Safety of Urate Elevation in Amyotrophic Lateral Sclerosis (ALS)

Study Overview
=================
Brief 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 Safety, as measured by adverse events 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).

Detailed Description
-----------------
Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disease for which there is no cure. Multiple lines of evidence have implicated oxidative stress in the pathophysiology of ALS. Urate (uric acid) is an endogenous antioxidant system, and urate may serve as a major defense against oxidative stress. Urate has emerged as a promising neuro-protectant and therapeutic target based on convergent epidemiological, laboratory, and clinical data in multiple neurodegenerative diseases, most notably Parkinson's disease (PD). In PD, urate elevation has been pursued as a potential therapy by administration of inosine, a urate precursor that is available as an over-the-counter supplement. Administration of inosine results in a predictable elevation of urate levels and has been shown to be safe and well tolerated in PD. Analysis of ALS databases revealed that higher urate levels are an independent predictor of slower progression and prolonged survival in ALS. However, whether elevating urate in people with ALS would result in better outcomes is unknown. The Principal Investigator has recently concluded a Pilot Study of Inosine in ALS, which was a short, open label, single center study involving 25 subjects [NCT02288091]. The study assessed safety and feasibility of urate elevation in patients with ALS. The Principal Investigator is now pursuing a multi-center Phase II trial to assess the findings of the open label study with longer exposure time.

Official Title
-----------------
Safety of Urate Elevation in Amyotrophic Lateral Sclerosis (ALS)

Conditions
-----------------
Amyotrophic Lateral Sclerosis

Intervention / Treatment
-----------------
* Drug: Inosine
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age 18-85. Sporadic or familial ALS diagnosed as possible, laboratory-supported probable, probable, or definite as defined by revised El Escorial criteria (Appendix 1). Slow vital capacity (SVC) ≥ 60% of predicted for age, height, and gender at the Screening Visit. Capable of providing informed consent and following trial procedures. Serum urate < 5.5 mg/dL at screening (i.e. below the population median serum urate levels). 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. Is able and willing to participate in the Mobile app study procedures. Exclusion Criteria: History of urolithiasis. Urine pH < 5.5 at screening (as acidic urine is a major determinant of uric acid urolithiasis). History of gout. History of stroke or myocardial infarction. History of symptomatic coronary artery disease (e.g. angina pectoris) or symptomatic peripheral arterial disease within 1 year prior to Screening. Symptomatic congestive heart failure with a documented ejection fraction below 45%. Poorly controlled arterial hypertension (SBP>160mmHg or DBP>100mmHg at Screening). Women who are pregnant or lactating. 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. 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. 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. Known hypersensitivity or intolerability to inosine. Renal insufficiency as defined by eGFR < 60 mL/min/1.73m2 at the time of screening.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inosine<br>Subjects will be administered oral inosine daily. The dose of inosine will be titrated to obtain serum urate levels of 7 - 8 mg/dL. | Drug: Inosine<br>* Subjects on inosine will receive 1-6 capsules a day of 500 mg inosine titrated to target urate levels of 7 - 8 mg/dL.<br>|
| Placebo Comparator: Placebo<br>Subjects will be administered oral placebo daily. The dose of placebo will be titrated to obtain serum urate levels of 7 - 8 mg/dL. | Drug: Placebo<br>* 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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | Safety will be assessed by the occurrence of adverse events such as kidney stones and gout (expected adverse events) in all participants receiving at least 1 dose of study drug | Baseline to Week 24 | 
| Tolerability to Complete the Entire 20 Week Study on Study Drug | Tolerance of study drug will be defined as the number of participants who able to complete the 20-week study without permanently discontinuing study drug or suspending study drug for greater than 28 days | Baseline to Week 20 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ALS, Inosine, Uric acid, Urate, Glutathione, Biomarker, Oxidative stress, Oxidative damage