Clinical trial NCT03168711: Safety of Urate Elevation in Amyotrophic Lateral Sclerosis (ALS)
Official title: Safety of Urate Elevation in Amyotrophic Lateral Sclerosis (ALS)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Amyotrophic Lateral Sclerosis
Keywords: ALS
Inosine
Uric acid
Urate
Glutathione
Biomarker
Oxidative stress
Oxidative damage
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: The Salah Foundation
name: Sean M. Healey & AMG Center for ALS
First posted: 2017-05-30
Enrollment: 48
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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).

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.

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.

Primary outcomes:
measure: Number of Participants With Adverse Events
timeFrame: Baseline to Week 24
measure: Tolerability to Complete the Entire 20 Week Study on Study Drug
timeFrame: Baseline to Week 20
Secondary outcomes:
Other outcomes:
Locations:
city: Fort Lauderdale
country: United States
facility: Holy Cross Hospital
state: Florida
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
Study officials:
affiliation: Massachusetts General Hospital
name: Sabrina Paganoni, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.