Amyotrophic Lateral Sclerosis
Conditions
Keywords
ALS, Inosine, Uric acid, Urate, Glutathione, Biomarker, Oxidative stress, Oxidative damage
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.
Interventions
DRUGInosine
Subjects on inosine will receive 1-6 capsules a day of 500 mg inosine titrated to target urate levels of 7 - 8 mg/dL.
DRUGPlacebo
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.
Sponsors
The Salah Foundation
Sean M. Healey & AMG Center for ALS
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
United States
Participant flow
Recruitment details
Participants age 18 and older who met the El Escorial criteria of possible, laboratory-supported probable, probable, or definite criteria for a diagnosis of ALS were recruited across three Northeast ALS Consortium (NEALS) Centers.
Pre-assignment details
According to the study protocol all participants who consent to the study are considered enrolled. 23 consented participants were deemed ineligible during screening procedures and 2 withdrew consent. Of the 23 ineligible participants, 13 did not meet inclusion criteria and 10 were ineligible due to meeting exclusion criteria.
Participants by arm
| Arm | Count |
|---|---|
| Inosine Subjects will be administered oral inosine daily. The dose of inosine will be titrated to obtain serum urate levels of 7 - 8 mg/dL.
Inosine: Subjects on inosine will receive 1-6 capsules a day of 500 mg inosine titrated to target urate levels of 7 - 8 mg/dL. | 14 |
| Placebo Subjects will be administered oral placebo daily. The dose of placebo will be titrated to obtain serum urate levels of 7 - 8 mg/dL.
Placebo: 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. | 9 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Inosine | Total | Placebo |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 3 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 20 Participants | 9 Participants |
| Age, Continuous | 60.0 years STANDARD_DEVIATION 9.9 | 58.6 years STANDARD_DEVIATION 9.8 | 56.4 years STANDARD_DEVIATION 10 |
| Amyotrophic Lateral Sclerosis Functional Rating Scale Bulbar Subdomain | 8.6 units on a scale STANDARD_DEVIATION 2.8 | 8.8 units on a scale STANDARD_DEVIATION 2.9 | 9.0 units on a scale STANDARD_DEVIATION 3.2 |
| Amyotrophic Lateral Sclerosis Functional Rating Scale Fine-Motor Subdomain | 8.5 units on a scale STANDARD_DEVIATION 3.3 | 8.5 units on a scale STANDARD_DEVIATION 3.1 | 8.4 units on a scale STANDARD_DEVIATION 3.1 |
| Amyotrophic Lateral Sclerosis Functional Rating Scale Gross-Motor Subdomain | 7.4 units on a scale STANDARD_DEVIATION 2.7 | 7.5 units on a scale STANDARD_DEVIATION 2.6 | 7.7 units on a scale STANDARD_DEVIATION 2.6 |
| Amyotrophic Lateral Sclerosis Functional Rating Scale Respiratory Subdomain | 10.5 units on a scale STANDARD_DEVIATION 2.5 | 10.9 units on a scale STANDARD_DEVIATION 2.05 | 11.4 units on a scale STANDARD_DEVIATION 0.88 |
| Amyotrophic Lateral Sclerosis Functional Rating Scale Total Score | 35.1 units on a scale STANDARD_DEVIATION 8.4 | 35.7 units on a scale STANDARD_DEVIATION 7.7 | 36.6 units on a scale STANDARD_DEVIATION 6.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants | 22 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 14 Participants | 23 Participants | 9 Participants |
| Region of Enrollment United States | 14 participants | 23 participants | 9 participants |
| Sex: Female, Male Female | 10 Participants | 14 Participants | 4 Participants |
| Sex: Female, Male Male | 4 Participants | 9 Participants | 5 Participants |
| Urate | 3.94 milligrams per deciliter STANDARD_DEVIATION 1.11 | 3.94 milligrams per deciliter STANDARD_DEVIATION 0.9 | 3.96 milligrams per deciliter STANDARD_DEVIATION 0.48 |
| Vital Capacity Percent Predicted Max | 81.9 percentage predicted STANDARD_DEVIATION 21.8 | 83.5 percentage predicted STANDARD_DEVIATION 24.3 | 86.1 percentage predicted STANDARD_DEVIATION 29.5 |
| Weight | 72.7 kilograms STANDARD_DEVIATION 10.3 | 71.5 kilograms STANDARD_DEVIATION 13.6 | 69.7 kilograms STANDARD_DEVIATION 17.9 |
| Years from Diagnosis to Screening | 0.79 years STANDARD_DEVIATION 0.73 | 1.06 years STANDARD_DEVIATION 1.04 | 1.47 years STANDARD_DEVIATION 1.33 |
| Years from Symptom onset to Diagnosis | 1.18 years STANDARD_DEVIATION 1.12 | 1.14 years STANDARD_DEVIATION 0.92 | 1.08 years STANDARD_DEVIATION 0.54 |
| Years from Symptom onset to Screening | 1.97 years STANDARD_DEVIATION 1.15 | 2.2 years STANDARD_DEVIATION 1.3 | 2.56 years STANDARD_DEVIATION 1.51 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 1 / 9 |
| other Total, other adverse events | 11 / 14 | 7 / 9 |
| serious Total, serious adverse events | 4 / 14 | 1 / 9 |
Outcome results
Primary
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
Time frame: Baseline to Week 24
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Inosine | Number of Participants With Adverse Events | 11 participants |
| Placebo | Number of Participants With Adverse Events | 7 participants |
Primary
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
Time frame: Baseline to Week 20
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Inosine | Tolerability to Complete the Entire 20 Week Study on Study Drug | 12 Participants |
| Placebo | Tolerability to Complete the Entire 20 Week Study on Study Drug | 7 Participants |