Amyotrophic Lateral SclerosisPhase 1NCT02288091
A Pilot Study of Inosine in Amyotrophic Lateral Sclerosis (ALS)
A Phase 1 study testing Inosine in people with Amyotrophic Lateral Sclerosis, run by Massachusetts General Hospital at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Amyotrophic Lateral Sclerosis
- What is being tested?
- Inosine
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 32 participants
- Where
- 1 siteUnited States
- Study dates
- Jan 2015to Mar 2016
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
Massachusetts General Hospital
Boston, Massachusetts, 02114
About this study
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.
Read the 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.
- Conditions
- Amyotrophic Lateral Sclerosis
- Being tested
- Inosine
- Keywords
- ALS, Inosine, Uric acid, Urate, Glutathione, Biomarker, Oxidative stress, Oxidative damage, proof-of-concept
- Medical subject headings
- Amyotrophic Lateral Sclerosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
InosineDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Open-label | Experimental | Subjects will receive oral inosine daily. Receives: Drug: Inosine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants Experiencing Adverse Events
Safety will be assessed by the occurrence of adverse events.
Measured: 12 weeks
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.
Measured: 12 weeks
Secondary outcomes (3)
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).
Measured: 12 weeks
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.
Measured: 12 weeks
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).
Measured: 12 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Nov 2014 (estimated)
- Study startJan 2015
- Primary completionMar 2016
- Study completionMar 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Amyotrophic Lateral SclerosisStudies of the same condition, open and under way.
- More trials run by Massachusetts General HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 32 participants (actual)
Sponsor and investigators
- Lead sponsor
- Massachusetts General Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- The Salah Foundation, Sean M. Healey & AMG Center for ALS
- Responsible party
- Principal investigator, Sabrina Paganoni, M.D., Massachusetts General Hospital
- Investigators
- Sabrina Paganoni, MD, PhD, Principal investigator, Massachusetts General Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02288091
- Sponsor's protocol ID
- 701
- Status last verified
- Oct 2017
- First submitted
- 5 Nov 2014
- Last updated
- 6 Nov 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 22323210Atassi 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.
PubMed 25298304Parkinson 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.
PubMed 24366103
Study at a glance
From the registry record, last updated by the sponsor on 6 Nov 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Pilot Study of Inosine in Amyotrophic Lateral Sclerosis (ALS)
- ClinicalTrials.gov ID
- NCT02288091
- Acronym / sponsor ID
- 701
- Conditions
- Amyotrophic Lateral Sclerosis
- Keywords
- ALS, Inosine, Uric acid, Urate, Glutathione, Biomarker, Oxidative stress, Oxidative damage
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 32 participants (actual)
- Lead sponsor
- Massachusetts General HospitalUniversity, hospital or other
- Collaborators
- The Salah Foundation, Sean M. Healey & AMG Center for ALS
- Study start
- Jan 2015
- Primary completion
- Mar 2016 (actual)
- Study completion
- Mar 2016 (actual)
- First posted
- 11 Nov 2014 (estimated)
- Results
- Posted 2 Oct 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Open-label | Experimental | Drug: InosineSubjects will receive oral inosine daily. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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.
Key exclusion criteria (14 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| InosineTwenty-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. | Drug | Open-label |
Primary outcome
Number of Participants Experiencing Adverse Events
Time frame: 12 weeks
Safety will be assessed by the occurrence of adverse events.
Tolerability to Complete the Entire 12 Week Study on Study Drug.
Time frame: 12 weeks
Tolerability will be defined as the ability of subjects to complete the entire 12-week study on study drug.
3 secondary outcomes
Blood Biomarkers (GSH) at Baseline and Week 12
Time frame: 12 weeks
Neuroimaging Biomarkers at Baseline and Week 12
Time frame: 12 weeks
Blood Biomarkers (FRAP) at Baseline and Week 12
Time frame: 12 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Nov 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 22323210Paganoni 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.
- Background: PubMed 25298304Atassi 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.
- Background: PubMed 24366103Parkinson 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Sabrina Paganoni, MD, PhD principal investigator
Massachusetts General Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Inosine in people with Amyotrophic Lateral Sclerosis, run by Massachusetts General Hospital at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 6 Nov 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 2 Oct 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants Experiencing Adverse Events (time frame: 12 weeks). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02288091, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Nov 2017.