Efficacy and Safety of Cyclophosphamide in Amyotrophic Lateral Sclerosis

Prior treatment

• Familial ALS, or a defined genetic ALS subtype such as SOD1-associated ALS currently receiving gene-targeted therapy or participating in another investigational drug trial.
• Severe concomitant neurological, cardiovascular, pulmonary, renal, hematologic, endocrine, or psychiatric disease that, in the investigator's judgment, may interfere with study participation or safety.
• Participation in another interventional clinical trial within 3 months before screening.

Other illness

• Presence of an ALS mimic or another condition that better explains the clinical presentation, including multifocal motor neuropathy, motor-predominant chronic inflammatory demyelinating polyneuropathy, cervical spinal cord compression, Kennedy disease, hereditary spastic paraplegia, myasthenia gravis, inclusion body myositis, or metabolic, infectious, or paraneoplastic disorders.
• Systemic autoimmune disease, such as systemic lupus erythematosus, rheumatoid arthritis, or Sjögren syndrome, requiring systemic immunosuppressive therapy.
• Active infection, or uncontrolled hepatitis B virus infection, hepatitis C virus infection, human immunodeficiency virus infection, or active tuberculosis identified during screening.
• Suspected or confirmed history of alcohol or drug abuse.
• Known hypersensitivity to cyclophosphamide.
• Any other condition that, in the investigator's judgment, makes the participant unsuitable for the study, including poor adherence or a high likelihood of loss to follow-up.

Lab values

• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>1.5 times the upper limit of normal, or serum creatinine above the upper limit of normal.
• White blood cell count \<3.5 × 10\^9/L, absolute neutrophil count \<1.5 × 10\^9/L, platelet count \<100 × 10\^9/L, or hemoglobin \<90 g/L.

Other

• Motor conduction block or clinically significant sensory nerve conduction abnormalities on nerve conduction studies.
• Pregnancy or breastfeeding, or unwillingness of participants of reproductive potential to use effective contraception.
• Baseline imaging data of inadequate quality for analysis, including severe motion artifacts or incorrect acquisition parameters.

• Age 18 to 75 years.
• Diagnosis of amyotrophic lateral sclerosis (ALS) according to the 2020 revised Gold Coast diagnostic criteria, confirmed by an ALS specialist at a participating study center.
• A decline of 1 to 4 points in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) during the 12-week observation period before randomization.
• Time from symptom onset to randomization ≤2 years.
• Positive TSPO-PET confirmed by the central imaging core laboratory.
• Each ALSFRS-R item score ≥2 at baseline; the dyspnea, orthopnea, and respiratory insufficiency items must each have a score of 4.
• Baseline forced vital capacity (FVC) ≥70% of the predicted value.
• Willing and able to comply with study treatment and follow-up procedures and provide written informed consent, including informed consent for off-label use of cyclophosphamide.