Clinical trial NCT06689982: Tofacitinib in Patients With Amyotrophic Lateral Sclerosis
Official title: Tofacitinib in Patients With Amyotrophic Lateral Sclerosis: A Proof-of-concept Clinical Trials
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: EARLY_PHASE1
Conditions: Amyotrophic Lateral Sclerosis
Keywords: Amyotrophic lateral sclerosis
Clinical trial
Tofacitinib
Neuroinflammation
Lead sponsor: Beijing Tiantan Hospital
Sponsor class: OTHER
Collaborators: name: Turing-Darwin Laboratory; West Institute of Computing Technology, Chongqing, China
First posted: 2024-11-15
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: tofacitinib (5mg per tablet)
Primary purpose: TREATMENT

Brief summary: 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.

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.

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.

Primary outcomes:
measure: Changes of ALSFRS-R scale scores in ALS patients
timeFrame: day 180±14
Secondary outcomes:
measure: Incidence of invasive mechanical ventilation in ALS patients
timeFrame: 180 days
measure: Changes of modified Norris scale scores in ALS patients
timeFrame: day 30±3, 90±7, and 180±14
measure: Changes of ALSAQ-40 scale scores in ALS patients
timeFrame: baseline, day 30±3, day 90±7, and day180±14
measure: Changes in EQ-5D-5L scale scores in ALS patients
timeFrame: baseline, day 30±3, day 90±7, and day180±14
measure: Changes of lung function in ALS patients
timeFrame: baseline, day 30±3, day 90±7, and day180±14
measure: Changes of electromyography indicators in ALS patients
timeFrame: baseline, day 30±3, day 90±7, and day180±14
Other outcomes:
measure: Changes of muscle strength in ALS patients
timeFrame: baseline, day 30±3, day 90±7, and day180±14
measure: Changes of gait function in ALS patients
timeFrame: baseline, day 30±3, day 90±7, and day180±14
measure: Changes of 7T MRI imaging indicators in ALS patients
timeFrame: baseline, day 30±3, day 90±7, and day180±14
measure: Changes of biomarkers in plasma in ALS patients
timeFrame: baseline, day 30±3, day 90±7, and day180±14
measure: Changes of biomarkers in CSF in ALS patients
timeFrame: day 180±14
measure: Changes of fatigue level in ALS patients
timeFrame: baseline, day 30±3, day 90±7, and day180±14
measure: Changes of anxious level in ALS patients
timeFrame: baseline, day 30±3, day 90±7, and day180±14
measure: Changes of depressive level in ALS patients
timeFrame: baseline, day 30±3, day 90±7, and day180±14
measure: Changes of King's College Staging progression in ALS patients
timeFrame: 180 days
measure: Changes of MiToS Staging progression in ALS patients
timeFrame: 180 days
measure: Correlation between germline etiology and ALS disease progression
timeFrame: 180 days
measure: The Wexner Constipation Score in ALS patients
timeFrame: baseline, day 30±3, day 90±7, and day180±14
measure: Overactive Bladder Syndrome Score (OABSS) Overactive Bladder Syndrome Score (OABSS) Overactive Bladder Syndrome Score (OABSS) Overactive Bladder Syndrome Score (OABSS) in ALS patients
timeFrame: baseline, day 30±3, day 90±7, and day180±14
measure: CNS-BFS score in ALS patients
timeFrame: baseline, day 30±3, day 90±7, and day180±14
measure: Multiple Omics Changes in ALS Patients During IIT Treatment
timeFrame: baseline, day 30±3, day 90±7, and day180±14
measure: Security purpose：adverse event
timeFrame: day180±14
measure: Security purpose：severe adverse event
timeFrame: day180±14
measure: Security purpose：serious infection
timeFrame: day180±14
measure: Security purpose：malignant tumor
timeFrame: day180±14
measure: Security purpose：lymphoproliferative disease
timeFrame: day180±14
measure: major cardiovascular adverse events
timeFrame: day180±14
measure: Security purpose：thrombogenesis
timeFrame: day180±14
measure: Security purpose：abnormal lymphocytes
timeFrame: day180±14
measure: Security purpose：neutrophilic granuloaytopenia
timeFrame: day180±14
Locations:
city: Beijing
country: China
facility: Beijing Tiantan Hospital
Study officials:
affiliation: Beijing Tiantan Hospital
name: Yilong Wang, PhD+MD
role: PRINCIPAL_INVESTIGATOR
References: