SURE-ALS2: Safety of Urate Elevation in Amyotrophic Lateral Sclerosis (ALS)

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT03168711
• Collaborator: The Salah Foundation (Other), MGH cure ALS Fund (Other)
• Enrollment: 48
• Locations: 3
• Arms: 2
• Actual Duration (Months): 27.2
• Patients Per Site: 16
• Patients Per Site Per Month: 0.6

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Amyotrophic Lateral Sclerosis	Drug: Inosine; Drug: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 48 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Safety of Urate Elevation in Amyotrophic Lateral Sclerosis (ALS)
• Actual Study Start Date: Oct 1, 2017
• Actual Primary Completion Date: Dec 10, 2019
• Actual Study Completion Date: Jan 7, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: 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.
Placebo Comparator: 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.	Drug: 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.

Outcome Measures

Primary Outcome Measures

1. 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

2. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Holy Cross Hospital	Fort Lauderdale	Florida	United States	33308
2	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
3	University of Minnesota	Minneapolis	Minnesota	United States	55455

Sponsors and Collaborators

• Massachusetts General Hospital
• The Salah Foundation
• MGH cure ALS Fund

Investigators

• Principal Investigator: Sabrina Paganoni, MD, PhD, Massachusetts General Hospital

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 1, 2019
• Informed Consent Form - Jul 1, 2019

More Information

Publications

• 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.
• Paganoni S, Zhang M, Quiroz Zárate 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.
• 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.

• Responsible Party: Sabrina Paganoni, M.D., Principal Investigator, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT03168711
• Other Study ID Numbers: SURE-ALS2
• First Posted: May 30, 2017
• Last Update Posted: Feb 18, 2021
• Last Verified: Feb 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Sabrina Paganoni, M.D., Principal Investigator, Massachusetts General Hospital: ALS; Inosine; Uric acid; Urate; Glutathione; Biomarker; Oxidative stress; Oxidative damage
• Additional relevant MeSH terms: Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Sclerosis

Study Results

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 Detail	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.

Arm/Group Title	Inosine	Placebo
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	14	9
COMPLETED	12	7
NOT COMPLETED	2	2

Baseline Characteristics

Arm/Group Title	Inosine	Placebo	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	14	9	23
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	11 78.6%	9 100%	20 87%
>=65 years	3 21.4%	0 0%	3 13%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.0 (9.9)	56.4 (10)	58.6 (9.8)
Sex: Female, Male (Count of Participants)
Female	10 71.4%	4 44.4%	14 60.9%
Male	4 28.6%	5 55.6%	9 39.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 7.1%	0 0%	1 4.3%
Not Hispanic or Latino	13 92.9%	9 100%	22 95.7%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	14 100%	9 100%	23 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	14 100%	9 100%	23 100%
Amyotrophic Lateral Sclerosis Functional Rating Scale Total Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	35.1 (8.4)	36.6 (6.8)	35.7 (7.7)
Amyotrophic Lateral Sclerosis Functional Rating Scale Bulbar Subdomain (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	8.6 (2.8)	9.0 (3.2)	8.8 (2.9)
Amyotrophic Lateral Sclerosis Functional Rating Scale Fine-Motor Subdomain (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	8.5 (3.3)	8.4 (3.1)	8.5 (3.1)
Amyotrophic Lateral Sclerosis Functional Rating Scale Gross-Motor Subdomain (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	7.4 (2.7)	7.7 (2.6)	7.5 (2.6)
Amyotrophic Lateral Sclerosis Functional Rating Scale Respiratory Subdomain (units on a scale) [Median (Standard Deviation) ]
Median (Standard Deviation) [units on a scale]	10.5 (2.5)	11.4 (0.88)	10.9 (2.05)
Vital Capacity Percent Predicted Max (percentage predicted) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage predicted]	81.9 (21.8)	86.1 (29.5)	83.5 (24.3)
Years from Symptom onset to Screening (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	1.97 (1.15)	2.56 (1.51)	2.2 (1.3)
Years from Diagnosis to Screening (years) [Median (Standard Deviation) ]
Median (Standard Deviation) [years]	0.79 (0.73)	1.47 (1.33)	1.06 (1.04)
Years from Symptom onset to Diagnosis (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	1.18 (1.12)	1.08 (0.54)	1.14 (0.92)
Weight (kilograms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms]	72.7 (10.3)	69.7 (17.9)	71.5 (13.6)
Urate (milligrams per deciliter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [milligrams per deciliter]	3.94 (1.11)	3.96 (0.48)	3.94 (0.90)

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inosine	Placebo
Arm/Group Description	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.	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.
Measure Participants	14	9
Number [participants]	11 78.6%	7 77.8%

2. Primary Outcome

Title	Tolerability to Complete the Entire 20 Week Study on Study Drug
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Inosine	Placebo
Arm/Group Description	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.	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.
Measure Participants	14	9
Count of Participants [Participants]	12 85.7%	7 77.8%

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.
Adverse Event Reporting Description	Adverse Events classified by MedDRA system organ class, higher level term, and preferred term
Arm/Group Title	Inosine		Placebo
Arm/Group Description	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.		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.
All Cause Mortality
	Inosine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		1/9 (11.1%)
Serious Adverse Events
	Inosine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/14 (28.6%)		1/9 (11.1%)
Cardiac disorders
Pericarditis	0/14 (0%)	0	1/9 (11.1%)	1
Infections and infestations
Device Related Infection	1/14 (7.1%)	1	0/9 (0%)	0
Renal and urinary disorders
Acute Kidney Injury	1/14 (7.1%)	1	0/9 (0%)	0
Nephrolithiasis	1/14 (7.1%)	1	0/9 (0%)	0
Respiratory, thoracic and mediastinal disorders
Laryngospasm	1/14 (7.1%)	1	0/9 (0%)	0
Respiratory Failure	0/14 (0%)	0	1/9 (11.1%)	1
Other (Not Including Serious) Adverse Events
	Inosine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/14 (78.6%)		7/9 (77.8%)
Blood and lymphatic system disorders
Anaemia Macrocytic	1/14 (7.1%)	1	0/9 (0%)	0
Leukopenia	1/14 (7.1%)	1	0/9 (0%)	0
Normochromic Normocytic Anaemia	1/14 (7.1%)	1	2/9 (22.2%)	2
Cardiac disorders
Cardiogenic Shock	0/14 (0%)	0	1/9 (11.1%)	1
Eye disorders
Eye Pruritus	1/14 (7.1%)	1	0/9 (0%)	0
Lacrimation Increased	1/14 (7.1%)	1	0/9 (0%)	0
Gastrointestinal disorders
Abdominal Discomfort	0/14 (0%)	0	1/9 (11.1%)	1
Abdominal Pain	1/14 (7.1%)	1	0/9 (0%)	0
Constipation	1/14 (7.1%)	1	1/9 (11.1%)	1
Gastrointestinal Pain	1/14 (7.1%)	1	0/9 (0%)	0
Hypoaesthesia Oral	1/14 (7.1%)	1	0/9 (0%)	0
Nausea	2/14 (14.3%)	2	1/9 (11.1%)	1
General disorders
Implant Site Pain	1/14 (7.1%)	1	0/9 (0%)	0
Infections and infestations
Subcutaneous Abscess	0/14 (0%)	0	1/9 (11.1%)	1
Upper Respiratory Tract Infection	1/14 (7.1%)	1	0/9 (0%)	0
Urinary Tract Infection	1/14 (7.1%)	1	0/9 (0%)	0
Injury, poisoning and procedural complications
Contusion	1/14 (7.1%)	1	0/9 (0%)	0
Eye Contusion	1/14 (7.1%)	1	0/9 (0%)	0
Fall	4/14 (28.6%)	6	0/9 (0%)	0
Skin Abrasion	2/14 (14.3%)	2	0/9 (0%)	0
Investigations
Blood Potassium Decreased	1/14 (7.1%)	1	0/9 (0%)	0
Electrocardiogram St Segment Elevation	0/14 (0%)	0	1/9 (11.1%)	1
Ph Urine Abnormal	1/14 (7.1%)	1	0/9 (0%)	0
Platelet Count Decreased	0/14 (0%)	0	1/9 (11.1%)	2
Weight Decreased	0/14 (0%)	0	1/9 (11.1%)	1
Metabolism and nutrition disorders
Hyperuricaemia	1/14 (7.1%)	1	0/9 (0%)	0
Hypokalaemia	1/14 (7.1%)	1	0/9 (0%)	0
Hyponatraemia	1/14 (7.1%)	1	0/9 (0%)	0
Hypophosphataemia	0/14 (0%)	0	1/9 (11.1%)	1
Hypoproteinaemia	0/14 (0%)	0	1/9 (11.1%)	1
Musculoskeletal and connective tissue disorders
Back Pain	1/14 (7.1%)	1	0/9 (0%)	0
Dupuytren's Contracture	1/14 (7.1%)	1	0/9 (0%)	0
Muscular Weakness	1/14 (7.1%)	1	0/9 (0%)	0
Nervous system disorders
Dysgeusia	0/14 (0%)	0	1/9 (11.1%)	1
Migraine	0/14 (0%)	0	1/9 (11.1%)	2
Muscle Contractions Involuntary	1/14 (7.1%)	1	0/9 (0%)	0
Presyncope	0/14 (0%)	0	1/9 (11.1%)	1
Syncope	0/14 (0%)	0	1/9 (11.1%)	1
Renal and urinary disorders
Acute Kidney Injury	1/14 (7.1%)	1	0/9 (0%)	0
Nephrolithiasis	1/14 (7.1%)	1	0/9 (0%)	0
Respiratory, thoracic and mediastinal disorders
Atelectasis	0/14 (0%)	0	1/9 (11.1%)	1
Cough	1/14 (7.1%)	1	0/9 (0%)	0
Respiratory Acidosis	0/14 (0%)	0	1/9 (11.1%)	1
Skin and subcutaneous tissue disorders
Eczema	0/14 (0%)	0	1/9 (11.1%)	1
Pruritus	1/14 (7.1%)	1	0/9 (0%)	0
Surgical and medical procedures
Central Venous Catheterisation	0/14 (0%)	0	1/9 (11.1%)	1
Medical Device Removal	1/14 (7.1%)	1	0/9 (0%)	0
Vascular disorders
Hypertension	1/14 (7.1%)	1	0/9 (0%)	0
Hypotension	0/14 (0%)	0	1/9 (11.1%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.