A Pilot Study of Inosine in Amyotrophic Lateral Sclerosis (ALS)

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT02288091
• Collaborator: The Salah Foundation (Other), MGH cure ALS Fund (Other)
• Enrollment: 32
• Location: 1
• Arm: 1
• Duration (Months): 14
• Patients Per Site Per Month: 2.3

Study Details

Study Description

Brief Summary

This is a single center, open label, 12-week study of inosine treatment. Inosine treatment leads to an increase in the levels of urate (uric acid) in the blood.

The primary objective of the study is to determine the tolerability of oral administration of inosine.

Secondary study objectives include the measurement of biomarkers of oxidative stress and damage in response to inosine treatment.

Condition or Disease	Intervention/Treatment	Phase
Amyotrophic Lateral Sclerosis	Drug: Inosine	Phase 1

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. As a first step towards development of inosine as a potential treatment for ALS, in this study we will test whether inosine administration in ALS is safe and correlates with changes in the levels of biomarkers of oxidative stress and damage (as biomarkers of the intended biological effect).

The primary outcome measures will be safety, as measured by adverse events and clinically meaningful changes in vital signs, physical examination, and standard clinical laboratory tests, and tolerability, defined as the ability of subjects to complete the entire 12-week study.

The secondary objective of the study is to quantify the effect of the treatment on biomarkers of oxidative damage and stress.

An exploratory objective of the study is to measure whether changes in these biomarkers are different in people with bulbar-onset ALS compared to people with limb-onset ALS.

This study will be conducted in people who meet the El Escorial criteria of possible, laboratory-supported probable, probable, or definite criteria for a diagnosis of ALS. At screening, eligible individuals must be at least 18 years old and must provide written informed consent prior to screening. Subjects on a stable dose of riluzole and those not taking riluzole, and women of child-bearing age at screening are eligible for inclusion as long as they meet specific protocol requirements.

Study participants will be administered oral inosine daily. The dose of inosine will be titrated to obtain serum urate levels of 7 - 8 mg/dL.

Study participants will remain on treatment until the Week 12 visit. Each participant will also have a Week 16 Follow-up Telephone Interview to assess for adverse events (AEs), changes in concomitant medications and to administer the ALSFRS-R.

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Study of Inosine in Amyotrophic Lateral Sclerosis (ALS)
• Study Start Date: Jan 1, 2015
• Actual Primary Completion Date: Mar 1, 2016
• Actual Study Completion Date: Mar 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Open-label Subjects will receive oral inosine daily.	Drug: Inosine; Twenty-five eligible subjects will receive inosine for 12 weeks (administered in the form of 500 mg capsules, 1 to 6 capsules a day for a total daily dose of up to 3 gm). The dose of inosine will be titrated to target urate levels of 7-8 mg/dL based on urate level measurement that will occur at Week 2, Week 4, Week 6, and Week 9 after Baseline.

Outcome Measures

Primary Outcome Measures

1. Number of Participants Experiencing Adverse Events [12 weeks]

   Safety will be assessed by the occurrence of adverse events.

2. Tolerability to Complete the Entire 12 Week Study on Study Drug. [12 weeks]

   Tolerability will be defined as the ability of subjects to complete the entire 12-week study on study drug.

Secondary Outcome Measures

1. Blood Biomarkers (GSH) at Baseline and Week 12 [12 weeks]

   Blood samples will be obtained at baseline and after 12 weeks of treatment to measure biomarkers of oxidative stress and damage such as glutathione (GSH).

2. Neuroimaging Biomarkers at Baseline and Week 12 [12 weeks]

   Magnetic resonance spectroscopy (MRS) will be performed to measure the levels of glutathione in the motor cortex; levels of glutathione at Week 12 (post-treatment) will be compared to pre-treatment levels.

3. Blood Biomarkers (FRAP) at Baseline and Week 12 [12 weeks]

   Blood samples will be obtained at baseline and after 12 weeks of treatment to measure biomarkers of oxidative stress and damage such as ferric reducing antioxidant power (FRAP).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Age 18 years or older.

2. Sporadic or familial ALS diagnosed as possible, laboratory-supported probable, probable, or definite as defined by revised El Escorial criteria (Appendix 1).

3. Capable of providing informed consent and following trial procedures.

4. Serum urate < 5.5 mg/dl at screening (i.e. below the population median serum urate levels).

5. Willingness to undergo magnetic resonance spectroscopy (MRS) at Baseline and at Week 12 of the study.

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.

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. Urate crystalluria at Screening.

4. History of gout.

5. History of stroke or myocardial infarction.

6. History of symptomatic coronary artery disease (e.g. angina pectoris) or symptomatic peripheral arterial disease within 1 year prior to Screening.

7. Symptomatic congestive heart failure with a documented ejection fraction below 45%.

8. Poorly controlled arterial hypertension (SBP>160mmHg or DBP>100mmHg at Screening).

9. Contraindications to undergo magnetic resonance spectroscopy (MRS) at Baseline and at Week 12 of the study such as history of claustrophobia, inability to lie flat for approximately one hour, or metal implants (metal pins or plates, extensive non-removable dental work, cerebral aneurysm clips, pacemaker).

10. Women who are pregnant or lactating.

11. The presence of unstable psychiatric disease, cognitive impairment, or dementia that would impair ability of the subject to provide informed consent, according to PI judgment, or a history of active substance abuse within the prior year.

12. Anything that, in the opinion of the investigator, would place the subject at increased risk or preclude the subject's full compliance with or completion of the study.

13. 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.

14. Known hypersensitivity or intolerability to inosine.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02114

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)

None provided.

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: NCT02288091
• Other Study ID Numbers: 701
• First Posted: Nov 11, 2014
• Last Update Posted: Nov 6, 2017
• Last Verified: Oct 1, 2017

• 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; proof-of-concept
• Additional relevant MeSH terms: Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Sclerosis

Study Results

Participant Flow

Arm/Group Title	Open-label
Arm/Group Description	Subjects will receive oral inosine daily. Inosine: Twenty-five eligible subjects will receive inosine for 12 weeks (administered in the form of 500 mg capsules, 1 to 6 capsules a day for a total daily dose of up to 3 gm). The dose of inosine will be titrated to target urate levels of 7-8 mg/dL based on urate level measurement that will occur at Week 2, Week 4, Week 6, and Week 9 after Baseline.
Period Title: Overall Study
STARTED	32
Randomized/Treated	25
COMPLETED	24
NOT COMPLETED	8

Baseline Characteristics

Arm/Group Title	Open-label
Arm/Group Description	Subjects will receive oral inosine daily. Inosine: Twenty-five eligible subjects will receive inosine for 12 weeks (administered in the form of 500 mg capsules, 1 to 6 capsules a day for a total daily dose of up to 3 gm). The dose of inosine will be titrated to target urate levels of 7-8 mg/dL based on urate level measurement that will occur at Week 2, Week 4, Week 6, and Week 9 after Baseline.
Overall Participants	25
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.2 (8.4)
Sex: Female, Male (Count of Participants)
Female	18 72%
Male	7 28%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 4%
Not Hispanic or Latino	24 96%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 4%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 4%
White	23 92%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	25 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Experiencing Adverse Events
Description	Safety will be assessed by the occurrence of adverse events.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

No expected adverse events of special interest, such as kidney stones and gout, occurred during the course of the study. However, twenty-two (22) out of twenty-five (25) participants did experience an adverse event during the course of the study.

Arm/Group Title	Open-label
Arm/Group Description	Subjects will receive oral inosine daily. Inosine: Twenty-five eligible subjects will receive inosine for 12 weeks (administered in the form of 500 mg capsules, 1 to 6 capsules a day for a total daily dose of up to 3 gm). The dose of inosine will be titrated to target urate levels of 7-8 mg/dL based on urate level measurement that will occur at Week 2, Week 4, Week 6, and Week 9 after Baseline.
Measure Participants	25
Count of Participants [Participants]	22 88%

2. Primary Outcome

Title	Tolerability to Complete the Entire 12 Week Study on Study Drug.
Description	Tolerability will be defined as the ability of subjects to complete the entire 12-week study on study drug.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Twenty-four (24) out of twenty-five (25) participants completed 12 weeks of study drug treatment.

Arm/Group Title	Open-label
Arm/Group Description	Subjects will receive oral inosine daily. Inosine: Twenty-five eligible subjects will receive inosine for 12 weeks (administered in the form of 500 mg capsules, 1 to 6 capsules a day for a total daily dose of up to 3 gm). The dose of inosine will be titrated to target urate levels of 7-8 mg/dL based on urate level measurement that will occur at Week 2, Week 4, Week 6, and Week 9 after Baseline.
Measure Participants	25
Count of Participants [Participants]	24 96%

3. Secondary Outcome

Title	Blood Biomarkers (GSH) at Baseline and Week 12
Description	Blood samples will be obtained at baseline and after 12 weeks of treatment to measure biomarkers of oxidative stress and damage such as glutathione (GSH).
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Two (2) subjects did not have blood drawn for GSH analysis at the Baseline Visit. Five (5) subjects did not have blood drawn for GSH analysis at the Week 12 visit. These missing samples are due to technical issues, such as a difficult blood draw or issue with sample processing.

Arm/Group Title	Open-label
Arm/Group Description	Subjects will receive oral inosine daily. Inosine: Twenty-five eligible subjects will receive inosine for 12 weeks (administered in the form of 500 mg capsules, 1 to 6 capsules a day for a total daily dose of up to 3 gm). The dose of inosine will be titrated to target urate levels of 7-8 mg/dL based on urate level measurement that will occur at Week 2, Week 4, Week 6, and Week 9 after Baseline.
Measure Participants	23
Glutathione at Baseline	94.0 (28.4)
Glutathione at Week 12	84.5 (42.6)

4. Secondary Outcome

Title	Neuroimaging Biomarkers at Baseline and Week 12
Description	Magnetic resonance spectroscopy (MRS) will be performed to measure the levels of glutathione in the motor cortex; levels of glutathione at Week 12 (post-treatment) will be compared to pre-treatment levels.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Five (5) subjects did not have a MRS done at the Baseline and Week 12 visits. Of the 20 that had a baseline MRS, 2 patients did not have a Week 12 MRS done. These missing MRS scans are due to technical difficulties, such as subjects were unable to complete the scan.

Arm/Group Title	Open-label
Arm/Group Description	Subjects will receive oral inosine daily. Inosine: Twenty-five eligible subjects will receive inosine for 12 weeks (administered in the form of 500 mg capsules, 1 to 6 capsules a day for a total daily dose of up to 3 gm). The dose of inosine will be titrated to target urate levels of 7-8 mg/dL based on urate level measurement that will occur at Week 2, Week 4, Week 6, and Week 9 after Baseline.
Measure Participants	20
Motor Cortex Precentral Gyri (Baseline)	0.424 (0.064)
Motor Cortex Precentral Gyri (Week 12)	0.392 (0.064)

5. Secondary Outcome

Title	Blood Biomarkers (FRAP) at Baseline and Week 12
Description	Blood samples will be obtained at baseline and after 12 weeks of treatment to measure biomarkers of oxidative stress and damage such as ferric reducing antioxidant power (FRAP).
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

One (1) subject did not have blood drawn for FRAP analysis at the Baseline Visit. Four (4) subjects did not have blood drawn for FRAP analysis at the Week 12 visit. These missing samples are due to technical issues, such as a difficult blood draw or issue with sample processing.

Arm/Group Title	Open-label
Arm/Group Description	Subjects will receive oral inosine daily. Inosine: Twenty-five eligible subjects will receive inosine for 12 weeks (administered in the form of 500 mg capsules, 1 to 6 capsules a day for a total daily dose of up to 3 gm). The dose of inosine will be titrated to target urate levels of 7-8 mg/dL based on urate level measurement that will occur at Week 2, Week 4, Week 6, and Week 9 after Baseline.
Measure Participants	24
Ferric Reducing Antioxidant Power (Baseline)	765.7 (155.1)
Ferric Reducing Antioxidant Power (Week 12)	1188.3 (294.1)

Adverse Events

Time Frame	Adverse events were collected from the time the subject signed consent until 28 days after a subject's last dose of study drug.
Arm/Group Title	Open-label
Arm/Group Description	Subjects will receive oral inosine daily. Inosine: Twenty-five eligible subjects will receive inosine for 12 weeks (administered in the form of 500 mg capsules, 1 to 6 capsules a day for a total daily dose of up to 3 gm). The dose of inosine will be titrated to target urate levels of 7-8 mg/dL based on urate level measurement that will occur at Week 2, Week 4, Week 6, and Week 9 after Baseline.
All Cause Mortality
	Open-label
	Affected / at Risk (%)	# Events
Total	1/25 (4%)
Serious Adverse Events
	Open-label
	Affected / at Risk (%)	# Events
Total	3/25 (12%)
Infections and infestations
Abdominal Abscess	1/25 (4%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/25 (4%)	1
Respiratory Failure	1/25 (4%)	1
Other (Not Including Serious) Adverse Events
	Open-label
	Affected / at Risk (%)	# Events
Total	22/25 (88%)
Gastrointestinal disorders
Constipation	2/25 (8%)	2
Dysphagia aggravated	2/25 (8%)	2
General disorders
Fatigue	2/25 (8%)	2
Weakness worsened	3/25 (12%)	3
Injury, poisoning and procedural complications
Ankle sprain	2/25 (8%)	2
Fall	8/25 (32%)	11
Investigations
Weight Loss	4/25 (16%)	4
Metabolism and nutrition disorders
Decreased appetite	2/25 (8%)	2
Musculoskeletal and connective tissue disorders
Weakness of arms	2/25 (8%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.