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

Primary Purpose

Amyotrophic Lateral Sclerosis

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Inosine

About this trial

This is an interventional treatment trial for Amyotrophic Lateral Sclerosis focused on measuring ALS, Inosine, Uric acid, Urate, Glutathione, Biomarker, Oxidative stress, Oxidative damage, proof-of-concept

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Age 18 years or older.
Sporadic or familial ALS diagnosed as possible, laboratory-supported probable, probable, or definite as defined by revised El Escorial criteria (Appendix 1).
Capable of providing informed consent and following trial procedures.
Serum urate < 5.5 mg/dl at screening (i.e. below the population median serum urate levels).
Willingness to undergo magnetic resonance spectroscopy (MRS) at Baseline and at Week 12 of the study.
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:

History of urolithiasis.
Urine pH < 5.5 at screening (as acidic urine is a major determinant of uric acid urolithiasis).
Urate crystalluria at Screening.
History of gout.
History of stroke or myocardial infarction.
History of symptomatic coronary artery disease (e.g. angina pectoris) or symptomatic peripheral arterial disease within 1 year prior to Screening.
Symptomatic congestive heart failure with a documented ejection fraction below 45%.
Poorly controlled arterial hypertension (SBP>160mmHg or DBP>100mmHg at Screening).
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).
Women who are pregnant or lactating.
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.
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.
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.
Known hypersensitivity or intolerability to inosine.

Sites / Locations

Massachusetts General Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Open-label

Arm Description

Subjects will receive oral inosine daily.

Outcomes

Primary Outcome Measures

Number of Participants Experiencing Adverse Events

Safety will be assessed by the occurrence of adverse events.

Tolerability to Complete the Entire 12 Week Study on Study Drug.

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

Secondary Outcome Measures

Blood Biomarkers (GSH) at Baseline and Week 12

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).

Neuroimaging Biomarkers at Baseline and Week 12

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.

Blood Biomarkers (FRAP) at Baseline and Week 12

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).

Full Information

NCT ID

NCT02288091

First Posted

November 5, 2014

Last Updated

October 5, 2017

Sponsor

Massachusetts General Hospital

Collaborators

The Salah Foundation, MGH cure ALS Fund

1. Study Identification

Unique Protocol Identification Number

NCT02288091

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

October 2017

Overall Recruitment Status

Completed

Study Start Date

January 2015 (undefined)

Primary Completion Date

March 2016 (Actual)

Study Completion Date

March 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Massachusetts General Hospital

Collaborators

The Salah Foundation, MGH cure ALS Fund

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Amyotrophic Lateral Sclerosis

Keywords

ALS, Inosine, Uric acid, Urate, Glutathione, Biomarker, Oxidative stress, Oxidative damage, proof-of-concept

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

32 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Open-label

Arm Type

Experimental

Arm Description

Subjects will receive oral inosine daily.

Intervention Type

Drug

Intervention Name(s)

Inosine

Intervention Description

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.

Primary Outcome Measure Information:

Title

Number of Participants Experiencing Adverse Events

Description

Safety will be assessed by the occurrence of adverse events.

Time Frame

12 weeks

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

Secondary Outcome Measure Information:

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

Title

Neuroimaging Biomarkers at Baseline and Week 12

Description

Time Frame

12 weeks

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Age 18 years or older. Sporadic or familial ALS diagnosed as possible, laboratory-supported probable, probable, or definite as defined by revised El Escorial criteria (Appendix 1). Capable of providing informed consent and following trial procedures. Serum urate < 5.5 mg/dl at screening (i.e. below the population median serum urate levels). Willingness to undergo magnetic resonance spectroscopy (MRS) at Baseline and at Week 12 of the study. 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: History of urolithiasis. Urine pH < 5.5 at screening (as acidic urine is a major determinant of uric acid urolithiasis). Urate crystalluria at Screening. History of gout. History of stroke or myocardial infarction. History of symptomatic coronary artery disease (e.g. angina pectoris) or symptomatic peripheral arterial disease within 1 year prior to Screening. Symptomatic congestive heart failure with a documented ejection fraction below 45%. Poorly controlled arterial hypertension (SBP>160mmHg or DBP>100mmHg at Screening). 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). Women who are pregnant or lactating. 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. 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. 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. Known hypersensitivity or intolerability to inosine.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Sabrina Paganoni, MD, PhD

Organizational Affiliation

Massachusetts General Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

Massachusetts General Hospital

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02114

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

22323210

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.

Results Reference

background

PubMed Identifier

25298304

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.

Results Reference

background

PubMed Identifier

24366103

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.

Results Reference

background

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

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