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BeatMG

Phase 2 Trial of Rituximab in Acetylcholine Receptor Antibody-Positive Generalized Myasthenia Gravis: The BeatMG Study

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Year of Publication: 2022

Authors: Richard J. Nowak, Christopher S. Coffey, Jonathan M. Goldstein, ..., Richard J. Barohn

Journal: Neurology

Citation: Neurology 2022;98:e376-e389. doi:10.1212/WNL.0000000000013121

Link: https://clinicaltrials.gov/ct2/show/NCT02110706

Clinical Question

Is rituximab safe and potentially beneficial as a steroid-sparing therapy in acetylcholine receptor antibody-positive generalized myasthenia gravis, warranting further investigation in a phase 3 efficacy trial?

Bottom Line

Rituximab was safe and well-tolerated but failed to demonstrate a clinically meaningful steroid-sparing effect compared to placebo in mild-moderate AChR-Ab+ gMG over 12 months. The study reached its futility endpoint, suggesting a low probability of success in a larger phase 3 trial with a similar population.

        Major Points
        Primary steroid-sparing outcome achieved in 60% rituximab vs 56% placebo (OR 1.14; 90% 1-sided CI 0-2.4)
Study reached futility endpoint (p=0.03), rejecting the null hypothesis that rituximab would provide ≥30% absolute improvement over placebo
No significant differences in secondary outcomes (MGC, QMG, MG-ADL, MG-QoL scores)
Rituximab group showed numerically lower MG exacerbation rate requiring rescue therapy (12% vs 29.6%, p=0.130)
Successful B-cell depletion achieved in rituximab group (median 2 cells/μL at week 24 vs 124 at baseline)
High placebo response rate (56%) may reflect mild disease severity and adequate response to concomitant therapies
42% of participants had B-cell counts below lower limit of normal at baseline, potentially limiting therapeutic opportunity
Trial results do not address efficacy in treatment-refractory or MuSK-Ab+ MG populations

      

Design

Study Type: Randomized, double-blind, placebo-controlled, multicenter phase 2 futility trial

Randomization: 1

Blinding: Double-blind; all participants, investigators, and study staff blinded to treatment assignment until database lock; clinical evaluators also blinded to adverse events

Enrollment Period: August 2014 to July 2016

Follow-up Duration: 52 weeks

Centers: 16

Countries: United States

Sample Size: 52

Analysis: Intent-to-treat analysis; logistic regression adjusted for stratification variables (baseline prednisone dose and concomitant IST use); 0.10 level of significance for midphase trial; nonparametric rank-based analysis for AUDTC and AChR-Ab levels; sensitivity analyses including observed data only, last observation carried forward, multiple imputation, best/worst case scenarios

Inclusion Criteria

Age 21-90 years
Diagnosis of AChR-Ab+ generalized myasthenia gravis
MGFA Clinical Class II-IV
Stable dose of prednisone ≥15 mg/d for 4 weeks prior to baseline, OR
Prednisone plus stable dose of another IST (azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, or methotrexate) for ≥6 months prior to baseline

Exclusion Criteria

History of thymic neoplasm
Thymectomy in the previous 6 months
Previous treatment with rituximab
IV immunoglobulin (IVIg) or plasma exchange (PLEX) treatment within 4 weeks of baseline

Arms

Field	Rituximab	Control
Intervention	2-cycle rituximab regimen: 375 mg/m² IV infusion weekly for 4 consecutive weeks per cycle; Cycle 1 administered weeks 0-3, Cycle 2 administered weeks 24-27; forced prednisone taper starting at week 8 based on MGC score stability	Infusion containing only vehicle components, administered on same schedule as rituximab; forced prednisone taper starting at week 8 based on MGC score stability
Duration	52 weeks	52 weeks

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Proportion achieving ≥75% reduction in mean daily prednisone dose in the 4 weeks prior to week 52 compared to the 4-week period prior to randomization AND clinical improvement or no significant worsening (≤2-point increase in MGC score from randomization to week 52)	Primary	56% (15/27)	60% (15/25)	1.14	0.03 (futility endpoint reached)
Change in MGC score from baseline to week 52	Secondary	-4.0 ± 4.1	-5.7 ± 7.3		0.93
Change in QMG score from baseline to week 52	Secondary	-1.7 ± 3.9	-4.0 ± 5.4		0.39
Change in MG-ADL score from baseline to week 52	Secondary	-2.0 ± 3.2	-2.7 ± 3.3		0.73
Change in MG-QoL score from baseline to week 52	Secondary	-7.5 ± 9.1	-8.0 ± 9.3		0.70
Area under the dose time curve (AUDTC) - prednisone burden	Secondary	Median 350 mg (range 115-1431)	Median 290 mg (range 114-1406)		0.47
MGC responder analysis (≥3 point improvement at week 52)	Secondary	67%	70%		0.85
QMG responder analysis (≥3 point improvement at week 52)	Secondary	39%	65%		0.18
MG exacerbations requiring rescue therapy (IVIg or PLEX)	Secondary	29.6% (8/27 participants; 11 events)	12% (3/25 participants; 3 events)		0.130
Relapse rate per 30 days requiring rescue therapy	Secondary	0.036	0.010		0.055
Any treatment-emergent AE	Adverse	96%	100%		1.00
Any treatment-emergent SAE	Adverse	52%	36%		0.25
Treatment-related AE	Adverse	82%	76%		0.63
Treatment-related SAE	Adverse	30%	24%		0.65
Worsening of MG (SAE)	Adverse	11.1%	4%		0.36
Pulmonary embolism	Adverse	3.7%	4%		0.96
Arthralgia	Adverse	37%	24%		0.31
Headache	Adverse	25.9%	32%		0.63
Upper respiratory tract infection	Adverse	18.5%	36%		0.16
Fatigue	Adverse	29.6%	12%		0.13
Back pain	Adverse	33.3%	8%		0.04
Nausea	Adverse	22.2%	8%		0.17
Muscular weakness	Adverse	11.1%	16%		0.61
Paresthesia	Adverse	18.5%	0%		0.05

Subgroup Analysis

Post hoc sensitivity analyses adjusting for baseline minimal symptom expression (MSE) showed OR 1.53 (90% 1-sided CI 0-3.43, p=0.095) for primary endpoint; adjusting for baseline MGC score showed OR 1.48 (90% 1-sided CI 0-3.31, p=0.086); adjusting for baseline MG-ADL showed OR 1.40 (90% 1-sided CI 0-3.11, p=0.072). All still rejected null hypothesis supporting futility. Modified primary endpoint imputing failure for rescue therapy recipients showed 56% vs 52% (OR 1.14, p=0.03).

Criticisms

Predominantly mild-moderate disease population (MGFA Class II 59.6%); did not include treatment-refractory or moderate-severe patients where rituximab may be more beneficial
Excluded MuSK-Ab+ patients, where prior studies suggest greater rituximab benefit
Baseline imbalance in disease burden with higher MGC, QMG, MG-ADL scores and lower MSE rate in rituximab group (4.2% vs 26.9%)
Higher than anticipated placebo response rate (56%) suggests participants may have had mild disease adequately responsive to concomitant therapies
42% of participants had B-cell counts below lower limit of normal at baseline, potentially limiting opportunity to demonstrate B-cell depletion benefit
Small sample size (n=52) with limited power for subgroup analyses
Only 80% of rituximab group completed intended 2-cycle regimen
No requirement to demonstrate failed prior steroid taper before enrollment
Protocol amended mid-study to allow concomitant IST use due to recruitment challenges, affecting population homogeneity
Steroid-sparing endpoint linked to MGC stability rather than clinical improvement, allowing participants already at symptom plateau to taper regardless of treatment effect
Imbalance in race/ethnicity between groups (African American 8% rituximab vs 33.3% placebo)

Funding

National Institute of Neurologic Disorders and Stroke (NINDS) under award U01NS084495 to Dr. Nowak; infrastructure support under NINDS awards U01NS077179 (Clinical Coordination Center), U01NS077352 (Data Coordination Center), and individual grants to trial sites; drug/placebo provided by Genentech through investigator-initiated trial agreement

Based on: BeatMG (Neurology, 2022)

Authors: Richard J. Nowak, Christopher S. Coffey, Jonathan M. Goldstein, ..., Richard J. Barohn

Citation: Neurology 2022;98:e376-e389. doi:10.1212/WNL.0000000000013121

Content summarized and formatted by NeuroTrials.ai.

BeatMG

(2022)

Objective

To determine whether rituximab is safe and potentially beneficial, warranting further investigation in an efficacy trial for acetylcholine receptor antibody-positive generalized myasthenia gravis (AChR-Ab+ gMG)

Study Summary

• Rituximab failed to demonstrate a meaningful steroid-sparing effect over placebo in mild-moderate AChR-Ab+ gMG (60% vs 56% achieved primary endpoint)
• Study reached futility endpoint (p=0.03), indicating low probability of success in a larger phase 3 trial with similar population
• Rituximab was safe and well-tolerated with no significant safety concerns identified

Intervention

Rituximab 375 mg/m² weekly x 4 weeks for 2 cycles (weeks 0-3 and 24-27) vs placebo, with forced prednisone taper starting at week 8

Inclusion Criteria

Age 21-90 years, AChR-Ab+ gMG, MGFA Class II-IV, prednisone ≥15 mg/d stable for 4 weeks (or with stable IST for ≥6 months)

Study Design

Arms: Rituximab vs Placebo

Patients per Arm: Rituximab: 25, Placebo: 27

Outcome

• Primary steroid-sparing outcome: 60% rituximab vs 56% placebo (OR 1.14; 90% 1-sided CI 0-2.4; p=0.03 for futility)
• MGC score change: -5.7 vs -4.0 (no significant difference)
• MG exacerbations requiring rescue therapy: 12% rituximab vs 29.6% placebo (p=0.130)

Bottom Line

Major Points

Primary steroid-sparing outcome achieved in 60% rituximab vs 56% placebo (OR 1.14; 90% 1-sided CI 0-2.4)
Study reached futility endpoint (p=0.03), rejecting the null hypothesis that rituximab would provide ≥30% absolute improvement over placebo
No significant differences in secondary outcomes (MGC, QMG, MG-ADL, MG-QoL scores)
Rituximab group showed numerically lower MG exacerbation rate requiring rescue therapy (12% vs 29.6%, p=0.130)
Successful B-cell depletion achieved in rituximab group (median 2 cells/μL at week 24 vs 124 at baseline)
High placebo response rate (56%) may reflect mild disease severity and adequate response to concomitant therapies
42% of participants had B-cell counts below lower limit of normal at baseline, potentially limiting therapeutic opportunity
Trial results do not address efficacy in treatment-refractory or MuSK-Ab+ MG populations

Study Design

Study Type: Randomized, double-blind, placebo-controlled, multicenter phase 2 futility trial
Randomization: Yes
Blinding: Double-blind; all participants, investigators, and study staff blinded to treatment assignment until database lock; clinical evaluators also blinded to adverse events
Sample Size: 52
Follow-up: 52 weeks
Centers: 16
Countries: United States

Primary Outcome

Definition: Proportion achieving ≥75% reduction in mean daily prednisone dose in the 4 weeks prior to week 52 compared to the 4-week period prior to randomization AND clinical improvement or no significant worsening (≤2-point increase in MGC score from randomization to week 52)

Control	Intervention	HR/OR	P-value
56% (15/27)	60% (15/25)	1.14 (90% 1-sided CI: 0-2.4)	0.03 (futility endpoint reached)

Limitations & Criticisms

Predominantly mild-moderate disease population (MGFA Class II 59.6%); did not include treatment-refractory or moderate-severe patients where rituximab may be more beneficial
Excluded MuSK-Ab+ patients, where prior studies suggest greater rituximab benefit
Baseline imbalance in disease burden with higher MGC, QMG, MG-ADL scores and lower MSE rate in rituximab group (4.2% vs 26.9%)
Higher than anticipated placebo response rate (56%) suggests participants may have had mild disease adequately responsive to concomitant therapies
42% of participants had B-cell counts below lower limit of normal at baseline, potentially limiting opportunity to demonstrate B-cell depletion benefit
Small sample size (n=52) with limited power for subgroup analyses
Only 80% of rituximab group completed intended 2-cycle regimen
No requirement to demonstrate failed prior steroid taper before enrollment
Protocol amended mid-study to allow concomitant IST use due to recruitment challenges, affecting population homogeneity
Steroid-sparing endpoint linked to MGC stability rather than clinical improvement, allowing participants already at symptom plateau to taper regardless of treatment effect
Imbalance in race/ethnicity between groups (African American 8% rituximab vs 33.3% placebo)

Citation

Neurology 2022;98:e376-e389. doi:10.1212/WNL.0000000000013121

View Original Publication →

BeatMG

Phase 2 Trial of Rituximab in Acetylcholine Receptor Antibody-Positive Generalized Myasthenia Gravis: The BeatMG Study

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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