Tofacitinib in Patients With Amyotrophic Lateral Sclerosis | NCT06689982

NCT06689982

Protocol Section

Identification Module

Results Section

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Annotation Section

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Document Section

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Derived Section

Miscellaneous Info Module

Status Module

Name	Class
Turing-Darwin Laboratory; West Institute of Computing Technology, Chongqing, China	UNKNOWN

Description Module

Detailed Description

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.

Arms/Interventions Module

Label	Type	Description	Intervention Names
Tofacitinib	Experimental	This group will receive tofacitinib citrate sustained-release tablets at 180 consecutive days .	Drug: Tofacitinib tablets

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Tofacitinib tablets	Drug	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.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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.	day 180±14

Secondary Outcomes

Measure	Description	Time Frame
Incidence of invasive mechanical ventilation in ALS patients	The incidence of invasive mechanical ventilation in ALS patients.	180 days
Changes of modified Norris scale scores in ALS patients

Other Outcomes

Measure	Description	Time Frame
Changes of muscle strength in ALS patients	The changes of muscle strength in ALS patients from baseline.	baseline, day 30±3, day 90±7, and day180±14
Changes of gait function in ALS patients	The changes of gait function in ALS patients from baseline.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

18 years old≤ age≤ 75 years old, males or females;
Forced vital capacity ≥ 60% of predicted vital capacity during the screening period;
The diagnosis conforms to the diagnostic criteria for amyotrophic lateral sclerosis on the Gold Coast;
Based on the analysis of whether the subject significantly deviates from the baseline healthy elderly population, whole exome sequencing (WES) revealed that the embryonic lineage etiology was interpreted as CD8+ T lymphocyte group and Th1 highly activated, and patients with pathways related to neural repair and energy metabolism pathways that were not significantly inhibited;(1.Obtain genomic data of patient embryonic samples (blood or oral swab) through whole exome sequencing (WES) technology;2.Utilizing the Damage Assessment of Genome shotgun (DAGG) system developed by the Turing Darwin Laboratory team, rare coding mutations in patient genomic data are converted into an activity profile of signaling pathways (APSP). If the patient's embryonic genomic interpretation of APSP compared to the baseline healthy population's embryonic APSP shows high activation of CD8+ T lymphocyte group and Th1 activity, and non-significant inhibition of Treg, neural repair, and energy metabolism pathways, the patient may be included in the clinical trial;3.This step is analyzed by the Turing Darwin Laboratory team, and based on the entry criteria of the clinical trial (high activation of CD8+ T lymphocyte group and Th1 activity, and non-significant inhibition of Treg, neural repair, and energy metabolism pathways), a modeling setting for the APSP score threshold for ALS will be established. Patients above the threshold can be included in the trial.
Subjects or their legal representatives clearly understand and voluntarily participate in the study and sign the informed consent form;
Subjects (including male subjects) are willing to have no birth plan and voluntarily take effective contraceptive measures during the entire study period and within 3 months after the end of the study, and have no plan to donate sperm or eggs.

Exclusion Criteria:

Patients who cannot cooperate with the clinical trial project cycle as determined by professional medical staff;
Individual whose use of tofacitinib is forbidden;
Absolute lymphocyte counts < 500 cells /mm^3, absolute neutrophil counts (ANC) < 1000 cells /mm^3 or hemoglobin level < 9 g/dL;
Serious infection;
Positive HIV test or history of positive test;
Positive hepatitis C virus antibody or positive test history;
Hepatitis B active infection (hepatitis B surface antigen positive and/or serum HBV DNA positive or serum HBV DNA > 2 × 10^8 IU/mL;
Positive syphilis test result or positive test history;
Lumbar spine diseases or malformation;
Have other conditions known to be associated with motor neuron dysfunction that may confuse or obscure an ALS diagnosis;
Other psychiatric disorders diagnosed according to DSM-V diagnostic criteria, or significant suicide intent;
With severe hepatic insufficiency, renal insufficiency or severe cardiac insufficiency (severe hepatic insufficiency refers to ALT value≥2.0 times the upper limit of normal value or AST value≥2.0 times the upper limit of normal value; severe renal insufficiency refers to CRE≥1.5 times the upper limit of normal value or eGFR<40mL/min/1.73m^2; severe cardiac insufficiency refers to NYHA class 3-4);
Permanently dependent on ventilator-assisted ventilation;
Individual who have difficulty communicating verbally to the extent that they are unable to communicate, understand or follow instructions normally, and are unable to cooperate with treatment and evaluation;
History of alcohol and drug abuse;
Patients who are pregnant, breast-feeding, or who are likely to become pregnant and plan to become pregnant;
Patients participating in other clinical trials or using other biological agents, drugs, or devices under investigation;
Unable to be cooperative and complete the follow-up due to other reasons.

ID	Term
D000690	Amyotrophic Lateral Sclerosis
D000090862	Neuroinflammatory Diseases

ID	Term
D013118	Spinal Cord Diseases
D002493	Central Nervous System Diseases
D009422	Nervous System Diseases
D016472	Motor Neuron Disease