A Pilot Study of Inosine in Amyotrophic Lateral Sclerosis (ALS)
Condition: Amyotrophic Lateral Sclerosis
MeSH terms: Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Sclerosis
Intervention: Inosine
Intervention description: Twenty-five eligible subjects will receive inosine for 12 weeks (administered in the form of 500 mg capsules, 1 to 6 capsules a day for a total daily dose of up to 3 gm). The dose of inosine will be titrated to target urate levels of 7-8 mg/dL based on urate level measurement that will occur at Week 2, Week 4, Week 6, and Week 9 after Baseline.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 32.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: ALS; Inosine; Uric acid; Urate; Glutathione; Biomarker; Oxidative stress; Oxidative damage; proof-of-concept

Summary:

      This is a single center, open label, 12-week study of inosine treatment. Inosine treatment
      leads to an increase in the levels of urate (uric acid) in the blood.

      The primary objective of the study is to determine the tolerability of oral administration of
      inosine.

      Secondary study objectives include the measurement of biomarkers of oxidative stress and
      damage in response to inosine treatment.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Age 18 years or older.

          2. Sporadic or familial ALS diagnosed as possible, laboratory-supported probable,
             probable, or definite as defined by revised El Escorial criteria (Appendix 1).

          3. Capable of providing informed consent and following trial procedures.

          4. Serum urate < 5.5 mg/dl at screening (i.e. below the population median serum urate
             levels).

          5. Willingness to undergo magnetic resonance spectroscopy (MRS) at Baseline and at Week
             12 of the study.

          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.

        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. Urate crystalluria at Screening.

          4. History of gout.

          5. History of stroke or myocardial infarction.

          6. History of symptomatic coronary artery disease (e.g. angina pectoris) or symptomatic
             peripheral arterial disease within 1 year prior to Screening.

          7. Symptomatic congestive heart failure with a documented ejection fraction below 45%.

          8. Poorly controlled arterial hypertension (SBP>160mmHg or DBP>100mmHg at Screening).

          9. Contraindications to undergo magnetic resonance spectroscopy (MRS) at Baseline and at
             Week 12 of the study such as history of claustrophobia, inability to lie flat for
             approximately one hour, or metal implants (metal pins or plates, extensive
             non-removable dental work, cerebral aneurysm clips, pacemaker).

         10. Women who are pregnant or lactating.

         11. The presence of unstable psychiatric disease, cognitive impairment, or dementia that
             would impair ability of the subject to provide informed consent, according to PI
             judgment, or a history of active substance abuse within the prior year.

         12. Anything that, in the opinion of the investigator, would place the subject at
             increased risk or preclude the subject's full compliance with or completion of the
             study.

         13. 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.

         14. Known hypersensitivity or intolerability to inosine.