The purpose of this study is to evaluate safety, effect on cramps, function and quality of life of ranolazine versus placebo for the treatment of ALS.

A prospective, multi center, double-blind, placebo-controlled, parallel group study of 2 doses of ranolazine (500 mg and 1000 mg twice daily) compared to placebo in patients with ALS.

Approximately 72 adults with ALS will be enrolled into the study in the United States at approximately 7 ALS treatment sites.

Participants will take oral ranolazine or placebo twice daily, attend a minimum of 5 onsite research visits, and 4 remote research visits.

The study is estimated to last 28 weeks for each participant.

Inclusion Criteria:

• 18 years or older
• Diagnosed with clinically definite, possible, probably, or lab-supported probable ALS per revised El Escorial criteria
• Breathing assessment called forced vital capacity (FVC) greater than or equal to 50%.
• Able to swallow pills at the start of the study and expected to for the length of the study.
• If on ALS modifying medications must be on a stable dose at least 30 days.
• Experiencing 4 or more cramps per week during a 2-week screening period.

Exclusion Criteria:

• Disease duration < 5 years
• Tracheostomy invasive ventilation, or noninvasive ventilation of more than 12 hours/day
• Pregnant or lactating, adults unable to consent, and prisoners
• Taking ranolazine or investigational drug or has received an investigational drug within 30 days (or 5 half-lives for drugs, whichever is longer) prior to screening
• Medically uncontrolled comorbidities (heart, liver, kidney disease)
• Baseline QTc interval prolongation >450 ms for men/ >470 ms for women, history of long QT syndrome, or medications which prolong the QT interval
• Participation in an experimental drug trial less than 30 days before screening
• Patients have to be on a stable dosage of any medications used to treat muscle cramps for ≥30 days or have been off these medications ≥30 days prior to randomization.