Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, of which motor-neuron's degeneration may be associated with neuroinflammation. Tofacitinib is a Janus kinase (JAK) inhibitor that affects cellular hematopoiesis and cellular immune function. At the same time, tofacitinib is suitable for rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. This study is a single center, single arm, proof of concept, clinical trial study, and it is planned to use tofacitinib to carry out a clinical trial to observe the treatment effect of ALS patients.
Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive loss and dysfunction of upper and lower motor neurons located in the brain and spinal cord, further resulting in paralysis. In the occurrence and development of ALS, the degeneration of motor neurons may be related to neuroinflammatory response, often accompanied by excessive proliferation of microglia, astrocyte and oligodendrocyte. Tofacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes that transport signals generated by cytokine or growth factor-receptor interactions on cell membranes, thereby influencing cellular hematopoietic processes and cellular immune function. At the same time, tofacitinib is a marketed drug suitable for rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. In this study, tofacitinib was selected to carry out a clinical randomized controlled trial to observe the treatment effect in ALS patients. This study is a single center, single arm, proof of concept, clinical trial study. In this study, 12 patients will be enrolled. The treatment will be 1 tablet (5 mg) twice a day, and be administered continuously for a total of 180 days. Follow up: Face to face interviews will be made on baseline, 30±3 days, 90±7 days, and 180±14 days. The primary outcome measure was the difference of changes in ALSFRS-R scale scores at 30±3 days, 90±7 days, and 180±14 days from baseline. Secondary outcomes included the incidence of invasive mechanical ventilation within 180 days , the changes in modified Norris scale scores, quality of life (ALSAQ-40, EQ-5D-5L), lung function, and electromyography indicators at 30±3 days, 90±7 days, and 180±14 days from baseline. Exploratory outcomes included the changes in muscle strength, gait function, 7T-MRI imaging indicators, biomarkers in plasma and CSF, fatigue level, anxious level and depressive level, constipation clinical score, overactive bladder symptom score and CNS-BFS score at 30±3 days, 90±7 days, and 180±14 days from baseline; clinical progression within 180 days; the relationship between embryological etiology of ALS patients and the severity and progression in ALS patients, as well as the multiple group changes in ALS patients during disease progression. Safe outcomes included the incidence in adverse event/severe adverse event, death, serious infection, malignant tumor, lymphoproliferative disease, major cardiovascular adverse events, thrombogenesis, abnormal lymphocytes and neutrophilic granuloaytopenia within 180 days.
All patients should be closely monitored for signs and symptoms of infection during and after treatment with tofacitinib tablets. If a patient develops a severe infection, opportunistic infection, or sepsis, medication should be discontinued. During treatment, patients with lymphocyte counts \< 500 cells/mm\^3 or ANC \< 500 cells/mm\^3 confirmed by repeated testing should be stopped. When 500≤ANC≤1000 cells/mm\^3, administration should be interrupted, and if ANC returns to more than 1000 cells/mm\^3, administration should be resumed. When hemoglobin \< 8 g/dL or decreases by more than 2 g/dL, administration should be interrupted until hemoglobin values return to normal.
Beijing Tiantan Hospital
Beijing, China
Changes of ALSFRS-R scale scores in ALS patients
Amyotrophiclateral sclerosis functional rating scale revised(ALSFRS-R) is the most common evaluation indicator in ALS related research, with scores ranging from 0 to 48. The higher the score, the better the functional retention and the milder the symptoms.
Time frame: day 180±14
Incidence of invasive mechanical ventilation in ALS patients
The incidence of invasive mechanical ventilation in ALS patients.
Time frame: 180 days
Changes of modified Norris scale scores in ALS patients
The changes of modified Norris scale scores in ALS patients from baseline. The modified Norris scale is a self-assessment scale for ALS patients, with scores ranging from 0 to 120, with higher scores indicating better functional retention.
Time frame: day 30±3, 90±7, and 180±14
Changes of ALSAQ-40 scale scores in ALS patients
The changes of ALSAQ-40 scale scores in ALS patients from baseline. The scale is an evaluation of the quality of life of ALS patients, with indicators including physical activity, dietary ability, social interaction ability, and emotional response. Simple and highly operable, it can be used for patients to self evaluate their quality of life, with scores ranging from 0 to 200. The higher the score, the milder the symptoms.
Time frame: baseline, day 30±3, day 90±7, and day180±14
Changes in EQ-5D-5L scale scores in ALS patients
The changes of EQ-5D-5L scale scores in ALS patients from baseline. It includes five dimensions(mobility, self-care, usual activities, pain/discomfort, anxiety/depression), and each dimension contains five levels of severity - no problem, minor problem, moderate problem, serious problem, extremely serious problem.
Time frame: baseline, day 30±3, day 90±7, and day180±14
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Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
12
Changes of lung function in ALS patients
The changes of lung function (forced vital capacity) in ALS patients from baseline. Value decline indicates worse outcome of ALS patients, or disease progression and disability.
Time frame: baseline, day 30±3, day 90±7, and day180±14
Changes of electromyography indicators in ALS patients
The changes of electromyography indicators in ALS patients from baseline. Muscle involvement will be assessed by needle electromyography, which analyzes muscle damage qualitatively based on spontaneous, motor unit action potential and recruitment. More muscle involvement indicates worse outcome of ALS patients, or disease progression and disability. The electromyographic indicators include the amplitude of CMAP, munix, and musix of different muscles.
Time frame: baseline, day 30±3, day 90±7, and day180±14