Safety of Urate Elevation in Amyotrophic Lateral Sclerosis (ALS)
Condition: Amyotrophic Lateral Sclerosis
MeSH terms: Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Sclerosis
Intervention: Inosine; Placebo
Intervention description: Subjects on inosine will receive 1-6 capsules a day of 500 mg inosine titrated to target urate levels of 7 - 8 mg/dL.; Subjects on placebo will receive 1-6 capsules a day of 500 mg placebo (sugar pill) titrated to target urate levels of 7 - 8 mg/dL.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 48.0
Sex: All
Minimum age: 18 Years
Maximum age: 85 Years
Healthy volunteers: No
Keywords: ALS; Inosine; Uric acid; Urate; Glutathione; Biomarker; Oxidative stress; Oxidative damage

Summary:

      This is a multi-center, 20-week study of inosine treatment.

      Study Objectives and Endpoints The primary objective of the study is to determine the safety
      and tolerability of oral administration of inosine (administered daily) dosed to moderately
      elevate serum urate over 20 weeks.

      The primary outcome measures will be

        1. Safety, as measured by adverse events

        2. Tolerability, defined as the ability of subjects to complete the entire 20-week study.

      As an exploratory objective, we will test the feasibility and utility of a smartphone
      application for monitoring symptoms and disease progression in patients with amyotrophic
      lateral sclerosis (ALS).
    

Eligibility criteria:

        Inclusion Criteria:

          1. Age 18-85.

          2. Sporadic or familial ALS diagnosed as possible, laboratory-supported probable,
             probable, or definite as defined by revised El Escorial criteria (Appendix 1).

          3. Slow vital capacity (SVC) ≥ 60% of predicted for age, height, and gender at the
             Screening Visit.

          4. Capable of providing informed consent and following trial procedures.

          5. Serum urate < 5.5 mg/dL at screening (i.e. below the population median serum urate
             levels).

          6. Women must not be able to become pregnant (e.g. post menopausal, surgically sterile,
             or using adequate birth control methods) for the duration of the study and 3 months
             after study completion. Adequate contraception includes: abstinence, hormonal
             contraception (oral contraception, implanted contraception, injected contraception or
             other hormonal (patch or contraceptive ring, for example) contraception), intrauterine
             device (IUD) in place for ≥ 3 months, barrier method in conjunction with spermicide,
             or another adequate method.

          7. Is able and willing to participate in the Mobile app study procedures.

        Exclusion Criteria:

          1. History of urolithiasis.

          2. Urine pH < 5.5 at screening (as acidic urine is a major determinant of uric acid
             urolithiasis).

          3. History of gout.

          4. History of stroke or myocardial infarction.

          5. History of symptomatic coronary artery disease (e.g. angina pectoris) or symptomatic
             peripheral arterial disease within 1 year prior to Screening.

          6. Symptomatic congestive heart failure with a documented ejection fraction below 45%.

          7. Poorly controlled arterial hypertension (SBP>160mmHg or DBP>100mmHg at Screening).

          8. Women who are pregnant or lactating.

          9. The presence of unstable psychiatric disease, cognitive impairment, or dementia that
             would impair ability of the subject to provide informed consent, according to Site
             Investigator judgment, or a history of active substance abuse within the prior year.

         10. Anything that, in the opinion of the Site Investigator, would place the subject at
             increased risk or preclude the subject's full compliance with or completion of the
             study.

         11. Use of the following within 30 days prior to Screening: inosine, allopurinol,
             probenecid, more than 300mg vitamin C daily (note that a subject may take a standard
             multivitamin up to one tablet or capsule daily). Use of thiazides is permissible as
             long as the subject is on a stable dose from 1 week prior to Screening.

         12. Known hypersensitivity or intolerability to inosine.

         13. Renal insufficiency as defined by eGFR < 60 mL/min/1.73m2 at the time of screening.