Safety of Urate Elevation in Amyotrophic Lateral Sclerosis (ALS)

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.

• Inosine (Drug): Subjects on inosine will receive 1-6 capsules a day of 500 mg inosine titrated to target urate levels of 7 - 8 mg/dL.
• Placebo (Drug): 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.

Primary outcomes

• Number of Participants With Adverse Events [Baseline to Week 24]: 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
• Tolerability to Complete the Entire 20 Week Study on Study Drug [Baseline to Week 20]: 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

Sex: All, ages: 18 Years to 85 Years

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.

Participant flow

Outcome results

• Number of Participants With Adverse Events (Primary), Number, participants: Inosine 11; Placebo 7
• Tolerability to Complete the Entire 20 Week Study on Study Drug (Primary), Count of participants, Participants: Inosine 12; Placebo 7

Adverse events

Time frame: Adverse event data were collected from the time of first participant consent through final participant's completion of the study. This covered an active study period of 2 years and 3 months. Participants were followed from time of consent through completion of their study participation or withdrawal of consent. Adverse event data was collected for 24 weeks.

Serious adverse events by term

Other adverse events by term

• Paganoni S, Zhang M, Quiroz Zarate A, Jaffa M, Yu H, Cudkowicz ME, Wills AM. Uric acid levels predict survival in men with amyotrophic lateral sclerosis. J Neurol. 2012 Sep;259(9):1923-8. doi: 10.1007/s00415-012-6440-7. Epub 2012 Feb 10. PMID 22323210
• Atassi N, Berry J, Shui A, Zach N, Sherman A, Sinani E, Walker J, Katsovskiy I, Schoenfeld D, Cudkowicz M, Leitner M. The PRO-ACT database: design, initial analyses, and predictive features. Neurology. 2014 Nov 4;83(19):1719-25. doi: 10.1212/WNL.0000000000000951. Epub 2014 Oct 8. PMID 25298304
• Parkinson Study Group SURE-PD Investigators; Schwarzschild MA, Ascherio A, Beal MF, Cudkowicz ME, Curhan GC, Hare JM, Hooper DC, Kieburtz KD, Macklin EA, Oakes D, Rudolph A, Shoulson I, Tennis MK, Espay AJ, Gartner M, Hung A, Bwala G, Lenehan R, Encarnacion E, Ainslie M, Castillo R, Togasaki D, Barles G, Friedman JH, Niles L, Carter JH, Murray M, Goetz CG, Jaglin J, Ahmed A, Russell DS, Cotto C, Goudreau JL, Russell D, Parashos SA, Ede P, Saint-Hilaire MH, Thomas CA, James R, Stacy MA, Johnson J, Gauger L, Antonelle de Marcaida J, Thurlow S, Isaacson SH, Carvajal L, Rao J, Cook M, Hope-Porche C, McClurg L, Grasso DL, Logan R, Orme C, Ross T, Brocht AF, Constantinescu R, Sharma S, Venuto C, Weber J, Eaton K. Inosine to increase serum and cerebrospinal fluid urate in Parkinson disease: a randomized clinical trial. JAMA Neurol. 2014 Feb;71(2):141-50. doi: 10.1001/jamaneurol.2013.5528. PMID 24366103
• Results publication: Beukenhorst AL, Burke KM, Scheier Z, Miller TM, Paganoni S, Keegan M, Collins E, Connaghan KP, Tay A, Chan J, Berry JD, Onnela JP. Using Smartphones to Reduce Research Burden in a Neurodegenerative Population and Assessing Participant Adherence: A Randomized Clinical Trial and Two Observational Studies. JMIR Mhealth Uhealth. 2022 Feb 4;10(2):e31877. doi: 10.2196/31877. PMID 35119373

• Study Protocol and Statistical Analysis Plan (PDF, 2019-07-01)
• Informed Consent Form (PDF, 2019-07-01)

• Sabrina Paganoni, MD, PhD, Principal investigator, Massachusetts General Hospital