Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year

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:
• Poorly controlled hypertension
• NYHA Class II or greater congestive heart failure
• Chronic obstructive pulmonary disease or asthma requiring daily use bronchodilator medications
• GI disorder that might impair absorption of study drug
• 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
• Poorly controlled diabetes mellitus
• History of vertigo within three months of study entry
• History of syncope without an explainable or treated cause
• History of untreated intracranial aneurysm or poorly controlled seizure disorder
• Amputation of a limb
• 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
• Cancer with metastatic potential (other than basal cell carcinoma, carcinoma in situ of the cervix, or squamous cell car