belgium, Czech Republic, Poland, Romania, Russian Federation, Argentina, France, South Africa, Canada

Sample Size: 49

Analysis: Paired t test for primary efficacy outcome with 95% CI; Wilcoxon signed rank test if parametric assumptions not met; Shapiro-Wilk test for normality; two-sided α = 0.05; sample size calculated for 90% power to detect 3.5-point mean change in QMG

Inclusion Criteria

Age ≥18 years
MG exacerbation not attributable to infection or change in medication
Worsening of MG symptoms to MGFA Class IVb or V
On long-term (≥8 weeks) corticosteroid MG treatment

Exclusion Criteria

Received IVIG or PLEX within 30 days
Modified corticosteroid dosage within the last 2 weeks
Known to be positive for antibodies against MuSK
MG exacerbation attributable to change in medication or infection (manifested by fever, positive blood culture, leukocytosis, pulmonary infiltrate on X-ray, and/or per investigator's judgment)

Arms

Field	IGIV-C
Intervention	Immune Globulin (Human) 10% Caprylate/Chromatography Purified (Gamunex-C) 2 g/kg body weight administered as 1 g/kg/day dose over 2 consecutive days; infusion given immediately after baseline assessments
Duration	2 days of treatment with 28 days follow-up

Outcomes

Outcome	Type	Intervention	P-value
Change in Quantitative MG (QMG) score from Baseline to Day 14	Primary		<0.001
QMG responder rate at Day 14 (≥3-point decrease) \| Result: 76.7% (33/43)	Secondary
MG Composite responder rate at Day 14 (≥3-point decrease) \| Result: 86.0% (37/43)	Secondary
MG-ADL responder rate at Day 14 (≥2-point decrease) \| Result: 88.4% (38/43)	Secondary
Change in QMG at Day 7 \| Result: -4.7 ± 4.58 (median -4.0)	Secondary		<0.001
Change in QMG at Day 21 \| Result: -7.9 ± 5.78 (median -8.0); 95% CI: -9.686 to -6.128	Secondary		<0.001
Change in QMG at Day 28 \| Result: -7.8 ± 5.71 (median -8.0); 95% CI: -9.572 to -6.056	Secondary		<0.001
Change in MG Composite at Day 14 \| Result: -12.1 ± 7.72 (median -11.0); 95% CI: -14.514 to -9.765	Secondary		<0.001
Change in MG Composite at Day 28 \| Result: -13.7 ± 8.38 (median -12.0); 95% CI: -16.231 to -11.071	Secondary		<0.001
Change in MG-ADL at Day 14 \| Result: -6.2 ± 3.87 (median -6.0); 95% CI: -7.400 to -5.018	Secondary		<0.001
Change in MG-ADL at Day 28 \| Result: -7.0 ± 4.41 (median -7.0); 95% CI: -8.334 to -5.619	Secondary		<0.001
QMG responder rate at Day 7 \| Result: 69%	Secondary
QMG responder rate at Day 21 \| Result: 81.4%	Secondary
QMG responder rate at Day 28 \| Result: 79.1%	Secondary
MG Composite responder rate at Day 28 \| Result: 90.7%	Secondary
MG-ADL responder rate at Day 28 \| Result: 90.7%	Secondary
Any treatment-emergent AE	Adverse	Result: 79.6% (39/49 subjects; 98 events)
Serious adverse events	Adverse	Result: 0%
Thromboembolic events	Adverse	Result: 0%
Headache	Adverse	Result: 38.8% (19/49)
Pyrexia	Adverse	Result: 16.3% (8/49)
Urticaria	Adverse	Result: 8.2% (4/49)
Influenza-like illness	Adverse	Result: 6.1% (3/49)
Rash	Adverse	Result: 6.1% (3/49)
Vomiting	Adverse	Result: 6.1% (3/49)
Positive direct antiglobulin test (DAT)	Adverse	Result: 42.9% (21/49)
Hemolysis algorithm fulfilled	Adverse	Result: 10.2% (5/49)
Anemia (potentially IGIV-C related)	Adverse	Result: 2 subjects, mild intensity, full recovery
Discontinuation due to AE	Adverse	Result: 6.1% (3/49) - did not receive second day infusion

Subgroup Analysis

Not formally performed. Six subjects were excluded from the Evaluable population: 4 received IGIV-C on first infusion day only due to non-serious AEs (3 received none and 1 received very little on second dosing day); 2 violated inclusion criteria (1 had QMG=6 inconsistent with MG exacerbation, 1 had <8 weeks CS treatment).

Criticisms

Open-label, non-controlled single-arm design without placebo or comparator group limits ability to establish causality
Cannot distinguish treatment effect from natural disease course or placebo effect
Small sample size (n=49 enrolled, n=43 evaluable)
All patients had MGFA Class IVb; no Class V patients enrolled despite being eligible
Excluded MuSK-Ab+ patients, limiting generalizability
Short follow-up duration (28 days) does not assess durability of response
No blinding of investigators or patients may introduce bias in subjective outcome assessments
6 subjects (12%) excluded from efficacy analysis due to AEs or inclusion criteria violations
Positive DAT in 43% of subjects and potential hemolysis in 10% raises safety considerations for broader use
Results may not be generalizable to patients not on chronic corticosteroids or with different disease characteristics

Funding

Grifols, Inc.

Based on: IGIV-C MG Exacerbation Study (European Neurology, 2019)

Authors: Guntis Karelis, Rodica Balasa, Jan L. De Bleecker, ..., Jaume Ayguasanosa

Citation: Eur Neurol 2019;81:223-230. doi:10.1159/000502818

Content summarized and formatted by NeuroTrials.ai.

IGIV-C MG Exacerbation Study

(2019)

Objective

To assess the efficacy and safety of immune globulin caprylate/chromatography purified (IGIV-C) in subjects with myasthenia gravis exacerbations

Study Summary

• IGIV-C 2 g/kg significantly improved QMG scores at Day 14 (−6.4 points, p < 0.001) in patients with severe MG exacerbations
• High responder rates at Day 14: 77% QMG, 86% MG Composite, 88% MG-ADL
• IGIV-C was safe and well-tolerated with no serious adverse events or thromboembolic events

Intervention

IGIV-C (Gamunex-C) 2 g/kg administered over 2 consecutive days (1 g/kg/day)

Inclusion Criteria

Age ≥18 years, MG exacerbation (MGFA Class IVb or V) not attributable to infection or medication change, on long-term (≥8 weeks) corticosteroid MG treatment

Study Design

Arms: Single-arm (IGIV-C only, no control)

Patients per Arm: 49 enrolled (Safety population), 43 evaluable for efficacy

Outcome

• Primary: QMG change from baseline to Day 14: −6.4 ± 5.15 (p < 0.001, 95% CI −7.957 to −4.787)
• Day 14 responders: QMG 76.7%, MG Composite 86.0%, MG-ADL 88.4%
• MG Composite change at Day 14: −12.1 ± 7.72 (p < 0.001)

Bottom Line

Major Points

Primary endpoint met: Significant decrease in QMG from baseline to Day 14 (-6.4 ± 5.15 points, p < 0.001)
High responder rates at Day 14: QMG 76.7%, MG Composite 86.0%, MG-ADL 88.4%
Improvement was evident by Day 7 and sustained through Day 28
MG Composite and MG-ADL scores reduced to approximately 50-60% of baseline by Day 14
No serious adverse events and no thromboembolic events
Most common adverse events were headache (38.8%) and pyrexia (16.3%)
AChR antibody levels decreased following IGIV-C administration
Results consistent with prior randomized controlled trials of IVIG in MG

Study Design

Study Type: Phase 3, multicenter, prospective, open-label, non-controlled, single-arm clinical trial
Randomization: No
Blinding: Open-label, no blinding
Sample Size: 49
Follow-up: 28 days
Centers: 15
Countries: Latvia, Belgium, Czech Republic, Poland, Romania, Russian Federation, Argentina, France, South Africa, Canada

Primary Outcome

Definition: Change in Quantitative MG (QMG) score from Baseline to Day 14

Control	Intervention	HR/OR	P-value
-	-	- (-7.957 to -4.787)	<0.001

Limitations & Criticisms

Open-label, non-controlled single-arm design without placebo or comparator group limits ability to establish causality
Cannot distinguish treatment effect from natural disease course or placebo effect
Small sample size (n=49 enrolled, n=43 evaluable)
All patients had MGFA Class IVb; no Class V patients enrolled despite being eligible
Excluded MuSK-Ab+ patients, limiting generalizability
Short follow-up duration (28 days) does not assess durability of response
No blinding of investigators or patients may introduce bias in subjective outcome assessments
6 subjects (12%) excluded from efficacy analysis due to AEs or inclusion criteria violations
Positive DAT in 43% of subjects and potential hemolysis in 10% raises safety considerations for broader use
Results may not be generalizable to patients not on chronic corticosteroids or with different disease characteristics

Citation

Eur Neurol 2019;81:223-230. doi:10.1159/000502818

View Original Publication →

IGIV-C MG Exacerbation Study

A Phase 3 Multicenter, Prospective, Open-Label Efficacy and Safety Study of Immune Globulin (Human) 10% Caprylate/Chromatography Purified in Patients with Myasthenia Gravis Exacerbations

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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