Treatment of MG, with an initial focus on patients with gMG treated with M281 injection and evaluation of the expected reduction of circulating levels of antibodies by blocking IgG recycling, including the pathogenic autoantibodies that cause MG, and to ameliorate manifestations of the disease. MedDRA version: 20.0 Level: PT Classification code 10028417 Term: Myasthenia gravis System Organ Class: 10029205 - Nervous system disorders
Conditions
Sponsors
Momenta Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Is a male or female outpatient =18 years of age. 2. Has a documented history of gMG and clinical signs/symptoms of gMG. 3. Has a documented diagnosis of gMG by a positive serologic test for a gMG-related pathogenic autoantibody (anti-AChR or anti-MuSK autoantibodies), confirmed at Screening, and is on stable therapy for MG. If the patient receives the first dose of M281 before the Screening results are available and the results are subsequently negative, the patient may be replaced. 4. Has a Myasthenia Gravis Foundation of America (MGFA) Clinical Classification Class II, III, or IVa at Screening. 5. Has a QMG score of =12 at Screening and Baseline. 6. If taking a glucocorticosteroid, the patient must provide/obtain documentation showing the dose and regimen has been stable for at least 4 weeks prior to Screening. 7. If taking an acetylcholinesterase inhibitor, the patient must provide/obtain documentation showing the dose and regimen has been stable for at least 2 weeks prior to randomization on Day 1. 8. If taking statins at Screening, the patient must provide/obtain documentation showing the dose and regimen has been stable for at least 2 months prior to Screening. 9. If currently receiving immunosuppressants, the patient must provide/obtain documentation showing that the patient has been on the given immunosuppressant for =6 months and has been on a stable dose for =3 months prior to Screening. Allowed concomitant immunosuppressants are azathioprine, mycophenolate mofetil/ mycophenolic acid, methotrexate, cyclosporine, tacrolimus, or cyclophosphamide. 10. Has total serum IgG, serum albumin, and serum calcium concentrations within the normal range of the reference laboratory at Screening. 11. Has sufficient venous access to allow drug administration by infusion and blood sampling as per the protocol. 12. Is up to date on all age-appropriate vaccinations as per routine local medical guidelines. 13. Women of childbearing potential, defined as women physiologically capable of becoming pregnant, must have a negative serum pregnancy test at the Screening visit and a negative urine pregnancy test at Baseline. Menopausal women must have an elevated serum follicle-stimulating hormone level (FSH) at Screening; if the FSH is not elevated, they are considered to be of childbearing potential and must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Baseline to be eligible. 14. Women of childbearing potential (including menopausal women who do not have elevated FSH) must agree to remain totally abstinent (ie, refrain from sexual intercourse during the study) or to consistently use a reliable and highly effective method of contraception (eg, condom plus diaphragm, condom plus spermicide, diaphragm plus spermicide, or intrauterine device or oral/injectable/implanted hormonal contraceptive used in combination with an additional barrier method) during the study and for 30 days after the last study treatment. Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method are not acceptable methods of contraception. Female condom and male condom should not be used together. 15. Male patients must agree to remain totally abstinent (ie, refrain from sexual intercourse during the study) or to consistently use a reliable and highly effective method of contraception (eg, condom plus diaphragm, condom plus spermicide
Exclusion criteria
Exclusion criteria: 1.Has MGFA Class I, IVb, or V disease, or presence of MG crisis (MGFA Class V) at Screening or Baseline, history of MG crisis within 1 month of the Screening visit, or fixed weakness (and/or ‘burnt out’ MG). 2.Has received rituximab or eculizumab within 12 months prior to Screening. 3.Has received plasmapheresis, immunoadsorption therapy, or IVIG within 6 weeks prior to randomization on Day 1. 4.Has a serious or clinically significant infection. 5.Has a chronic infection. 6.Has any confirmed or suspected clinical immunodeficiency syndrome not related to treatment of his/her gMG, including human immunodeficiency virus (HIV) infection, or has a family history of congenital or hereditary immunodeficiency. 7.Has a positive or equivocal QuantiFERON®-TB Gold test, and/or a known close exposure to family or individuals known to have tuberculosis. 8.Has had a splenectomy. 9.Received treatment for malignancy within the 5 years prior to Screening, with the exceptions of properly treated basal or squamous cell carcinoma of the skin or properly treated carcinoma in situ of the cervix. 10.Has a hypersensitivity to M281 or any constituent of the study drug solution. 11.Has had a prior severe drug reaction that included shock or severe hypersensitivity.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the safety and tolerability of treatment with M281 injection in patients with gMG who have an insufficient clinical response to ongoing, stable standard of care therapy. To determine the efficacy of M281 injection for gMG as measured by the change in Myasthenia Gravis – Activities of Daily Living (MG-ADL) score.;Secondary Objective: To evaluate the efficacy of M281 injection as measured by changes in the Quantitative Myasthenia Gravis (QMG) score and the revised Myasthenia Gravis Quality of Life - 15 Scale (MG-QoL15r). To determine the pharmacokinetics (PK) of M281 injection. To estimate the pharmacodynamic (PD) activity of M281 injection as measured by effects on total serum immunoglobulin (Ig)G concentrations.;Primary end point(s): 1. M281 safety will be evaluated in terms of the incidence of AEs compared to placebo. 2. Change of MG-ADL score for each treatment group from baseline to Day 57. It will be evaluated via dose-response analyses and with mixed-effects model repeated measures (MMRM) analyses.;Timepoint(s) of evaluation of this end point: Dose-respond analyses and MMRM analyses will be performed using data from Day 15, 29, 43 and 57. MMRM analyses will include variables for baseline MG-ADL score, treatment-by-study week interaction, and autoantibody type, with variance-covariance structure assumed as compound symmetry. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. A model-based analysis of total MG-ADL score change from Baseline and difference from placebo in relationship to total serum IgG percent of Baseline and treatment frequency. All five study arms will be included in a simultaneous analysis of total MG-ADL score as a function of total serum IgG (Baseline to Day 57). 2. A model-based analysis of total MG-ADL score change from Baseline and difference from placebo during the study as a response to percent change in total serum IgG (Baseline to Day 57), for patients positive for anti-AChR antibodies only. 3. Responder analysis: number of patients with a 2-, 3-, 4-, 5-, 6-, 7-, or =8-point improvement in total MG-ADL score from Baseline to Day 57. 4. Change in total QMG score from Baseline to Day 57. 5. Change in total MG-QoL15r score from Baseline to Day 57. 6. Shift in MGFA classification from Baseline to Day 57 for each treatment group. 7. Change in total serum IgG from Baseline to Day 57 for each treatment group. 8. Change in total MG-ADL, QMG, and MG-QoL15r scores over time after the last dose. 9. Responder analysis: number of patients with a 2-, 3-, 4-, 5-, 6-, 7-, or =8-point improvement in total QMG score over time after the last dose. 10. Shift in MGFA classification over time after the last dose. 11. Change in total serum IgG over time after the last dose.;Timepoint(s) of evaluation of this end point: The model-based analysis of total MG-ADL score change from Baseline, change from placebo will assess a set of monotonic models to define the effect of IgG lowering on MG-ADL changes from baseline to Day 57. The models will be averaged and the effects will be summarized by median IgG lowering for each of the treatment groups. A second analysis will perform the same model-based assessment (from Baseline to Day 57) including only patients positive for anti-AChR antibodies. | — |
Countries
Belgium, Canada, France, Germany, Italy, Poland, Spain, United Kingdom, United States
Contacts
Public ContactClinical Trial Information Desk
Momenta Pharmaceuticals, Inc.
Outcome results
None listed