Trial of Oral Digoxin in Individuals With Amyotrophic Lateral Sclerosis (ALS)

Inclusion Criteria:

1. Ability to provide written informed consent.

2. Adults >18 years of age with a diagnosis of symptomatic ALS as determined by an ALSneurologist, and meets either the revised El Escorial Criteria (clinically possible,probable, probable lab-supported, or definite) or the Gold Coast Criteria.

3. Available or pending CLIA certified ALS genetic panel report.

4. Less than or equal to 24-months since onset of weakness attributed to ALS.

5. Vital capacity (VC) of > 65% predicted value for gender, height and age atscreening.

6. Clinically unremarkable Complete Blood Counts, including but not limited toHemoglobin ≥ 9 g/dL, Platelets ≥ 150 x 109 cells/L.

7. No clinically significant abnormalities in the Comprehensive Metabolic Panel persite/sub-investigator's judgment, including but not limited to:

8. Serum alanine aminotransferase or aspartate aminotransferase < 3× upper limitof normal, or serum total bilirubin <1.5× upper limit of normal

9. Estimated GFR (eGFR) of > 30 mL/min/1.73m2

10. Other clinically significant electrolyte and metabolic abnormalities

11. Ability and willingness to complete all study procedures per the Site Investigator'sclinical assessment.

12. Negative pregnancy test within 7 days prior to first dose for women of child-bearingpotential (WOCB), defined as a sexually mature woman who has not undergone ahysterectomy or who has not been naturally postmenopausal for at least 24consecutive months (i.e., who has had menses any time in the preceding 24consecutive months).

13. Individuals enrolling in the C9orf72 cohort of the trial must have CLIA certifiedALS gene panel demonstrating >31 repeats of C9orf72 hexanucleotide repeat expansion,deemed pathologic.

Exclusion Criteria:

• 1. Clinically significant unstable medical or surgical condition that would pose arisk to the participant's trial procedural participation or interfere with datacollection, according to the Site Investigator's judgment (e.g., active infectionrequiring antibiotics).

2. Presence of cognitive or mental health disorders impairing ability to provideinformed consent for the study per Site investigator assessment.

3. Active cancer or history of cancer, unless it was successfully treated fordurable remission or cure more than 3 years ago. (Note that basal cell carcinoma,squamous cell carcinoma in situ, cervical carcinoma in situ, prostatic carcinoma insitu, or other malignancies that have been curatively excised at any time previouslyand with no evidence of disease recurrence for at least 3 years are notexclusionary.) 4. Prior solid organ transplantation. 5. Concomitant use ofinvestigational treatments for ALS within 5 half-lives or 30 days, whichever longer.

4. Screening 12-lead ECG showing QT interval corrected for rate (QTcF) > 470 msecfor women and > 450 msec for men, absence of second degree or higher AV block orother clinically significant cardiac arrythmias.

5. If female, breastfeeding, pregnant, or of child-bearing potential and unwillingto use effective contraception for duration of the trial and after discontinuingtreatment.

6. Serious cardiac condition within the last 6 months, such as uncontrolledarrhythmia, myocardial infarction, unstable angina, or heart disease defined by theNew York Heart Association (NYHA) Class III or Class IV or hereditary long QTsyndrome.

7. Exclusion criteria for Lumbar Punctures: active bleeding tendencies OR inabilityto withhold antiplatelets or anticoagulants safely as per institutional guidelinesaround LPs OR anatomical spine considerations making it unsafe or challenging forserial LPs OR allergy to local anesthesia used for procedure.

8. Clinically active cardiac disorders including sinus bradycardia (HR <40 bpm) orsinus tachycardia (HR>140 bpm), cardiac arrythmias [first-degree, second-degree (Wenckebach), or third-degree heart block; atrial tachycardia with block; AVdissociation; accelerated junctional (nodal) rhythm; unifocal or multiformventricular premature contractions (especially bigeminy or trigeminy); ventriculartachycardia; and ventricular arrythmias]; Persistent or chronic atrial fibrillationthat is not controlled using standard medications 11. Concomitant treatment withamiodarone at any dose or quinidine at a dose greater than 20 mg/day