IRB Study Number 25-961
Status Recruiting
Phase Phase 3
Location Cleveland Clinic Main Campus
Institute Neurological Institute
Description
The purpose of this study is to evaluate the efficacy, safety and tolerability of remibrutinib in patients with generalized Myasthenia Gravis (gMG) who are acetylcholine receptor positive (AChR+), muscle-specific tyrosine kinase positive (MuSK+), or double-seronegative (AChRand MuSK-) who are on stable, standard-of-care (SOC) treatment. The study aims to evaluate whether treatment with remibrutinib will result in the reduction of the total score in Myasthenia Gravis Activity of Daily Living (MG-ADL) scale as compared to placebo.
Inclusion Criteria
Participants eligible for inclusion in this study must meet all of the following criteria:
Adult patients with gMG (age 18-75 years) able to understand the requirements of the trial, provide written informed consent, and comply with the trial protocol procedures
Confirmed diagnosis of MGFA Class II-IV gMG at screening and likely not in need of a respirator for the duration of the study, as judged by the Investigator.
The confirmation of the diagnosis of gMG should be documented and supported by ≥1 (AChR+ and MuSK+ patients) or by ≥ 2 (double sero-negative patients) of the following 3 tests:
• History of abnormal neuromuscular transmission demonstrated by single-fiber electromyography or repetitive nerve stimulation
• History of positive test with short-acting acetylcholinesterase inhibitors (e.g., neostigmine or edrophonium chloride)
• Patient has demonstrated improvement in MG signs on oral acetylcholinesterase inhibitors as assessed by the treating physician
Documented evidence of positive serologic testing for AChR+ antibody or MuSK+ antibody at screening, OR seronegative for both AChR and MuSK antibodies at screening
Baseline MG-ADL score ≥ 6, with ≥ 50% of the total score due to non-ocular symptoms
Participants receiving at least one of the following treatments for gMG and who have been on a stable dose for the specified time periods prior to baseline:
• just one NSIST for ≥ 6 months; and/or
• acetylcholinesterase inhibitors for ≥ 1 month on a maximum stable dose; and/or
• steroids for ≥ 4 months including the inability to taper to an acceptable level
Note: Non-steroidal immunosuppressive therapies (NSIST) include azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, or tacrolimus
Participants who are receiving azathioprine, are required to have been on azathioprine for at least 6 months and on a stable dose for at least 2 months prior to baseline
Participants who are receiving other immunosuppressive therapies (i.e., mycophenolate mofetil, methotrexate, cyclosporine, or tacrolimus) are required to be on these immunosuppressive therapies for at least 6 months and to have been on a stable dose for at least 1 month prior to baseline
Participants receiving oral corticosteroids are required to be on a stable dose for at least 4 weeks (i.e., 28 days or longer) prior to baseline
Participants receiving a cholinesterase inhibitor, are required be on a stable dose for at least 2 weeks prior to baseline
Able to safely swallow the study medication according to investigator clinical judgement based on a bedside swallowing test or another formal swallowing test in line with local practice, both at Screening and Baseline
Exclusion Criteria
Participants meeting any of the following criteria are not eligible for inclusion in this study.
Prior to baseline have been treated with IVIg/PLEX in the past month, with rituximab in the past 6 months, eculizumab in the past 2 months, ravulizumab or other complement inhibitors in the past 3 months, efgartigimod or other anti-FcRn therapies in the past 3 months, or had a thymectomy in the past 6 months or a planned thymectomy during the trial period
Participants at risk of developing or having reactivation of hepatitis: Positive results at screening for serological markers for hepatitis (H) A, B, C, and E indicating acute or chronic infection:
• anti-HA Immunoglobulin (Ig) M (IgM)
• HB surface Antigen (HBs Ag) and/or anti-HBc IgM and/or HB virus deoxyribonucleic acid (DNA)
• anti-HBc positive
• anti-HC IgG (if positive IgG, HC Virus (HCV)-RNA Polymerase Chain Reaction will be performed and if negative, participant can be randomized)
• anti-HE IgM positive (regardless of IgG status)
Participants with a known immunodeficiency syndrome (AIDS, hereditary immune deficiency, drug induced immune deficiency), or tested positive for HIV antibody, at screening
Pregnant or nursing (breast feeding) women
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and for 1 week after stopping study treatment. Highly effective contraception methods include:
• Total abstinence (when this is in line with the preferred and usual lifestyle of the participant. Periodic abstinence (e.g. calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.
• Bilateral tubal ligation, bilateral oophorectomy with or without hysterectomy, total hysterectomy, or bilateral salpingectomy at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered to be not of child-bearing potential.
• Male sterilization (vasectomy) of male partner(s) of the female participant at least 6 months prior to screening.
• Use of oral (estrogen and progesterone), injected or implanted hormonal methods of contraception or transdermal hormone contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example, hormone vaginal ring or transdermal hormone contraception.
In case of use of hormonal contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.
Women are considered post-menopausal if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age-appropriate history of vasomotor symptoms). Women participants are considered not of child-bearing potential if they are post-menopausal or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral salpingectomy at least six weeks prior to enrollment on study. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she considered to be not of child-bearing potential.
If local regulations are more stringent than the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the ICF.
Active systemic bacterial, viral (incl. COVID-19), parasitic, or fungal infection or any major episode of infection that required hospitalization or injectable antimicrobial therapy within 14 days prior to study drug administration
Have received any live or live-attenuated vaccines (including but not limited to varicella-zoster virus or measles, oral polio, nasal influenza) within 6 weeks prior to randomization or requirement to receive these vaccinations at any time during the study.
Note: It is generally encouraged to perform necessary last dose of vaccinations (including
COVID-19) at least 4 weeks before randomizing participants into the trial, if available,
and according to local practice. Timing of SARS-CoV-2 vaccination should be planned
according to the local guidelines, e.g., at least 7 (Medicines and Healthcare products
Regulatory Agency (MHRA)) to 14 (Centres for Disease Control and Prevention) days
apart from any prior vaccination (e.g., flu vaccine). Immune modulation of B-cells is
expected to affect the response to vaccination, and thus during treatment with
remibrutinib, vaccination (non-live vaccines) may be less effective.
Participants with worsening muscle weakness secondary to concurrent infections or medications (aminoglycosides, fluoroquinolones, beta-blockers, etc.)
History of hepatic disease that currently requires treatment or ongoing hepatic disease including, but not limited to, acute or chronic hepatitis, cirrhosis (including all Child-Pugh classes) or hepatic failure or any chronic liver or biliary disease or aspartate aminotransferase (AST) / alanine aminotransferase (ALT) levels of more than 2.0 x upper limit of normal (ULN) or total or conjugated bilirubin (TBL) greater than 1.5 x upper limit of normal (ULN), unless in the context of Gilbert’s syndrome, or International Normalized Ratio (INR) of more than 1.5, at screening
History of severe renal disease or creatinine level above 1.5 x ULN at screening
History of significant bleeding risk or coagulation disorders, at screening
Hematology parameters at screening:
• Hemoglobin: < 10 g/dl (<100g/L)
• Platelets: < 100000/mm3 (<100 x 109/L)
• Absolute lymphocyte count < 800/mm3 (<0.8 x 109/L)
• White blood cells: <3 000/mm3 (<3.0 x 109/L)
• Neutrophils: < 1 500/mm3 (<1.5 x 109/L)
Documented lack of clinical response to PLEX
Major surgery within 8 weeks prior to screening
Evidence of clinically significant cardiovascular (such as but not limited to myocardial infarction, unstable ischemic heart disease, New York Heart Association (NYHA) Class III/IV left ventricular failure, arrhythmia and uncontrolled hypertension within 6 months prior to screening), neurological, psychiatric, pulmonary (including, history of or active severe respiratory disease, including Chronic Obstructive Pulmonary Disease, interstitial lung disease or pulmonary fibrosis), renal, hepatic, endocrine, metabolic (e.g., severe hypoproteinemia due to nephrotic syndrome), hematological disorders or gastrointestinal disease that, in the Investigator's opinion, would compromise the safety of the participant, interfere with the interpretation of the study results or otherwise preclude participation or protocol adherence of the participant, prior to randomization
History of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases, at screening
History of autoimmune disease other than MG (e.g., thyroiditis, rheumatoid arthritis, etc.) that would interfere with an accurate assessment of clinical symptoms
Score “yes” on item 4 or item 5 of the suicidal ideation section of the C-SSRS, if this ideation occurred in the past 6 months, or “yes” on any item of the suicidal behavior section, except for the “Non-Suicidal Self-Injurious Behavior” (item also included in the suicidal behavior section), if this behavior occurred in the past 2 years, prior to randomization
Requirement for anticoagulant medication (e.g. warfarin or NOAC) or use of dual antiplatelet therapy (e.g., acetylsalicylic acid + clopidogrel). The use of acetylsalicylic acid up to 100 mg/day or clopidogrel up to 75 mg/day is permitted
History or current diagnosis of ECG abnormalities indicating significant risk of safety for subjects participating in the study such as:
• Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular tachycardia, and clinically significant second or third degree atrioventricular (AV) block without a pacemaker or requiring anti-arrhythmic treatment with Class Ia or Class III anti-arrhythmic drugs
• History of familial long QT syndrome or known family history of Torsades de Pointes
• Resting QTcF ≥ 450 msec (male) or ≥ 460 msec (female) as per central ECG reading at screening visit
• Use of agents known to prolong the QT interval unless they can be permanently discontinued for the duration of the study
Use of strong CYP3A4 inhibitors, or use of moderate or strong CYP3A4 inducers within two weeks prior to randomization.
Patient not controlled on rituximab (2 cycles) or other high efficacy therapies like complement inhibitors and FcRn antagonists
Patient requiring frequent (quarterly or more frequent) plasmapheresis, plasma exchange, or intravenous immunoglobulin to control symptoms
History of hypersensitivity to any of the study drugs or excipients (including rare hereditary problems of galactose intolerance, total lactase deficiency and glucosegalactose malabsorption) or to drugs of similar chemical classes, at screening
Ongoing drug or alcohol abuse that could interfere with patient's participation in the trial
Participation in any other investigational drug trial or use of other investigational drugs at the time of enrollment, or within 5 elimination half-lives of enrollment, or within 30 days of enrollment whichever is longer; or longer if required by local regulations
Use of prohibited medication prior to screening/randomization (as defined in Table 6-5)
Participants who have not previously responded to other BTK inhibitors
Participants who have had a splenectomy
Participants with electrolyte abnormalities (hypokalemia or hypomagnesemia) that cannot be corrected
