BeatMG: Phase II Trial of Rituximab In Myasthenia Gravis

• Sponsor: Yale University (Other)
• Overall Status: Completed
• CT.gov ID: NCT02110706
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS) (NIH)
• Enrollment: 52
• Locations: 26
• Arms: 2
• Duration (Months): 48
• Patients Per Site: 2
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The specific primary objective of this study is to determine whether rituximab is a safe and beneficial therapeutic for Myasthenia Gravis (MG) that warrants further study in a phase III efficacy trial.

Condition or Disease	Intervention/Treatment	Phase
Myasthenia Gravis	Drug: Rituximab; Drug: Placebo	Phase 2

Detailed Description

Investigators plan on conducting a multicenter randomized, double-blind, placebo controlled Phase II clinical trial utilizing a futility design. The study would include acetylcholine receptor (AChR) antibody positive generalized MG subjects. This study also presents a unique opportunity to study both drug and disease mechanisms because unlike many other autoimmune diseases in which rituximab has been used, MG affords the investigation of antigen-specific components that participate in the immunopathology of the disease, namely autoantibodies, autoantibody-producing B cells, and antigen-specific T cells. This work will further our understanding of MG immunopathology and it represents the first step toward gaining a more complete understanding of the immune mechanisms underlying treatment of MG with rituximab leading to new ways to treat the disease.

The specific aim of this study is to determine whether rituximab is a safe and effective treatment for subjects with MG.

The SNOMED code for MG is 31839002.

Study Design

• Study Type: Interventional
• Actual Enrollment: 52 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: B Cell Targeted Treatment In Myasthenia Gravis (BeatMG): A Phase II Trial of Rituximab In Myasthenia Gravis
• Study Start Date: May 1, 2014
• Actual Primary Completion Date: Jul 1, 2017
• Actual Study Completion Date: May 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo The placebo group will receive a vehicle control infusion	Drug: Placebo; The placebo group will receive a vehicle control infusion
Experimental: Rituximab Intervention (rituximab): The treatment group will receive a total of two cycles of rituximab separated by 6 months. Each cycle is defined as one infusion (375mg/m2 IV) per week for four consecutive weeks	Drug: Rituximab; Intervention (rituximab): The treatment group will receive a total of two cycles of rituximab separated by 6 months. Each cycle is defined as one infusion (375mg/m2 IV) per week for four consecutive weeks

Outcome Measures

Primary Outcome Measures

1. Steroid Sparing Effect [4 weeks prior baseline and 4 weeks prior to week 52]

   Percent of subjects that achieve a ≥ 75% reduction in mean daily prednisone dose in the 4 weeks prior to week 52 and have clinical improvement or no significant worsening of symptoms (≤ 2 point increase in MGC score) as compared to 4-week period prior to randomization and initiation of treatment.

2. Safety:Percentage of Study Participants With Treatment-related Adverse Experiences [52 weeks]

   Evaluate treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs)

Secondary Outcome Measures

1. Change in Myasthenia Gravis Composite (MGC) Scores From Baseline to Week 52 [baseline and 52 weeks]

   Evaluate whether there is a trend towards clinical benefit at end of 52 week treatment period, as measured by mean change in the MGC score, an MG-specific clinical outcomes scale used as endpoint in prior MG clinical trials. The Myasthenia Gravis Composite (MGC) scale consists of test items from the MG-ADL (Myasthenia Gravis Activities of Daily Living) scale and the QMG (Quantitative Myasthenia Gravis Scale) that measure symptoms and signs of MG, with weighted response options. The minimum score is 0, and the maximum score is 50. Higher scores correlate with clinical worsening of the disease.

2. Change in Quantitative Myasthenia Gravis(QMG) Scores From Baseline to Week 52 [baseline and 52 weeks]

   Evaluate whether there is a trend towards clinical benefit at end of 52 week treatment period, as measured by the mean change in the QMG score - a specific clinical outcome scale used as endpoint in prior MG clinical trials. The Quantitative Myasthenia Gravis Score (QMG) is a commonly used objective outcome measure in myasthenia gravis (MG) comprising 13 items, each with a possible score from 0 to 3, and a maximum possible of 39 points, where a higher score indicates more severe disease.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 90 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Subjects 21 to 90 years old

2. Subjects must have generalized MG, defined as MGFA clinical classification grades 2 (mild), 3 (moderate), or 4 (severe, but not intubated) at the time of screening/randomization.

3. Elevated AChR antibody titer

4. Subject's signs and symptoms should not be better explained by another disease process.

5. Subjects must be on a stable standard immunosuppressive regimen:

6. Prednisone only: Prednisone dose must be at least 15mg/day (or the equivalent on alternate days), and the dose of prednisone must have been stable for at least 4 weeks (28 days) prior to the baseline visit.

7. Prednisone plus another immunosuppressive therapy (IST). Immunosuppressive therapies other than prednisone, specifically azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus or methotrexate, are permitted, but the dose must have been stable for at least 6 months prior to the baseline visit.

(Note: The prednisone dose must be stable as defined in the prednisone only group. The IST dose must remain stable throughout the course of the study).

1. Subjects must be willing to complete the study and return for follow-up visits.

2. No history of thymoma, tumor, infection, or interstitial lung disease on chest CT, MRI, or chest x-ray. Note: Chest x-ray will be completed at screening to look of interstitial lung disease. A chest CT or MRI to evaluate for thymoma must be completed as part of prescreening.

3. Able and willing to give written informed consent and comply with the requirements of the study protocol.

4. Subjects must be able to give written informed consent before participating in this study. A copy of the signed consent must be kept in the subject's medical record.

5. Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment and for twelve months (1 year) after completion of treatment.

Exclusion Criteria:

1. A history of chronic degenerative, psychiatric, or neurologic disorder other than MG that can produce weakness or fatigue.

2. Other major chronic or debilitating illnesses within six months prior to study entry.

3. Female subjects who are premenopausal and are:

4. pregnant on the basis of a serum pregnancy test,

5. breast-feeding, or

6. not using an effective method of double barrier (1 hormonal plus 1 barrier method or 2 simultaneous barrier methods) or birth control (birth control pills, male condom, female condom, intrauterine device, Norplant, tubal ligation, or other sterilization procedures).

7. Altered levels of consciousness, dementia, or abnormal mental status.

8. Thymectomy in the previous six months.

9. Subjects who have been medicated with immunosuppressive drugs not listed in inclusion #5 within the last 8 weeks (56 days) prior to the baseline visit

10. Subjects who have been medicated with an immunosuppressive agent such as azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus or methotrexate, that is withdrawn within 8 weeks (56 days) of the Baseline Visit.

11. Subjects who have received IVIg or PLEX treatment within the last 4 weeks (28 days) prior to the baseline visit.

12. Unstable dose or a stable dose of > 480 mg/day of pyridostigmine in 2 weeks prior to screening visit.

13. Daily use of non-steroidal anti-inflammatory drugs (NSAIDs).

14. History of renal or hepatic insufficiency or elevated liver enzymes (AST or ALT >2.5 x Upper Limit of Normal).

15. History of bone marrow hypoplasia, leucopenia, thrombocytopenia, significant anemia, clinical or laboratory evidence of immunodeficiency syndromes.

16. Forced Vital Capacity (FVC) <50% of percent predicted.

General Safety & Laboratory Exclusion Criteria

1. ANC < 1.5 x 103 cells/microliter

2. Hemoglobin: < 8.0 gm/dL

3. Platelets: < 100,000/mm

4. Positive Hepatitis B or C serology (Hep B surface antigen and Hep C antibody)

5. History of positive HIV (HIV conducted during screening if applicable)

6. Treatment with any investigational agent within 4 weeks of screening or 5 half-lives of the investigational drug (whichever is longer)

7. Receipt of a live vaccine within 4 weeks prior to randomization

8. Previous treatment with rituximab (MabThera® / Rituxan®)

9. Previous treatment with natalizumab (Tysabri®)

10. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies

11. History of recurrent significant infection or history of recurrent bacterial infections

12. Known active bacterial, viral fungal mycobacterial, or other infection (including tuberculosis or atypical mycobacterial disease, but excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to screening

13. Unstable steroid dose in the past 4 weeks (28 days)

14. Lack of peripheral venous access

15. History of drug, alcohol, or chemical abuse within 6 months prior to screening

16. Concomitant malignancies or previous malignancies, with the exception of adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or prostate.

17. History of psychiatric disorder that would interfere with normal participation in this protocol

18. Significant cardiac or pulmonary disease (including obstructive pulmonary disease)

19. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the subject at high risk from treatment complications

20. Subjects that do not record daily prednisone doses for at least 28 days before the Baseline Visit, or subjects whose prednisone dose varies by ≥6mg/day on average.

21. Prednisone dose of more than 100 mg/day (or 200 mg over a two day period).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35233
2	University of California - Davis	Davis	California	United States	95616
3	University of California - Los Angeles	Los Angeles	California	United States	90095
4	University of Colorado - Denver	Denver	Colorado	United States	80217
5	Yale School of Medicine, Department of Neurology	New Haven	Connecticut	United States	06510
6	University of Miami School of Medicine	Miami	Florida	United States	33136
7	Emory University	Atlanta	Georgia	United States	30322
8	Northwestern University	Evanston	Illinois	United States	60208
9	University of Kansas Medical Center	Kansas City	Kansas	United States	66160
10	Brigham & Women's Hospital	Boston	Massachusetts	United States	02115
11	Washington University	Saint Louis	Missouri	United States	63130
12	Montefiore Medical Center	Bronx	New York	United States	10461
13	SUNY Downstate Medical Center	Brooklyn	New York	United States	11203
14	SUNY Buffalo	Buffalo	New York	United States	14260
15	Columbia University Medical Center	New York	New York	United States	10032
16	Weill Cornell Medical Center	New York	New York	United States	10065
17	University of Rochester	Rochester	New York	United States	14627
18	SUNY Stony Brook	Stony Brook	New York	United States	11790
19	University of Cincinnati	Cincinnati	Ohio	United States	45220
20	Ohio State University	Columbus	Ohio	United States	43210
21	Oregon Health and Science University	Portland	Oregon	United States	97239
22	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15260
23	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75235
24	University of Utah	Salt Lake City	Utah	United States	84112
25	University of Virginia	Charlottesville	Virginia	United States	22904
26	Swedish Medical Center	Seattle	Washington	United States	98107

Sponsors and Collaborators

• Yale University
• National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

• Principal Investigator: Richard J Nowak, MD, MS, Yale University

Study Documents (Full-Text)

• Study Protocol - Jul 5, 2017
• Statistical Analysis Plan - Nov 17, 2017

More Information

Additional Information:

• NeuroNEXT Network
• Yale School of Medicine, Department of Neurology
• National Institutes of Health

Publications

None provided.

• Responsible Party: Yale University
• ClinicalTrials.gov Identifier: NCT02110706
• Other Study ID Numbers: 1401013253-0; 1U01NS084495-01A1; U01NS077179-01; U01NS077352
• First Posted: Apr 10, 2014
• Last Update Posted: Mar 6, 2020
• Last Verified: Mar 1, 2020

• Keywords provided by Yale University: Myasthenia Gravis; Rituximab; SNOMED code 31839002
• Additional relevant MeSH terms: Myasthenia Gravis; Muscle Weakness; Rituximab

Study Results

Participant Flow

Pre-assignment Detail	68 study participants were consented and assessed for eligibility. 14 participants were ineligible. 2 participants declined. 52 study participants were randomized.

Arm/Group Title	Rituximab	Placebo Group
Arm/Group Description	- Treatment group received two cycles of rituximab (375mg/m2 iv), separated by 6 months. Each cycle defined as one infusion per week for four consecutive weeks. For the main study, participants were followed for 52 weeks. Study participants had clinical evaluations performed by a blinded evaluator at baseline and every 4 weeks thereafter.	- Placebo group received infusion containing only vehicle components of rituximab solution. Infusion was done in 2 cycles, separated by 6 months. Each cycle defined as one infusion per week for four consecutive weeks. For the main study, participants were followed for 52 weeks. Study participants had clinical evaluations performed by a blinded evaluator at baseline and every 4 weeks thereafter.
Period Title: Overall Study
STARTED	25	27
No. Completing Study Through Week 52	23	24
COMPLETED	20	23
NOT COMPLETED	5	4

Baseline Characteristics

Arm/Group Title	Rituximab	Placebo	Total
Arm/Group Description	- Treatment group received two cycles of rituximab (375mg/m2 iv), separated by 6 months. Each cycle defined as one infusion per week for four consecutive weeks. For the main study, participants were followed for 52 weeks. Study participants had clinical evaluations performed by a blinded evaluator at baseline and every 4 weeks thereafter.	- Placebo group received infusion containing only vehicle components of rituximab solution. Infusion was done in 2 cycles, separated by 6 months. Each cycle defined as one infusion per week for four consecutive weeks. For the main study, participants were followed for 52 weeks. Study participants had clinical evaluations performed by a blinded evaluator at baseline and every 4 weeks thereafter.	Total of all reporting groups
Overall Participants	25	27	52
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.2 (17.5)	56.8 (17.0)	55.1 (17.1)
Sex: Female, Male (Count of Participants)
Female	11 44%	12 44.4%	23 44.2%
Male	14 56%	15 55.6%	29 55.8%
Race/Ethnicity, Customized (Count of Participants)
Asian	0 0%	1 3.7%	1 1.9%
African American	2 8%	9 33.3%	11 21.2%
Hispanic	3 12%	2 7.4%	5 9.6%
Non-Hispanic white	20 80%	15 55.6%	35 67.3%
Baseline Prednisone Dose (mg/day) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/day]	23 (11.2)	21.3 (8.3)	22.1 (9.7)
Baseline Myasthenia Gravis Composite (MGC) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	11.1 (6.1)	8.5 (4.0)	9.8 (5.2)
Baseline Quantitative Myasthenia Gravis (QMG) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	11.0 (5.1)	9.2 (3.9)	10.1 (4.5)
Baseline MG-Activities of Daily Living Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	5.8 (3.6)	4.0 (3.4)	4.9 (3.6)
Baseline MG-Quality of Life (MG-QOL) score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	22.7 (14.1)	17.7 (10.6)	20.1 (12.5)
Baseline MGFA Clinical Classification Grade (Count of Participants)
Class I	0 0%	1 3.7%	1 1.9%
Class II	15 60%	16 59.3%	31 59.6%
Class III	9 36%	9 33.3%	18 34.6%
Class IV	1 4%	1 3.7%	2 3.8%
Thymectomy (Count of Participants)
Count of Participants [Participants]	8 32%	4 14.8%	12 23.1%

Outcome Measures

1. Primary Outcome

Title	Steroid Sparing Effect
Description	Percent of subjects that achieve a ≥ 75% reduction in mean daily prednisone dose in the 4 weeks prior to week 52 and have clinical improvement or no significant worsening of symptoms (≤ 2 point increase in MGC score) as compared to 4-week period prior to randomization and initiation of treatment.
Time Frame	4 weeks prior baseline and 4 weeks prior to week 52

Outcome Measure Data

Analysis Population Description

Intention to treat participants

Arm/Group Title	Rituximab	Placebo
Arm/Group Description	- Treatment group received two cycles of rituximab (375mg/m2 iv), separated by 6 months. Each cycle defined as one infusion per week for four consecutive weeks. For the main study, participants were followed for 52 weeks. Study participants had clinical evaluations performed by a blinded evaluator at baseline and every 4 weeks thereafter.	- Placebo group received infusion containing only vehicle components of rituximab solution. Infusion was done in 2 cycles, separated by 6 months. Each cycle defined as one infusion per week for four consecutive weeks. For the main study, participants were followed for 52 weeks. Study participants had clinical evaluations performed by a blinded evaluator at baseline and every 4 weeks thereafter.
Measure Participants	25	27
Count of Participants [Participants]	15 60%	15 55.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab, Placebo
	Comments	This futility design tests the following hypothesis: H0: Rituximab improves outcome by at least 30% compared to placebo (pR - pP ≥ 0.30 - not futile) versus HA: Rituximab does not improve outcome by at least 30% compared to placebo (pR - pP < 0.30 - futile)
	Type of Statistical Test	Other
	Comments	A futility (non-superiority) design is a screening tool to identify whether agents should be candidates for phase III trials while minimizing costs/sample size If "futility" is declared, results would imply not cost effective to conduct a future phase III clinical trial If "futility" is not declared, suggests that there could be a clinically meaningful effect - supports exploration in a larger, phase III trial
Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.14
	Confidence Interval	(1-Sided) 90%; to 2.41
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Safety:Percentage of Study Participants With Treatment-related Adverse Experiences
Description	Evaluate treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Intention to treat participants

Arm/Group Title	Rituximab	Placebo
Arm/Group Description	- Treatment group received two cycles of rituximab (375mg/m2 iv), separated by 6 months.Each cycle defined as one infusion per week for four consecutive weeks.For the main study, participants were followed for 52 weeks.Study participants had clinical evaluations performed by a blinded evaluator at baseline and every 4 weeks thereafter.	- Placebo group received infusion containing only vehicle components of rituximab solution. Infusion was done in 2 cycles , separated by 6 months. Each cycle defined as one infusion per week for four consecutive weeks. For the main study, participants were followed for 52 weeks. Study participants had clinical evaluations performed by a blinded evaluator at baseline and every 4 weeks thereafter.
Measure Participants	25	27
% of participants with treatment related AEs	19 76%	22 81.5%
% participants with treatment related SAEs	6 24%	8 29.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab, Placebo
	Comments	% of study participants with treatment related AEs
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.63
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.72
	Confidence Interval	(2-Sided) 90%; 0.23 to 2.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Rituximab, Placebo
	Comments	% study participants with treatment related SAEs
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.65
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.75
	Confidence Interval	(2-Sided) 90%; 0.27 to 2.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change in Myasthenia Gravis Composite (MGC) Scores From Baseline to Week 52
Description	Evaluate whether there is a trend towards clinical benefit at end of 52 week treatment period, as measured by mean change in the MGC score, an MG-specific clinical outcomes scale used as endpoint in prior MG clinical trials. The Myasthenia Gravis Composite (MGC) scale consists of test items from the MG-ADL (Myasthenia Gravis Activities of Daily Living) scale and the QMG (Quantitative Myasthenia Gravis Scale) that measure symptoms and signs of MG, with weighted response options. The minimum score is 0, and the maximum score is 50. Higher scores correlate with clinical worsening of the disease.
Time Frame	baseline and 52 weeks

Outcome Measure Data

Analysis Population Description

Intention to treat participants

Arm/Group Title	Rituximab	Placebo
Arm/Group Description	- Treatment group received two cycles of rituximab (375mg/m2 iv), separated by 6 months. Each cycle defined as one infusion per week for four consecutive weeks. For the main study, participants were followed for 52 weeks. Study participants had clinical evaluations performed by a blinded evaluator at baseline and every 4 weeks thereafter.	- Placebo group received infusion containing only vehicle components of rituximab solution. Infusion was done in 2 cycles, separated by 6 months. Each cycle defined as one infusion per week for four consecutive weeks. For the main study, participants were followed for 52 weeks. Study participants had clinical evaluations performed by a blinded evaluator at baseline and every 4 weeks thereafter.
Measure Participants	25	27
Mean (Standard Deviation) [score on a scale]	-5.7 (7.26)	-4.0 (4.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab, Placebo
	Comments	This objective was assessed longitudinally by comparing the final score at the end of the study to the score obtained at baseline. The outcome was defined as the change from baseline to week 52 in the MGC. This hypothesis was assessed using a linear regression model, adjusted for differences in baseline MGC scores.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.93
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.11
	Confidence Interval	(1-Sided) 90%; to 2.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change in Quantitative Myasthenia Gravis(QMG) Scores From Baseline to Week 52
Description	Evaluate whether there is a trend towards clinical benefit at end of 52 week treatment period, as measured by the mean change in the QMG score - a specific clinical outcome scale used as endpoint in prior MG clinical trials. The Quantitative Myasthenia Gravis Score (QMG) is a commonly used objective outcome measure in myasthenia gravis (MG) comprising 13 items, each with a possible score from 0 to 3, and a maximum possible of 39 points, where a higher score indicates more severe disease.
Time Frame	baseline and 52 weeks

Outcome Measure Data

Analysis Population Description

Intention to treat participants

Arm/Group Title	Rituximab	Placebo
Arm/Group Description	- Treatment group received two cycles of rituximab (375mg/m2 iv), separated by 6 months.Each cycle defined as one infusion per week for four consecutive weeks.For the main study, participants were followed for 52 weeks.Study participants had clinical evaluations performed by a blinded evaluator at baseline and every 4 weeks thereafter.	- Placebo group received infusion containing only vehicle components of rituximab solution. Infusion was done in 2 cycles , separated by 6 months. Each cycle defined as one infusion per week for four consecutive weeks. For the main study, participants were followed for 52 weeks. Study participants had clinical evaluations performed by a blinded evaluator at baseline and every 4 weeks thereafter.
Measure Participants	25	27
Mean (Standard Deviation) [score on a scale]	-3.95 (5.43)	-1.70 (3.91)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab, Placebo
	Comments	This objective was assessed longitudinally by comparing the final score at the end of the study to the score obtained at baseline. The outcome was defined as the change from baseline to week 52 in the QMG. This hypothesis was assessed using a linear regression model, adjusted for differences in baseline QMG scores.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.39
	Comments
	Method	Regression, Linear
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.09
	Confidence Interval	(1-Sided) 90%; to 1.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	52 weeks
Arm/Group Title	Rituximab		Placebo Group
Arm/Group Description	- Treatment group received two cycles of rituximab (375mg/m2 iv), separated by 6 months. Each cycle defined as one infusion per week for four consecutive weeks. For the main study, participants were followed for 52 weeks. Study participants had clinical evaluations performed by a blinded evaluator at baseline and every 4 weeks thereafter.		- Placebo group received infusion containing only vehicle components of rituximab solution. Infusion was done in 2 cycles, separated by 6 months. Each cycle defined as one infusion per week for four consecutive weeks. For the main study, participants were followed for 52 weeks. Study participants had clinical evaluations performed by a blinded evaluator at baseline and every 4 weeks thereafter.
All Cause Mortality
	Rituximab		Placebo Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/25 (0%)		0/27 (0%)
Serious Adverse Events
	Rituximab		Placebo Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/25 (36%)		14/27 (51.9%)
Blood and lymphatic system disorders
Anaemia	0/25 (0%)	0	1/27 (3.7%)	1
Leukopenia	1/25 (4%)	1	0/27 (0%)	0
Cardiac disorders
Cardiac failure congestive	0/25 (0%)	0	1/27 (3.7%)	1
Coronary artery disease	0/25 (0%)	0	1/27 (3.7%)	2
Gastrointestinal disorders
Colonic obstruction	0/25 (0%)	0	1/27 (3.7%)	1
Diverticulum intestinal	0/25 (0%)	0	1/27 (3.7%)	1
Small intestinal obstruction	0/25 (0%)	0	1/27 (3.7%)	1
General disorders
Chest pain	0/25 (0%)	0	1/27 (3.7%)	1
Pyrexia	0/25 (0%)	0	1/27 (3.7%)	1
Immune system disorders
Hypersensitivity	1/25 (4%)	1	0/27 (0%)	0
Infections and infestations
Abscess neck	0/25 (0%)	0	1/27 (3.7%)	2
Cellulitis	0/25 (0%)	0	1/27 (3.7%)	1
Clostridium difficile colitis	0/25 (0%)	0	1/27 (3.7%)	1
Diverticulitis	1/25 (4%)	1	0/27 (0%)	0
Pneumonia	0/25 (0%)	0	1/27 (3.7%)	1
Sepsis	0/25 (0%)	0	1/27 (3.7%)	1
Septic shock	1/25 (4%)	1	0/27 (0%)	0
Injury, poisoning and procedural complications
Spinal compression fracture	0/25 (0%)	0	1/27 (3.7%)	1
Vascular pseudoaneurysm	1/25 (4%)	1	0/27 (0%)	0
Investigations
Platelet count decreased	1/25 (4%)	1	0/27 (0%)	0
Metabolism and nutrition disorders
Hyperglycaemia	1/25 (4%)	1	0/27 (0%)	0
Hyperkalaemia	0/25 (0%)	0	1/27 (3.7%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate cancer	0/25 (0%)	0	1/27 (3.7%)	1
Nervous system disorders
Worsening of MG	1/25 (4%)	1	3/27 (11.1%)	4
Psychiatric disorders
Psychotic disorder	1/25 (4%)	1	0/27 (0%)	0
Renal and urinary disorders
Nephrolithiasis	1/25 (4%)	1	0/27 (0%)	0
Reproductive system and breast disorders
Menorrhagia	1/25 (4%)	1	0/27 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/25 (0%)	0	1/27 (3.7%)	1
Pulmonary embolism	1/25 (4%)	1	1/27 (3.7%)	1
Surgical and medical procedures
Micrographic skin surgery	0/25 (0%)	0	1/27 (3.7%)	1
Vascular disorders
Hypotension	1/25 (4%)	1	0/27 (0%)	0
Thrombosis	0/25 (0%)	0	1/27 (3.7%)	1
Venous thrombosis limb	1/25 (4%)	1	0/27 (0%)	0
Other (Not Including Serious) Adverse Events
	Rituximab		Placebo Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/25 (100%)		26/27 (96.3%)
Ear and labyrinth disorders
Vertigo	2/25 (8%)	2	0/27 (0%)	0
Eye disorders
Vision blurred	1/25 (4%)	1	2/27 (7.4%)	2
Gastrointestinal disorders
Abdominal pain	3/25 (12%)	3	2/27 (7.4%)	2
Constipation	1/25 (4%)	1	2/27 (7.4%)	2
Diarrhoea	3/25 (12%)	4	2/27 (7.4%)	2
Nausea	2/25 (8%)	3	6/27 (22.2%)	10
Vomiting	2/25 (8%)	2	2/27 (7.4%)	2
Pyrexia	2/25 (8%)	2	1/27 (3.7%)	1
General disorders
Fatigue	3/25 (12%)	3	8/27 (29.6%)	9
Influenza like illness	3/25 (12%)	4	2/27 (7.4%)	2
Oedema peripheral	1/25 (4%)	1	2/27 (7.4%)	3
Injection site reaction	2/25 (8%)	3	0/27 (0%)	0
Immune system disorders
Hypersensitivity	3/25 (12%)	3	0/27 (0%)	0
Infections and infestations
Bronchitis	1/25 (4%)	1	3/27 (11.1%)	4
Cellulitis	2/25 (8%)	2	1/27 (3.7%)	1
Gastroenteritis	0/25 (0%)	0	3/27 (11.1%)	3
Oral candidiasis	1/25 (4%)	1	2/27 (7.4%)	2
Rhinitis	2/25 (8%)	3	2/27 (7.4%)	2
Sinusitis	2/25 (8%)	2	3/27 (11.1%)	4
Upper respiratory tract infection	9/25 (36%)	12	5/27 (18.5%)	5
Urinary tract infection	2/25 (8%)	2	3/27 (11.1%)	5
Pneumonia	2/25 (8%)	2	0/27 (0%)	0
Fungal skin infection	2/25 (8%)	2	0/27 (0%)	0
Injury, poisoning and procedural complications
Contusion	2/25 (8%)	2	1/27 (3.7%)	1
Fall	0/25 (0%)	0	3/27 (11.1%)	3
Neck pain	0/25 (0%)	0	2/27 (7.4%)	2
Investigations
Weight increased	0/25 (0%)	0	2/27 (7.4%)	2
Metabolism and nutrition disorders
Dehydration	2/25 (8%)	2	1/27 (3.7%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	6/25 (24%)	6	10/27 (37%)	15
Back pain	2/25 (8%)	2	9/27 (33.3%)	11
Muscle spasms	3/25 (12%)	3	1/27 (3.7%)	1
Muscular weakness	4/25 (16%)	4	3/27 (11.1%)	4
Musculoskeletal pain	3/25 (12%)	3	1/27 (3.7%)	1
Myalgia	1/25 (4%)	2	4/27 (14.8%)	5
Pain in extremity	3/25 (12%)	3	4/27 (14.8%)	9
Nervous system disorders
Dizziness	3/25 (12%)	3	1/27 (3.7%)	1
Headache	8/25 (32%)	11	7/27 (25.9%)	13
Paraesthesia	0/25 (0%)	0	5/27 (18.5%)	7
Tremor	2/25 (8%)	3	3/27 (11.1%)	4
Renal and urinary disorders
Urinary retention	0/25 (0%)	0	2/27 (7.4%)	2
Respiratory, thoracic and mediastinal disorders
Cough	0/25 (0%)	0	3/27 (11.1%)	3
Dysphonia	0/25 (0%)	0	2/27 (7.4%)	3
Dyspnoea	2/25 (8%)	2	1/27 (3.7%)	1
Nasal congestion	2/25 (8%)	2	1/27 (3.7%)	1
Oropharyngeal pain	3/25 (12%)	3	0/27 (0%)	0
Respiratory tract congestion	0/25 (0%)	0	2/27 (7.4%)	2
Rhinorrhoea	3/25 (12%)	3	0/27 (0%)	0
Skin and subcutaneous tissue disorders
Rash	3/25 (12%)	3	2/27 (7.4%)	2
Rash maculo-papular	1/25 (4%)	1	3/27 (11.1%)	3
Skin lesion	0/25 (0%)	0	2/27 (7.4%)	3
Surgical and medical procedures
Cataract operation	0/25 (0%)	0	2/27 (7.4%)	2
Vascular disorders
Hypotension	2/25 (8%)	2	0/27 (0%)	0

Limitations/Caveats

[Not Specified]

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Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.