Tofacitinib in Patients With Amyotrophic Lateral Sclerosis

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.

The incidence of invasive mechanical ventilation 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.

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.

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.

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.

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.

The changes of muscle strength in ALS patients from baseline.

The changes of gait function in ALS patients from baseline.

The changes of 7T MRI imaging indicators in ALS patients from baseline. 7T mainly observes the range and degree of iron deposition in the central anterior gyrus. 7T MRI enables the visualization and quantification of motor neuron degeneration in ALS patients, providing valuable information on the extent and distribution of neuronal loss in the brain and spinal cord.

The changes of biomarkers in plasma in ALS patients from baseline, including neurofilament light chain protein (NFL), Janus kinase (JAK) enzymes (JAK1/JAK2, JAK1/JAK3, and JAK2/JAK3), signal transducers and activators of transcription (STAT), and phosphorylated STAT (p-STAT). They have the same units of measure.

The changes of biomarkers in CSF in ALS patients from baseline, including neurofilament light chain protein (NFL), Janus kinase (JAK) enzymes (JAK1/JAK2, JAK1/JAK3, and JAK2/JAK3), signal transducers and activators of transcription (STAT), and phosphorylated STAT (p-STAT). They have the same units of measure.

The changes of fatigue level (FSS scale scores) in ALS patients from baseline. FSS is a single dimensional fatigue scale with 9 items, requiring patients to rate the impact of fatigue on different functional areas on a 7-point scale, and then take the average score. The FSS score range is from 0 to 7, with higher scores indicating more fatigue.

The changes of anxious level (HAMA scale scores) in ALS patients from baseline. If the total score of HAMA exceeds 29 points, it may indicate severe anxiety. Exceeding 21 points indicates obvious anxiety. If it exceeds 14 points, there must be anxiety. Exceeding 7 points may indicate anxiety. If the score is less than 7, there are no anxiety symptoms.

The changes of depressive level (HAMD scale scores) in ALS patients from baseline. If the total score of HAMD exceeds 24 points, it may indicate severe depression. Exceeding 17 points may indicate mild or moderate depression. If it is less than 7 points, there are no depressive symptoms.

Stage 1: This stage is characterized by symptoms limited to one region, such as muscle weakness or speech difficulties.

Stage 2: Symptoms begin to spread to other regions, affecting more muscles and functions.

Stage 3: Symptoms further progress, leading to significant disability but with some independence in daily activities.

Stage 4: Severe disability where the individual requires assistance for most activities of daily living.

Stage 5: Advanced stage with total dependence on others for care and assistance.

Stage 1: Early stage with symptoms limited to one region or limb. Stage 2: Symptoms spread to other regions or limbs. Stage 3: Symptoms progress to involve both upper and lower limbs. Stage 4: Respiratory muscles become affected, leading to breathing difficulties.

Stage 5: Severe respiratory impairment requiring ventilation support.

The severity and progression rate of the disease will be assessed before enrollment into the clinical trial. After enrollment, blood will be drawn for whole exome sequencing. Through the newly developed multilevel data-driven AI modelDamage Assessment of Genomic shotGun(DAGG) by TD-LAB, the rare coding variations (gRCVs) in the germ line genome will be translated into functional spectra of hundreds of cellular functions and signaling pathways (including growth factors, immune functions, nerve repair, and other related functional pathways) to identify potential pathogenic factors in ALS patients. Furthermore, in conjunction with the patient's clinical phenotype, the correlation between the severity of the pathogenicity encoded by the germ line genome and the progression of ALS disease will be determined. And the disease progression of the disease will be comprehensively evaluated through electromyography, the ALSFRS-R scale, lung function tests, and physical examinations.

The changes of constipation clinical score in ALS patients from baseline. This scoring system consists of several questions related to bowel habits, such as frequency of bowel movements, difficulty in passing stool, feeling of incomplete evacuation, and use of laxatives. Each question is assigned a score based on the severity of the symptom, with higher scores indicating more severe constipation. The score is ranging from 0 to 30.

The changes of OABSS in ALS patients from baseline. Change in Overactive Bladder Syndrome Score (OABSS, from 0 to 15, score increase indicates worse outcome of ALS patients, or disease progression and disability).

The changes of CNS-BFS score in ALS patients from baseline.

This study will assess the multi-omics changes (including genomics, transcriptomics, and proteomics data) in ALS patients during the treatment process, analyze the correlation between multi-omics data and clinical manifestations, and drug responses to evaluate the multi-omics changes as the condition of ALS patients changes.

The number of adverse event within 180 days. Adverse medical events occurring in subjects during the use of the investigational drug, or worsening of pre-existing medical conditions, regardless of causality with the investigational drug treatment, should be reported. Adverse medical events can be clinical symptoms/signs, diseases, or abnormal test results. Adverse events (AEs) encompass any adverse medical events that occur at any time during the entire clinical study, including the screening or washout periods, even if the patient has not yet received the investigational drug treatment.

The number of evere adverse event within 180 days. Adverse events meeting one or more of the following criteria during the study period:

• Result in death
• Pose an immediate life-threatening condition Note: Life-threatening is defined as an event that at the time of occurrence places the patient in immediate danger of death, not necessarily an event that would have caused death if it were more severe.
• Require hospitalization or prolongation of existing hospitalization
• Result in persistent or significant disability/incapacity, or loss of a major ability to maintain normal life functions
• Congenital anomaly, congenital defect, birth defect, or fertility impairment
• Significant medical events that may jeopardize the subject or require medical intervention to prevent the above outcomes.

The number of serious infection within 180 days. This refers to severe infections that have spread throughout the body, not just in one small area, which can be potentially life-threatening, requiring urgent medical attention and often hospitalization.

The number of malignant tumor within 180 days. malignant tumor refers to a mass or growth of abnormal cells that are cancerous and can spread to other parts of the body or invade surrounding tissues, causing serious health problems.

The number of lymphoproliferative disease within 180 days. This is a type of disease where lymphocytes, a type of white blood cell, are produced in excessive quantities. This may lead to immune system dysfunction and increase the risk of infections or cancer.

The number of major cardiovascular adverse events within 180 days. It refers to serious, unwanted health occurrences related to the cardiovascular system like heart attacks, strokes, heart failures or death.

The number of thrombogenesis within 180 days. The process of clot formation within blood vessels, which can block the flow of blood, leading to serious conditions such as stroke or heart attack.

The number of abnormal lymphocytes within 180 days. Abnormal lymphocytes are lymphocytes, a type of white blood cell, that appear abnormal under a microscope. They may be unusually large or small, or have an unusual shape or structure, which could be a sign of an infection or disease like leukemia.

The number of neutrophilic granuloaytopenia within 180 days. This is a condition characterized by a low level of neutrophils, a type of white blood cell important for fighting off infections, particularly those caused by bacteria and fungi. When the neutrophil count is low, it makes a person more vulnerable to infectious diseases.