This study assessed the effect of tirasemtiv versus placebo on respiratory function in patients with ALS.

CY 4031 was a multi-national, double-blind, randomized, placebo-controlled, stratified, parallel group study of tirasemtiv in patients with ALS. The study had three phases: an open-label phase (2 weeks), a double-blind, placebo-controlled phase (48 weeks), and a double-blind, placebo-controlled tirasemtiv withdrawal phase (4 weeks). Patients who completed 2 weeks of treatment with open-label tirasemtiv (125 mg twice daily) were randomized 3:2:2:2 to placebo or one of three dose levels of tirasemtiv (250 mg/day, 375 mg/day, or 500 mg/day). Approximately 600 patients were planned to be enrolled into the open-label treatment phase.

Patients taking riluzole at study entry could continue use of riluzole during the study as long as they had been on a stable dose for at least 30 days prior to study screening. In addition, for patients randomized to tirasemtiv, the riluzole dose was reduced to half the approved dose (ie, reduced to 50 mg once daily) because administration of tirasemtiv approximately doubles the exposure to concomitant riluzole. Patients randomized to placebo continued riluzole at 50 mg twice daily. This was accomplished without unmasking the study's blind as follows:

1. All patients on riluzole took their morning 50 mg dose of riluzole from their personal riluzole supply.
2. The sponsor supplied the evening riluzole dose as double-blind study medication, as follows: (a) for patients randomized to placebo, the double-blind, evening riluzole dose was 50 mg of active riluzole; (b) for patients randomized to tirasemtiv, the double-blind, evening riluzole dose was a matching placebo for riluzole.

Inclusion Criteria:

• A diagnosis of familial or sporadic ALS (defined as meeting the possible, laboratory-supported probable, probable, or definite criteria for a diagnosis of ALS according to the World Federation of Neurology El Escorial criteria) ≤ 24 months prior to screening
• Upright SVC ≥ 70 % of predicted for age, height and sex
• Able to swallow tablets without crushing, and in the opinion of the Investigator, is expected to continue to be able to do so during the trial
• A caregiver if one is needed
• Clinical laboratory findings within the normal range or, if outside the normal range, deemed not clinically significant by the Investigator
• Male patients must agree for the duration of the study and 10 weeks after the end of the study to use a condom during sexual intercourse with female partners who are of childbearing potential (i.e., following menarche until post-menopausal if not anatomically and physiologically incapable of becoming pregnant) and to have female partners use an additional effective means of contraception (e.g., diaphragm plus spermicide, or oral contraceptives) or the male patient must agree to abstain from sexual intercourse during and for 10 weeks after the end of the study, unless the male patient has had a vasectomy and confirmed sperm count is zero
• Female patients must be post-menopausal (≥ 1 year) or sterilized, or, if of childbearing potential, not be breastfeeding, have a negative pregnancy test, have no intention to become pregnant during the course of the study, and use effective contraceptive drugs or devices while requiring male partner to use a condom for the duration of the study and for 10 weeks after the end of the study
• Patients must be either on a stable dose of riluzole 50 mg twice daily for at least 30 days prior to screening or have not taken riluzole for at least 30 days prior to screening and are willing not to begin riluzole use until they complete study drug dosing

Exclusion Criteria:

• At the time of screening, any use of non-invasive positive pressure ventilation (NIPPV, e.g. continuous positive airway pressure [CPAP] or bi-level positive airway pressure [BiPAP]) for any portion of the day, or mechanical ventilation via tracheostomy, or on any form of oxygen supplementation

• Patients with a diaphragm pacing system (DPS) at study entry or who anticipate DPS placement during the course of the study

• BMI of 20.0 kg/m2 or lower

• Unwilling or unable to discontinue tizanidine and theophylline-containing medications during study participation

• Serum chloride outside the normal reference range

• Neurological impairment due to a condition other than ALS, including history of transient ischemic attack within the past year

• Presence at screening of any medically significant cardiac, pulmonary, GI, musculoskeletal, or psychiatric illness that might interfere with the patient's ability to comply with study procedures or that might confound the interpretation of clinical safety or efficacy data, including, but not limited to:

  1. Poorly controlled hypertension
  2. NYHA Class II or greater congestive heart failure
  3. Chronic obstructive pulmonary disease or asthma requiring daily use bronchodilator medications
  4. GI disorder that might impair absorption of study drug
  5. History of significant liver disease defined by bilirubin > 2 times the upper limit of normal (ULN) or ALT or AST > 3 times the ULN on repeat testing
  6. Poorly controlled diabetes mellitus
  7. History of vertigo within three months of study entry
  8. History of syncope without an explainable or treated cause
  9. History of untreated intracranial aneurysm or poorly controlled seizure disorder
  10. Amputation of a limb
  11. Cognitive impairment, related to ALS or otherwise, sufficient to impair the patient's ability to give informed consent and to understand and/or comply with study procedures
  12. Cancer with metastatic potential (other than basal cell carcinoma, carcinoma in situ of the cervix, or squamous cell carcinoma of the skin excised with clean margins) diagnosed and treated within the last two years
  13. Any other condition, impairment or social circumstance that, in the opinion of the Investigator, would render the patient not suitable to participate in the study
  14. Patient judged to be actively suicidal or a suicide risk by the Investigator

• Has taken any investigational study drug within 30 days or five half-lives of the prior agent, whichever is greater, prior to dosing

• Prior participation in any form of stem cell therapy for the treatment of ALS

• Previously received tirasemtiv in any previous clinical trial