A Phase 2 Clinical Trial of Tolebrutinib, a Brain-penetrant Bruton's Tyrosine Kinase Inhibitor, for the Modulation of Chronically Inflamed White Matter Lesions in Multiple Sclerosis
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Disappearance of Paramagnetic Rim Lesions at 48 Weeks of 60 mg of Tolebrutinib.
研究概览
简要总结
Background:
Some multiple sclerosis (MS) lesions stay inflamed for very long periods of time. This type of inflammation is not affected by any MS medications. These lesions can lead to slow worsening of MS symptoms. Researchers want to see if a new drug can help.
Objective:
To see if tolebrutinib can help clear inflammation in MS brain lesions.
Eligibility:
Adults ages 18 and older with MS who are on an anti-CD20 therapy.
Design:
Participants will be screened under protocol #89-N-0045.
Participants will have a medical history. They will have physical and neurological exams. They will have blood and urine tests. The progression of their MS will be assessed.
Participants will have MRIs of the brain. The MRI scanner is shaped like a cylinder. It uses a magnetic field and radio waves to take pictures of the body. During the MRIs, participants will lie on a table that slides in and out of the scanner. Soft padding or a coil will be placed around their head.
Participants may have electrocardiograms to measure the heart s electrical activity.
Participants may have lumbar punctures ( spinal taps ). A small needle will be inserted into the spinal canal in the lower back. Fluid will be collected.
Some participants will take tolebrutinib pills by mouth once a day for at least 96 weeks. They will stop their anti-CD20 therapy. They will have at least 10 study visits.
Some participants will not take tolebrutinib. They will stay on their anti-CD20 therapy. They will have 5 study visits.
Participation will last at least 96 weeks.
详细描述
Study Description:
The primary goal of this protocol is to test whether 48 weeks of treatment with tolebrutinib, an investigational, orally available, brain-penetrant, Bruton's tyrosine kinase (BTK) inhibitor, affects an imaging marker (the paramagnetic rim) associated with chronically inflamed white matter lesions in multiple sclerosis (MS). In this rater-blinded but otherwise open- label study, 16 adults with MS who are on stable disease-modifying treatment with anti-CD20 antibody therapy and are within 6 months of their most recent dose, have at least one paramagnetic rim lesion on 7-tesla magnetic resonance imaging (MRI), and have developed no new white matter lesions or clinical relapses for at least 6 months, will initiate treatment with tolebrutinib and agree to forego further anti- CD20 or other disease-modifying therapy for the duration of the trial.
An initial 7 enrolled study participants started tolebrutinib at 60 mg/day (Initial Cohort). Of the Initial Cohort, participants (n=3), who had initiated tolebrutinib 60 mg will remain at 60 mg and not be escalated to 120 mg/day. The remaining participants (n=4) consented to Cohort A, who had initiated tolebrutinib 60 mg and previously escalated to 120 mg/day will remain at that dose.
Radiological, clinical, and biological outcomes are measured at 24, 48, 72, 96, and 144 (Cohort A) weeks, with additional interspersed visits for safety monitoring. Participants may subsequently continue treatment until tolebrutinib is marketed or commercial development halted. A comparison group of 10 participants who meet enrollment criteria but choose to stay on anti-CD20 therapy will also be enrolled. The primary outcome measure is disappearance of one or more paramagnetic rims from white matter lesions identified at baseline. Secondary outcomes include safety and tolerability and additional radiological outcomes. Exploratory clinical, radiological, and laboratory investigations are planned to study the mechanism of action of tolebrutinib and for biomarker development, and to compare the tolebrutinib and anti-CD20 cohorts.
Objectives:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 120 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Able to provide informed consent
- •Willingness to comply with all study procedures and availability for the duration of the study
- •Male or female, aged greater than or equal to 18
- •Diagnosed with multiple sclerosis according to the 2017 revision of the McDonald diagnostic criteria, with no new lesion formation by comparison of baseline MRI scan with a historical MRI scan at least 6 months prior
- •On anti-CD20 antibody treatment for at least 6 months, with the most recent dose at most 6 months prior to enrollment. (Participants in this cohort should remain on their baseline anti-CD20 treatment at least through week 48.)
- •Has a prior 7-tesla MRI scan, no more than 1 year prior to enrollment, demonstrating at least one white matter lesion with a paramagnetic rim
- •For females of reproductive potential: agrees to use highly effective contraception during study participation
- •Agrees not to participate in any other interventional study while participating in this protocol
- •EXCLUSION CRITERIA:
- •An individual who meets any of the following criteria will be excluded from participation in this study:
- •Tolebrutinib Cohorts Exclusion Criteria
- •Pregnancy or lactation
- •MS relapse in the 6 months prior to dosing
- •Febrile illness within 4 weeks prior to dosing, or persistent chronic or active infection requiring treatment with systemic antibiotics, antivirals, or antifungals.
- •Treatment with another investigational drug or other investigational intervention within 3 months prior to baseline
- •Contraindications for 7-tesla MRI
- •Presence of screening laboratory or ECG values outside normal limits that are considered in the PI or MAI s judgment to be clinically significant, including but not limited to:
- •Presence of liver injury defined as underlying hepatobiliary disease or screening alanine aminotransferase (ALT) more than 1.5 times the upper limit of normal (ULN)
- •At screening, positive for hepatitis B surface antigen and/or hepatitis B core antibody and/or positive for hepatitis C antibody
- •Any of the following:
- •Bleeding disorder or known platelet dysfunction at any time prior to the first screening visit
- •Platelet count less than 150,000/microL at the screening visit
- •Lymphocyte count less than 1000 cells/dL at the screening visit
- •Is HIV-positive
- •Has received any live (attenuated) vaccine (including but not limited to varicella zoster, oral polio, and nasal influenza) within 2 months before dosing
- •Has received any of the following medications/treatments within the specified time frame before baseline assessment:
- •Medication: Systemic corticosteroids, adrenocorticotropic hormone (other than used for premedication); Exclusionary if used/used within required wash-out period: 1 month prior to baseline MRI scan
- •Medication: Dimethyl fumarate; Exclusionary if used/used within required wash-out period: 6 months prior to dosing
- •Medication: Intravenous immunoglobulin, fingolimod, natalizumab; Exclusionary if used/used within required wash-out period: 6 months prior to dosing
- •Medication: Teriflunomide; Exclusionary if used/used within required wash-out period: 2 years prior to dosing or 1 month prior to dosing
- •if participant undergoes an accelerated elimination procedure and has documented teriflunomide plasma level below 0.02 mg/L
- •before dosing
- •Medication: Mildly to moderately immunosuppressive/chemotherapeutic medications such azathioprine and methotrexate; Exclusionary if used/used within required wash-out period: 6 months prior to dosing
- •Medication: Highly immunosuppressive/chemotherapeutic medications: mitoxantrone up to 120 mg/m2 body surface area, cyclophosphamide, cladribine; Exclusionary if used/used within required wash-out period: 2 years prior to dosing
- •Medication: Alemtuzumab; Exclusionary if used/used within required wash-out period: 4 years prior to dosing
- •Medication: Lymphoid irradiation, bone marrow transplantation, mitoxantrone (with evidence of cardiotoxicity following treatment, or cumulative lifetime dose >120 mg/m2), other strongly immunosuppressive treatments with very long-lasting effects; Exclusionary if used/used within required wash-out period: Any time
- •Medication: Any BTK inhibitor; Exclusionary if used/used within required wash-out period: Any time
- •Is receiving potent and moderate inducers and inhibitors of cytochrome P450 3A (CYP3A) or potent inhibitors of CYP2C8 hepatic enzymes.
- •Is receiving anticoagulant/antiplatelet therapies, including:
- •Acetylsalicylic acid (aspirin); half-life elimination: Parent drug: Plasma concentration: 15 to 20 minutes; Salicylates (dose dependent): 3 hours at lower doses (300 to 600 mg), 5 to 6 hours (after 1 g), 10 hours with higher doses
- •Antiplatelet drugs (eg, clopidogrel); half-life: 6 hours
- •Warfarin (vitamin K antagonist); half-life: 20-60 hours
- •Heparin, including low molecular weight heparin (antithrombin agents); half-life: 60-90 minutes
- •Dabigatran (direct thrombin inhibitor); half-life:12-17 hours
- •Apixaban (IV half-life: approximately 5 hours, oral half-life: approximately 12 hours), edoxaban (half-life: 10-14 hours), rivaroxaban (half-life: 5-9 or 11-13 hours in younger or elderly individuals, respectively) (direct factor Xa inhibitors)
- •Note: All above drugs need to be stopped at least 5 half-lives before study drug administration except for aspirin, which needs to be stopped at least 8 days before.
- •Has a history or presence of significant other concomitant illness that, according to the PI or MAI s judgment, would adversely affect participation in this study; examples include but are not limited to clinically significant cardiovascular, renal, hepatic, or metabolic
- •Acute liver disease, cirrhosis, chronic liver disease (unless considered stable for >6 months)
- •Has untreated hepatitis C
- •Has chronic hepatitis B unless stable on oral suppression and/or followed by a local hepatologist to monitor for reactivation
- 另有 9 项未显示
排除标准
- •Pregnancy or lactation
- •MS relapse in the 6 months prior to baseline
- •Treatment with another investigational drug or other investigational intervention within 3 months prior to baseline
- •Contraindications for 7-tesla MRI
- •Has received any of the following medications/treatments within the specified time frame before baseline assessment:
- •Medication: Systemic corticosteroids, adrenocorticotropic hormone (other than used for premedication); Exclusionary if used/used within required wash-out period: 1 month prior to baseline MRI scan
- •Medication: Dimethyl fumarate; Exclusionary if used/used within required wash-out period: 6 months prior to dosing
- •Medication: Intravenous immunoglobulin, fingolimod, natalizumab; Exclusionary if used/used within required wash-out period: 6 months prior to dosing
- •Medication: Teriflunomide; Exclusionary if used/used within required wash-out period: 2 years prior to dosing or 1 month prior to dosing if participant undergoes an accelerated elimination procedure and has documented teriflunomide plasma level below 0.02 mg/L before dosing
- •Medication: Mildly to moderately immunosuppressive/chemotherapeutic medications such azathioprine and methotrexate; Exclusionary if used/used within required wash-out period: 6 months prior to dosing
- •Medication: Highly immunosuppressive/chemotherapeutic medications: mitoxantrone up to 120 mg/m2 body surface area, cyclophosphamide, cladribine; Exclusionary if used/used within required wash-out period: 2 years prior to dosing
- •Medication: Alemtuzumab; Exclusionary if used/used within required wash-out period: 4 years prior to dosing
- •Medication: Lymphoid irradiation, bone marrow transplantation, mitoxantrone (with evidence of cardiotoxicity following treatment, or cumulative lifetime dose >120 mg/m2), other strongly immunosuppressive treatments with very long-lasting effects; Exclusionary if used/used within required wash-out period: Any time
- •Medication: Any BTK inhibitor; Exclusionary if used/used within required wash-out period: Any time
- •Has a history or presence of significant other concomitant illness that, according to the PI or MAI s judgment, would adversely affect participation in this study; examples include but are not limited to clinically significant cardiovascular, renal, hepatic, or metabolic
- •Unwilling to allow coded samples to be processed offsite
- •Unwilling to have coded samples and/or data saved or used in other studies
研究组 & 干预措施
Tolebrutinib (Cohort A)
Tolebrutinib 60 mg/day for 48 weeks, Tolebrutinib 120 mg/day for 96 weeks
干预措施: tolebrutinib 60mg (Drug)
Tolebrutinib (Cohort A)
Tolebrutinib 60 mg/day for 48 weeks, Tolebrutinib 120 mg/day for 96 weeks
干预措施: tolebrutinib 120mg (Drug)
Tolebrutinib (cohort B)
Tolebrutinib 120 mg daily
干预措施: tolebrutinib 120mg (Drug)
tolebrutinib (initial cohort)
Tolebrutinib 60 mg daily
干预措施: tolebrutinib 60mg (Drug)
结局指标
主要结局
Disappearance of Paramagnetic Rim Lesions at 48 Weeks of 60 mg of Tolebrutinib.
时间窗: 48 weeks
Paramagnetic rims indicate the presence of inflammation and ongoing demyelination and axonal transection at the lesion edge. The lesions under study were present for at least 6 months. The results represent the number of participants in whom at least the paramagnetic rim has disappeared in at least 1 lesion at the end of 48 weeks of tolebrutinib 60 mg.
次要结局
- Safety and Tolerability of Tolebrutinib.(each patient visit)
- Repair of Chronically Inflamed White Matter Lesions(baseline vs. 96 weeks)