復發型多發性硬化症

本試驗將評估fenebrutinib相較於teriflunomide使用於復發型多發性硬化症(RMS)成人病患的療效和安全性。也將評估fenebrutinib的藥物動力學(PK)。

Fenebrutinib
Aubagio

Fenebrutinib
Teriflunomide

film-coated tablet
film-coated tablet (will be supplied in hard capsule in this trial for bouble-dummy purpose)

100 mg
14 mg

主要療效目的
本試驗的主要療效目的乃是根據年復發率(ARR)的主要指標，評估fenebrutinib相較於teriflunomide的療效

納入條件
納入試驗的病患必須符合以下條件：
●已簽署受試者同意書
●簽署受試者同意書時年齡為18-55歲(台灣僅納入20歲以上者)
●能夠遵守試驗計畫書
●篩選時EDSS分數為0至5.5分
●根據2017年修訂的McDonald標準以及以下條件之一診斷為RMS*：
-過去2年內至少有兩次臨床復發紀錄，或篩選前12個月內(但不得在篩選前30天內)有一次臨床復發紀錄
-在隨機分配前12個月內有書面證據顯示MRI上至少出現一個T1Gd+病灶
*依照2014年Lublin之定義，RMS得包括活動性繼發漸進型多發性硬化症(aSPMS)。
●在隨機分配和基準期評估前至少30天處於神經學穩定狀態
●兩隻手都能在＜ 240秒內完成9-HPT
●能夠在＜150秒內執行T25FWT
●針對具生育能力的女性：同意持續禁慾(不進行異性間性行為)或使用避孕方法，且同意不捐贈卵子，定義如下：
在治療期間、最後一劑試驗藥物後8週、一直到完成teriflunomide 排除程序為止，女性都必須保持禁慾，或使用每年失敗率＜ 1%的避孕方法(請見AUBAGIO的當地仿單)。女性在此相同期間內不得捐贈卵子。
若女性已有月經來潮且未達停經狀態(連續? 12個月沒有月經且未發現其他非更年期造成停經的原因)，並且沒有因為手術而導致永久不孕(移除卵巢、輸卵管及/或子宮)，或其他由試驗主持人判定的原因(例如：苗勒管發育不全)，即認定為具有生育能力。具有生育能力的定義可以依據當地指引或法規來修正。
每年失敗率＜ 1%的避孕方法範例包括雙側輸卵管結紮、男性絕育、使用可抑制排卵的荷爾蒙避孕劑、釋放荷爾蒙之子宮內避孕器，與含銅子宮內避孕器。
荷爾蒙避孕法必須搭配屏障式避孕法一同使用。
應依據臨床試驗期間以及病患的偏好與一般生活型態評估禁慾的可靠性。週期禁慾法(例如：月曆、排卵、基礎體溫法或排卵後期法)和性交中斷法均不是可接受的避孕方法。若當地規範或法規規定，將於當地受試者同意書內說明當地認可且接受的避孕方法以及有關禁慾可靠性的資料。
●針對男性：同意持續禁慾(不進行異性間性行為)或使用保險套，且同意不捐贈精子，定義如下：
若男性的女性伴侶具有生育能力或已懷孕，在治療期間、最後一劑試驗藥物後8週、一直到完成teriflunomide排除計畫為止，男性都必須保持禁慾或使用保險套(請見AUBAGIO的當地仿單)。男性在此相同期間內也不得捐贈精子。
應依據臨床試驗期間以及病患的偏好與一般生活型態評估禁慾的可靠性。週期禁慾法(例如：月曆、排卵、基礎體溫法或排卵後期法)和性交中斷法均不是可接受之避免藥物暴露的方法。若當地規範或法規規定，將於當地受試者同意書內說明有關禁慾可靠性的資料。

Patients who meet any of the following criteria will be excluded from study entry:
•Disease duration of 10 years from the onset of symptoms and an EDSS score at screening 2.0
•Pregnant or breastfeeding, or intending to become pregnant during the study or within 8 weeks (with ATEP) after the final dose of study drug (see Section 5.4.3.1 for more information regarding pregnancy)
Women of childbearing potential must have a negative serum pregnancy test at screening and negative urine pregnancy tests at all subsequent visits. If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test, ideally from the central laboratory.
•Men intending to father a child during the study or within 8 weeks (with ATEP) after final dose of study drug
•A diagnosis of PPMS or non-active SPMS
•Any known or suspected active infection at screening or baseline, or any major episode of infection requiring hospitalization or treatment with IV anti-microbials within 8 weeks prior to and during screening or treatment with oral anti-microbials within 2 weeks prior to and during screening
•History of confirmed or suspected progressive multifocal leukoencephalopathy (PML)
•History of cancer, including hematologic malignancy and solid tumors, within 10 years of screening
Basal or squamous cell carcinoma of the skin that has been excised and is considered cured and in situ carcinoma of the cervix treated with apparent success by curative therapy 1 year prior to screening is not exclusionary.
•Known presence of other neurological disorders, including, but not limited to, the following:
– History of ischemic cerebrovascular disorders (e.g., stroke, transient ischemic attack, spontaneous intracranial hemorrhage, or traumatic intracranial hemorrhage) or ischemia of the spinal cord
– History or known presence of CNS or spinal cord tumor (e.g., meningioma, glioma)
– History or known presence of potential metabolic causes of myelopathy (e.g., untreated vitamin B12 deficiency)
– History or known presence of infectious causes of myelopathy (e.g., syphilis, Lyme disease, HTLV-1, herpes zoster myelopathy)
– History of genetically inherited progressive CNS degenerative disorder (e.g., hereditary paraparesis, mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes [MELAS] syndrome)
– Neuromyelitis optica spectrum disorder
– History or known presence of systemic autoimmune disorders potentially causing progressive neurological disease (e.g., lupus, anti-phospholipid antibody syndrome, Sjögren syndrome, Behçet disease)
– History or known presence of sarcoidosis
– History of severe, clinically significant brain or spinal cord trauma (e.g., cerebral contusion, spinal cord compression)
•Evidence of clinically significant psychiatric, pulmonary, renal, hepatic (including Gilbert syndrome), metabolic, gastrointestinal (GI), or cardiovascular disease (including arrhythmias or QTc prolongation), or endocrine disease (including uncontrolled diabetes, non-gallstone pancreatitis, or chronic pancreatitis) that, in the investigator’s opinion, would preclude patient participation
•Presence of the New York Heart Association Class III and Class IV criteria for congestive heart failure
•Screening 12-lead ECG that demonstrates clinically relevant abnormalities that may affect patient safety or interpretation of study results, including QT interval corrected through use of Fridericia’s formula (QTcF) 440 ms demonstrated by at least two ECGs 30 minutes apart
•Current treatment with medications that are well known to prolong the QT interval at doses that have a clinically meaningful effect on QT, as determined by the investigator
•History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such as long QT syndrome and other genetic risk factors (e.g., Brugada syndrome); structural heart disease; coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic testing, prior coronary artery bypass grafting, or coronary lesions 70% diameter stenosis that have not been or cannot be re-vascularized); clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia); family history of sudden, unexplained death; or cardiac ion channel genetic mutations (e.g., congenital long QT syndrome)
•Rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption
•Hypoproteinemia (e.g., in case of severe liver disease or nephrotic syndrome) with serum albumin 3.0 g/dL
•Patients with severe renal impairment undergoing dialysis and/or estimated glomerular filtration rate (eGFR) 60 mL/min/1.73 m2 (may be repeated if eGFR 4559 mL/min/1.73 m2)
•Severe hepatic disease impairment (Child-Pugh Class C)
•One or more of the following laboratory results:
– ALT or AST 2 upper limit of normal (ULN; may be repeated if 23 ULN)
– Total bilirubin greater than 1.5 ULN (may be repeated if 1.63 ULN), with the exception of patients with Gilbert syndrome
– Persisting elevations of serum amylase or lipase greater than 2 ULN
•Patients with significantly impaired bone marrow function or significant anemia, leukopenia, neutropenia or thrombocytopenia, and/or any of the following laboratory results:
– Hemoglobin 9.5 g/dL (may be repeated if 99.4 g/dL)
– Absolute white cell count 4000 cells/mm3 (L)
– Platelet count 100 cells 109/L (may be repeated if 80100 109/L)
– Absolute neutrophil 1500 cells/mm3 (L)
•Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study
•History of alcohol or other drug abuse within 12 months prior to screening
•Positive screening tests for active, latent, or inadequately treated hepatitis B (as evidenced by either of the following):
– Positive hepatitis B surface antigen (HBsAg)
– Positive hepatitis B core antibody [total HBcAb] with detectable hepatitis B virus (HPV) DNA
•Positive screening tests for hepatitis C (positive hepatitis C antibodies)
•Evidence of active or latent or inadequately treated infection with tuberculosis (TB) as defined by the following:
– A positive QuantiFERONTB-Gold (QFT) test is found at screening. QFT testing should be performed through the central laboratory
– Patients with a history of Bacille Calmette-Guérin vaccination should be screened using the QFT test.
– An indeterminate QFT test should be repeated.
– A positive QFT test or two successive indeterminate QFT results should be considered positive diagnostic TB test.
– An indeterminate QFT test followed by a negative QFT test should be considered a negative diagnostic TB test.
•Abnormalities in hepatic synthetic function tests (e.g., PT, INR, aPTT) judged by the investigator to be clinically significant
•History of hospitalization or transfusion for a GI bleed
•Known bleeding diathesis
•Any condition possibly affecting oral drug absorption
•History of or currently active primary or secondary (nondrug-related) immunodeficiency, including known history of HIV infection
•Patients with IgG 500 mg/dL
•Inability to complete an MRI scan (contraindications for MRI scan, including but not restricted to, pacemaker, cochlear implants, intracranial vascular clips, surgery within 6 weeks of entry in the study, coronary stent implanted within 8 weeks prior to the time of the intended MRI scan) or contraindication to gadolinium (Gd) administration
•Any previous history of transplantation or anti-rejection therapy
•Adrenocorticotropic hormone or systemic corticosteroid therapy within 4 weeks prior to screening
For a patient to be eligible, systemic corticosteroids must not be administered between screening and baseline.
•Receiving an unstable dosing regimen of proton pump inhibitors (PPIs) or H2-receptor agonists (H2RAs) during the screening phase prior to the initiation of study drug and/or no plan to remain at a stable dose for the duration of study treatment Patients must not initiate PPIs or H2RAs within 2 weeks of randomization.
•Receiving an unstable regimen of symptomatic treatment of MS (e.g., fampridine, cannabis). Patients must be treated at a stable dose during the screening phase prior to the initiation of study drug and and/or no plan to remain at a stable dose for the duration of study treatment Patients must not initiate symptomatic treatment of MS within 4 weeks of randomization. Patients must not initiate physiotherapy within 4 weeks of randomization.
•Treatment with IV Ig or plasmapheresis within 12 weeks prior to randomization
•Sensitivity or intolerance to any ingredient (including excipients) of fenebrutinib or teriflunomide
•Previously discontinued teriflunomide therapy for safety and/or efficacy reasons
•Receipt of a live-attenuated vaccine within 6 weeks prior to randomization Influenza vaccination is permitted if the inactivated vaccine formulation is administered.
•Need for systemic anticoagulation (oral or injectable) or anti-platelet agent other than nonsteroidal anti-inflammatory drugs, aspirin, and other salicylates (aspirin up to 162 mg QD is allowed)
•Previous treatment with fenebrutinib or another BTK inhibitor for any indication
•Patients with a history of a hypersensitivity reaction to teriflunomide, leflunomide, or to any inactive ingredients in teriflunomide
•Treatment with strong CYP3A4 inhibitors, strong or moderate CYP3A4 inducers, within 7 days or 5 drug-elimination half-lives (whichever is longer) prior to randomization
•Treatment with CYP3A4 substrates with a narrow therapeutic window within 7 days or 5 drug-elimination half-lives (whichever is longer) prior to randomization.
•Previous use of anti-CD20 therapies, including ocrelizumab, unless the last infusion was more than 2 years prior to screening, B-cell count is normal at screening, and treatment discontinuation was not motivated by safety reasons or lack of efficacy
•Previous use of fingolimod, siponimod, or ozanimod within 8 weeks of randomization
•Previous use of natalizumab for more than 1 year and within 6 months of randomization
•Previous treatment with mycophenolate mofetil or methotrexate within 12 weeks of randomization
•Previous use of teriflunomide, unless 24 months from screening or teriflunomide plasma concentrations are 0.02 mg/L at screening
•Any previous treatment with cladribine, mitoxantrone, daclizumab, alemtuzumab, or cyclophosphamide
•Treatment with any investigational agent (including high-dose biotin) within 24 weeks prior to screening or 5 half-lives of the investigational drug (whichever is longer), or treatment with any experimental procedure for MS (e.g., treatment for chronic cerebrospinal venous insufficiency)
•Requirement for any prohibited concomitant medications
•Chronic use of cholestyramine or activated charcoal
•Previous treatment with any other immunomodulatory or immunosuppressive medication not already listed above without appropriate washout as described in the applicable local label
If the washout requirements are not described in the applicable local label, then the wash out period must be 5 times the half-life of the medication. The PD effects of the previous medication must also be considered when determining the required time for washout.