The Evaluation of Belimumab in Myasthenia Gravis (MG)

Study Overview
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Brief Summary
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Study BEL115123 is a randomized, placebo-controlled, double-blind, multinational study of belimumab (10 mg/kg) to investigate the efficacy and safety of belimumab in subjects with MG. The study will enroll male and female outpatients (> or equal to 18 years of age) with a diagnosis of MG who are 1) acetylcholine receptor (AChR) antibody positive or muscle specific kinase (MuSK) antibody positive, 2) on current standard of care therapy, and 3) continue to exhibit signs of MG. The study will include 3 phases: a 4 week screening period, a 24 week treatment period, and a 12 week follow-up period. IP will be administered intravenously on Days 0, 14, 28 and then every 28 days through and including Week 20. At Week 24, primary outcomes will be obtained. Follow up evaluations will be conducted at Weeks 28, 32 and 36 for all subjects. The primary objective of this study is to assess the efficacy of belimumab as evaluated by the change in the quantitative myasthenia gravis (QMG) score.

Official Title
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A Randomized, Placebo-Controlled, Double-Blind Study to Evaluate the Efficacy, Safety, Tolerability, and Pharmacodynamics of Belimumab in Subjects With Generalized Myasthenia Gravis (MG)

Conditions
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Myasthaenia Gravis

Intervention / Treatment
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* Biological: Belimumab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years and older, with life expectancy of greater than 1 year. MG of class II to IVa inclusive. Acetylcholine receptor (AChR) or muscle specific kinase (MuSK) antibody positive. Stable dose (defined as no dose changes) not exceeding the maximum doses given in Section 5.6.1 of the following therapy(ies) prior to screening: Cholinesterase inhibitor(pyridostigmine or equivalent) for at least 2 weeks prior to screening and no immunosuppressants; Cholinesterase inhibitor (pyridostigmine or equivalent) for at least 2 weeks prior to screening and/or only one of the following: prednisone (up to 40 mg/day or equivalent) for at least 1 month prior to screening; azathioprine for at least 6 months prior to screening; mycophenolate for at least 6 months prior to screening, or cyclosporine for at least 3 months prior to screening; or Cholinesterase inhibitor (pyridostigmine or equivalent) for at least 2 weeks prior to screening and/or prednisone (up to 20 mg/day or equivalent) for at least 1 month prior to screening and only one of the following: azathioprine for at least 6 months prior to screening, mycophenolate for at least 6 months prior to screening, or cyclosporine for at least 3 months prior to screening Quantitative Myasthenia Gravis (QMG) score of 8 or greater, with at least 4 points derived from signs other than ocular A female subject is eligible to participate if she is: Of non-childbearing potential; Of childbearing potential and NOT pregnant or nursing, has a negative serum pregnancy test at screening, and agrees to one of the following: Complete abstinence from penile-vaginal intercourse, when this is the female's preferred and usual lifestyle, for the period from consent into the study until 16 weeks after the last dose of investigational product; or Consistent and correct use of one of the following acceptable methods of birth control for the period from consent into the study until 16 weeks after the last dose of investigational product: Oral contraceptives (either combined or progesterone only), Injectable progesterone, Implants of etonogestrel or levonorgestrel, Estrogenic vaginal ring, Percutaneous contraceptive patches, Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of less than 1% per year, Male partner sterilization (vasectomy with documentation of azoospermia) prior to the female subject's entry into the study; this male must be the sole partner for the subject, Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository). Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. Single QTc less than 450 msec; or QTc less than 480 msec in subjects with Bundle Branch Block. AST and ALT less than 2xULN; alkaline phosphatase and bilirubin less or = to 1.5xULN (isolated bilirubin greater than 1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin less than 35%). Exclusion Criteria: Participated in a clinical trial and has received an investigational product within 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer) prior to screening or planning to take any investigational drug for the planned duration of study participation (6 months after the last dose of study drug). Presence or previous history of thymoma. Thymectomy within 12 months Clinically significant (in the opinion of investigator) abnormal laboratory values. Pregnant females as determined by positive (serum) hCG test at screening or prior to dosing, or lactating females or planning to become pregnant within 16 weeks after last dose of investigational product. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation. May require (in the opinion of investigator) treatment with IVIg and/or plasmapheresis during the 24 week treatment period. Have received IVIg and/or plasmapheresis within 90 days prior to screening. Have received any other biopharmaceutical agent (except IVIg as described in exclusion criteria #8) in the 364 days prior to screening. Have received treatment with any B cell targeted therapy (e.g., rituximab, belimumab), at any time. Have received a live vaccine within 30 days of study Day 0 (baseline). Have received cyclophosphamide or any other immunosuppressive agent apart from the ones allowed by the inclusion criteria #4, within the past 6 months. Have another medical condition that requires treatment with steroids or immunosuppressive agents. Hospitalization due to infection or use of parenteral antibacterial, antifungal or antiviral agents within 60 days prior to screening; or history of recurrent or chronic infection, or currently active systemic infection. Have a history of malignant neoplasm within the last 5 years, except for adequately treated cancers of the skin (basal or squamous cell) or carcinoma in situ of the uterine cervix. Have a history of a major organ transplant (eg, heart, lung, kidney, liver) or hematopoietic stem cell/marrow transplant. Have a historically positive test or test positive at screening for HIV-1, hepatitis B surface antigen or hepatitis C antibody. Have an IgG Grade 3 or greater deficiency (less than or = to 400mg/dL). Have an IgA deficiency (IgA less than 10mg/dL). Have a history of an anaphylactic reaction to parenteral administration of contrast agents, human or murine proteins or monoclonal antibodies. Has a progressive medical, neurological or psychological condition or situation that, in the investigator's judgment, is likely to cause the subject to be unable or unwilling to participate in study procedures, to complete all scheduled assessments, or precludes accurate assessments. Is currently abusing drugs or alcohol or has history of abuse in the last 12 months. Subjects who have evidence of serious suicide risk including any history of suicidal behavior in the last 6 months and/or any suicidal ideation of type 4 or 5 on the C-SSRS in the last 2 months or who in the investigator's judgment, pose a significant suicide risk.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Belimumab<br>10mg/kg | Biological: Belimumab<br>* 10mg/kg IV infusion<br>|
| Placebo Comparator: Placebo<br>placebo IV infusion | Other: Placebo<br>* placebo IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline for Quantitative Myasthenia Gravis (QMG) Score at Week 24 | The QMG is a 13 item ordinal scale which measures ocular, bulbar, extremity fatigue and strength, along with respiratory function. The total QMG score was calculated by adding the score of each of the 13 individual QMG questions. Possible scoring on the QMG range from 0 (normal) to 39 (severe). A lower score indicates a better clinical outcome. The QMG score at Baseline is the average of the screening and Week 0 Baseline scores. Change from Baseline was calculated by subtracting the Baseline value from the post-baseline value. The differences in adjusted least square means were presented (Belimumab 10 mg/kg minus Placebo). A negative treatment difference indicates benefit relative to placebo. The analysis method was Mixed-Model Repeated Measures adjusted for Treatment, Visit, Baseline QMG Score, Treatment by Visit, and Baseline QMG Score by Visit. | Baseline and Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Worsening by >=3 Points From Baseline Through to Week 24 in the MGC Score | The total MGC score was calculated by adding the score of each of the 10 individual MGC questions. Possible total MGC scores range from 0 (normal) to 50 (severe). A lower score indicates a better clinical outcome. Baseline is defined as the participants last available assessment prior to initiation of study IV infusion. Proportions compared using exact analyses stratified by the observed median baseline score (<= median, > median). Exact odds ratios, double the exact one-sided p-values and exact confidence intervals were presented. Participants with missing data were assumed to have a worsening response. | Baseline and up to Week 24 | 
| Number of Participants With a Sustained Response in the MGC Score | AA sustained response during the treatment phase is when a participant improves by >=3 points from Baseline at Week 12, and the participant maintains at least a 3 point improvement from Baseline through Week 24. The total MGC score was calculated by adding the score of each of the 10 individual MGC questions. Possible total MGC scores range from 0 (normal) to 50 (severe). A lower score indicates a better clinical outcome. Baseline is defined as the participants last available assessment prior to initiation of study IV infusion. Odds ratios are calculated by Cochran-Mantel-Haenszel method without adjusting for any strata. Wald confidence intervals and p-values were presented. | Baseline and up to Week 24 | 
| Median Time to MGC Response Which is Sustained From Earliest Time Point at Which Improvement by >=3 Points From Baseline is Observed and Maintained Through Week 24 | A sustained response during the treatment phase is when a participant improves by >=3 points from Baseline at Week 12, and the participant maintains at least a 3 point improvement from Baseline through Week 24. The total MGC score was calculated by adding the score of each of the 10 individual MGC questions. Possible total MGC scores range from 0 (normal) to 50 (severe). A lower score indicates a better clinical outcome. Baseline is defined as the participants' last available assessment prior to initiation of study intravenous (IV) infusion. | Baseline and up to Week 24 | 
| Number of Participants With Improvement by Greater Than or Equal to (>=) 3 Points From Baseline Through to Week 24 in the QMG Score | The QMG is a 13 item ordinal scale which measures ocular, bulbar, extremity fatigue and strength, along with respiratory function. The total QMG score was calculated by adding the score of each of the 13 individual QMG questions. Possible scoring on the QMG range from 0 (normal) to 39 (severe). A lower score indicates a better clinical outcome. The QMG score at Baseline is the average of the screening and Week 0 Baseline scores. Proportions compared using exact analyses stratified by the observed median Baseline score (less than or equal to [<=] median, greater than [ >] median). Exact odds ratio, double the exact one-sided p-value and exact confidence intervals were presented. Participants with missing data were assumed to have a negative response. | Baseline and up to Week 24 | 
| Number of Participants Worsening by >=3 Points in QMG Score From Baseline Through to Week 24 | The QMG is a 13 item ordinal scale which measures ocular, bulbar, extremity fatigue and strength, along with respiratory function. The total QMG score was calculated by adding the score of each of the 13 individual QMG questions. Possible scoring on the QMG range from 0 (normal) to 39 (severe). A lower score indicates a better clinical outcome. The QMG score at Baseline is the average of the screening and Week 0 Baseline scores. Proportions compared using exact analyses stratified by the observed median Baseline score (<=median, > median). Exact odds ratio, double the exact one-sided p-value and exact confidence interval were presented. Participants with missing data were assumed to have a worsening response. | Baseline and up to Week 24 | 
| Number of Participants With a Sustained Response in the QMG Score | A sustained response during the treatment phase is when a participant improves by >=3 points from Baseline at Week 12, and the participant maintains at least a 3 point improvement from Baseline through Week 24. The QMG is a 13 item ordinal scale which measures ocular, bulbar, extremity fatigue and strength, along with respiratory function. The total QMG score was calculated by adding the score of each of the 13 individual QMG questions. Possible scoring on the QMG range from 0 (normal) to 39 (severe). A lower score indicates a better clinical outcome. The QMG score at Baseline is the average of the screening and Week 0 Baseline scores. Odds ratios are calculated by Cochran-Mantel-Haenszel method stratified by the observed median baseline score (<= median, > median). Wald confidence intervals and p-values were presented. | Baseline and up to Week 24 | 
| Median Time to QMG Response Which is Sustained From Earliest Time Point at Which Improvement by >=3 Points From Baseline is Observed and Maintained Through Week 24 | A sustained response during the treatment phase is when a participant improves by >=3 points from Baseline at Week 12, and the participant maintains at least a 3 point improvement from Baseline through Week 24. The QMG is a 13 item ordinal scale which measures ocular, bulbar, extremity fatigue and strength, along with respiratory function. The total QMG score was calculated by adding the score of each of the 13 individual QMG questions. Possible scoring on the QMG range from 0 (normal) to 39 (severe). A lower score indicates a better clinical outcome. The QMG score at Baseline is the average of the screening and Week 0 Baseline scores. | Baseline and up to Week 24 | 
| Mean Change From Baseline for QMG Score at Week 28, Week 32 and Week 36 | The QMG is a 13 item ordinal scale which measures ocular, bulbar, extremity fatigue and strength, along with respiratory function. Total QMG score was calculated by adding the score of each of the 13 individual QMG questions. Possible scoring on the QMG range from 0 (mild) to 39 (severe). A lower score indicates a better clinical outcome. The QMG score at baseline (BL) is the average of the screening and Week 0 BL scores. Change from BL was calculated by subtracting the BL value from the post-BL value. The differences in adjusted least square means are presented (Belimumab 10 mg/kg minus Placebo). A negative trt difference indicates benefit relative to placebo. Analysis method was Mixed-Model Repeated Measures adjusted for Trt, Visit, BL QMG Score, Trt by Visit and BL QMG Score by Visit. Only follow-up visits are presented but the analysis also includes all trt phase visits. Only those par. available at indicated time points (represented by n=X in the category titles) were analyzed. | Baseline, Week 28, Week 32 and Week 36 | 
| Mean Change From Baseline in Myasthenia Gravis Composite (MGC) Scale Through to Week 24 | The total MGC score was calculated by adding the score of each of the 10 individual MGC questions. Possible total MGC scores range from 0 (normal) to 50 (severe). A lower score indicates a better clinical outcome. Baseline is defined as the participants last available assessment prior to initiation of study IV infusion. Change from Baseline was calculated by subtracting the Baseline value from the post-baseline value. The differences in adjusted least square means are presented (Belimumab 10 mg/kg minus Placebo). A negative treatment difference indicates benefit relative to placebo. The analysis method was Mixed-Model Repeated Measures adjusted for Treatment, Visit, Baseline MGC Score, Treatment by Visit, and Baseline MGC Score by Visit. | Baseline and up to Week 24 | 
| Number of Participants With Improvement by >=3 Points From Baseline Through to Week 24 in the MGC Score | The total MGC score was calculated by adding the score of each of the 10 individual MGC questions. Possible total MGC scores range from 0 (normal) to 50 (severe). A lower score indicates a better clinical outcome. Baseline is defined as the participants last available assessment prior to initiation of study IV infusion. Proportions compared using exact analyses stratified by the observed median baseline score (<= median, > median). Exact odds ratios, double the exact one-sided p-values and exact confidence intervals were presented. Participants with missing data were assumed to have a negative response. | Baseline and up to Week 24 | 
| Mean Change From Baseline for MGC Score at Week 28, Week 32 and Week 36 | The total MGC score was calculated by adding the score of each of the 10 individual MGC questions. Possible total MGC scores range from 0 (normal) to 50 (severe). A lower score indicates a better clinical outcome. Baseline is defined as the participant's last available assessment prior to initiation of study IV infusion. Change from Baseline was calculated by subtracting the Baseline value from the post-BL value. The differences in adjusted least square means are presented (Belimumab 10 mg/kg minus Placebo). A negative treatment difference indicates benefit relative to placebo. The analysis method was Mixed-Model Repeated Measures adjusted for Treatment, Visit, Baseline MGC Score, Treatment by Visit, and Baseline MGC Score by Visit. Only follow-up visits are presented but the analysis also includes all treatment phase visits. Only those participants available at the indicated time points (represented by n=X in the category titles) were analyzed. | Baseline, Week 28, Week 32 and Week 36 | 
| Number of Participants With a Myasthenia Foundation of America-post Intervention Status (MGFA-PIS) of Minimal Manifestation or Better at Week 24 and Week 36. | Myasthenia Foundation of America-post intervention status assesses whether subjects can be categorized as being in a status of Minimal Manifestation (MM), Pharmacologic Remission (PR) or Complete Remission (CR). Only MM and PR were assessed in this study as CR is not achievable based on the definition. | Week 24 and Week 36 | 
| Number of Participants With MGFA-PIS of Pharmacologic Remission or Better at Week 24 and Week 36 | Myasthenia Foundation of America (MGFA) post intervention status (PIS) assesses whether subjects can be categorized as being in a status of Minimal Manifestation (MM), Pharmacologic Remission (PR) or Complete Remission (CR). Only MM and PR were assessed in this study as CR is not achievable based on the definition. | Week 24 and Week 36 | 
| Number of Participants With MGFA-PIS of Minimal Manifestation Sustained Response (MM at Week 12 and Maintained the Response Through Week 24) | Myasthenia Foundation of America (MGFA) post intervention status (PIS) assesses whether subjects can be categorized as being in a status of Minimal Manifestation (MM), Pharmacologic Remission (PR) or Complete Remission (CR). Only MM and PR were assessed in this study as CR is not achievable based on the definition. | Week 12 through Week 24 | 
| Number of Participants With MGFA-PIS of Pharmacologic Response Sustained Response (PR at Week 12 and Maintained the Response Through Week 24) | Myasthenia Foundation of America (MGFA) post intervention status (PIS) assesses whether subjects can be categorized as being in a status of Minimal Manifestation (MM), Pharmacologic Remission (PR) or Complete Remission (CR). Only MM and PR were assessed in this study as CR is not achievable based on the definition. | Week 12 through Week 24 | 
| Number of Participants With MGFA-PIS (Unchanged, Improved, Worsened) at Week 24 and Week 36 | Myasthenia Foundation of America (MGFA) post intervention status (PIS) assesses whether subjects can be categorized as being unchanged, improved or worsened. | Week 24 and Week 36 | 
| Mean Change From Baseline in the Myasthenia Gravis Activities of Daily Living Scale (MG-ADL) at Week 12 and Week 24 | The total MG-ADL score was calculated by adding the score of each of the 8 individual MG-ADL questions. Possible total MG-ADL scores ranges from 0 (normal) to 24 (severe). A lower score indicates a better clinical outcome. Baseline is defined as the participants last available assessment prior to initiation of study IV infusion. Change from Baseline was calculated by subtracting the Baseline value from the post-baseline value. The differences in adjusted least square means are presented (Belimumab 10 mg/kg minus Placebo). A negative treatment difference indicates benefit relative to placebo. The analysis method was Mixed-Model Repeated Measures adjusted for Treatment, Visit, Baseline MG-ADL Score, Treatment by Visit, and Baseline MG-ADL Score by Visit. Only those participants available at the indicated time points (represented by n=X in the category titles) were analyzed. | Baseline, Week 12 and Week 24 | 
| Mean Change From Baseline in the Myasthenia Gravis Activities of Daily Living Scale (MG-ADL) at Week 28, Week 32 and Week 36 | The total MG-ADL score was calculated by adding the score of each of the 8 individual MG-ADL questions. Possible total MG-ADL scores range from 0 (normal) to 24 (severe). A lower score indicates a better clinical outcome. Baseline is defined as the participant's last available assessment prior to initiation of study IV infusion. Change from Baseline was calculated by subtracting the Baseline value from the post-Baseline value. The differences in adjusted least square means are presented (Belimumab 10 mg/kg minus Placebo). A negative treatment difference indicates benefit relative to placebo. The analysis method was Mixed-Model Repeated Measures adjusted for Treatment, Visit, Baseline MG-ADL Score, Treatment by Visit, and Baseline MG-ADL Score by Visit. Only follow-up visits are presented but the analysis also includes all treatment phase visits. Only those participants available at the indicated time points (represented by n=X in the category titles) were analyzed. | Baseline, Week 28, Week 32 and Week 36 |