Inosine 5'-Monophosphate to Raise of Serum Uric Acid Level in Patients With Multiple System Atrophy: a Multi-center, Randomized Controlled, Double Blind, Parallel Assigned Clinical Trial

NCT ID: NCT03403309

Last Updated: 2019-07-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 43 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-05-02
• Study Completion Date: 2019-06-10

Brief Summary

A purpose of the present study is to investigate the capability of serum uric acid elevation, safety, and tolerability of inosine 5'-monophosphate in patients with multiple system atrophy with multicenter, randomized, placebo controlled, parallel assigned design. This may provide the cornerstone for future extended trial in multiple system atrophy, a debilitating disease to date.

Detailed Description

Background and objective:

Uric acid (UA) is the end product of purine metabolism in human body, which is converted from the precursor metabolite inosine and finally excreted via route of urine and gastrointestinal tract. A high level of UA, usually ≥ 7.0 mg/dL, may lead to development of gout, nephrolithiasis, or to give detrimental effect to a variety of medical diseases, such as chronic kidney disease, cardiovascular disorders, and diabetes. Meanwhile, UA is the very well-known antioxidant, in which the biological antioxidant act as scavenging free radicals (e.g. peroxynitrite), chelating iron, and preventing peroxidation of lipid. Although there have been two faced aspects on UA, antioxidant versus pro-inflammatory potentials, toward neurodegenerative disorders, converging evidences have been highlighting the effects of potential disease modification so far. Given the certain contribution of oxidative stress to the pathogenesis of various neurodegenerative disorders, a therapeutic attempts to anti-oxidation may be promising and feasible. In observational study, ample evidence has been suggested to be beneficial associations between higher uric acid level and lower the risk of disease, clinical severity and progression in Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, ischemic stroke, and even up to myasthenia gravis across clinical, epidemiological, and radiological studies. In addition, on aspect of interventional study, there have been 4 randomized clinical trials of increasing serum uric acid via administration of inosine so far in multiple sclerosis, stroke, amyotrophic lateral sclerosis, and Parkinson's disease. All of the studies have demonstrated reliable capability of increasing serum uric acid level, and favorable safety and tolerability profile. Currently, a phase II trial in Parkinson's disease demonstrated hopeful view in disease modifying strategy by modulating disease progression rate on the inosine administered group with a dose dependent manner.

In case of multiple system atrophy (MSA), there have been a couple of previous reports including increased serum level of UA in MSA compared to healthy control, and strong correlation in serum uric acid level with either motor or cognitive functions. However, no interventional studies have been undertaken to date at all regarding UA. We aimed to investigate the UA elevating capability, safety, and tolerability of inosine 5'-monophosphate, a precursor of uric acid, in MSA patients with randomized, placebo controlled, and parallel assigned design.

Methods:

All participants are randomized to study drugs, either tablet of placebo or inosine 5'-monophosphate, in 1 to 1 ratio and then undergo scheduled titration. Study drugs are initiated with 1 tablet 2 times per day, and then titrate up by 1 tablet per every visit up to visit 2. That is, 1 tablet two times per day for initial 2 weeks, 1 tablet three times per day from next week 3 to 4, and 2 tablets two times per day from next week 4 to 6, and then maintain throughout to week 24. Laboratory tests including serum uric acid level, urine analysis, and stone analysis are scheduled to be checked at time of week 2, 4, 6, 12, 18, and 24, respectively. A maximum limit of elevated serum uric acid level is 9 mg/dL, and thus reducing dose of administration may be considered in case of exceeding the limited level. Comparison of the extent of altered serum uric acid level, safety, and tolerability from baseline to week 24 will be analyzed after study termination.

Conditions

Multiple System Atrophy

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Inosine 5'-monophosphate arm

Subjects are treated with inosine 5'-monophosphate to increase serum uric acid level.

Group Type: EXPERIMENTAL

1) Inosine 5'-monophosphate

Intervention Type: DRUG

1\) Subjects are initiated with 1 tablet (500mg of inosine 5'-monophosphate per one tablet) two times per day, and then titrated up by 1 tablet per every visit up to visit 2, i.e. increased up to 2 tablets two times a day by week 6. A maximum limit of elevated serum uric acid level is 9 mg/dL, so that reducing dose of administration may be considered in case of being way over the top of limited level.

Placebo arm

Subjects are treated with placebo not to increase serum uric acid level.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

2\) Subjects are initiated with 1 tablet (500mg of placebo tablet with inactive therapeutic effect) two times a day, and then titrated up by 1 tablet per every visit up to visit 2, i.e. increased up to 2 tablets two times a day by week 6. A maximum limit of elevated serum uric acid level is 9 mg/dL.

Interventions

1) Inosine 5'-monophosphate

1\) Subjects are initiated with 1 tablet (500mg of inosine 5'-monophosphate per one tablet) two times per day, and then titrated up by 1 tablet per every visit up to visit 2, i.e. increased up to 2 tablets two times a day by week 6. A maximum limit of elevated serum uric acid level is 9 mg/dL, so that reducing dose of administration may be considered in case of being way over the top of limited level.

Intervention Type: DRUG

Placebo

2\) Subjects are initiated with 1 tablet (500mg of placebo tablet with inactive therapeutic effect) two times a day, and then titrated up by 1 tablet per every visit up to visit 2, i.e. increased up to 2 tablets two times a day by week 6. A maximum limit of elevated serum uric acid level is 9 mg/dL.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Subjects who met the clinical criteria of either probable or possible multiple system atrophy, age ranged from 19 to 75 at their onset of symptom.

2. Subjects who underwent brain magnetic resonance imaging or 18F-fluorodeoxyglucose positron emission tomography at the time of their diagnosis in which showed any findings compatible to multiple system atrophy, such as cerebellar or putaminal atrophy, putaminal hyperintense rim or iron accumulation, hot cross bun sign or T2 high signal intensities on middle cerebellar peduncle, and decreased glucose metabolism on putamen or cerebellum.

3. Total score of unified multiple system atrophy rating scale 30 or more at baseline screening.

4. Serum uric acid level ≤ 6.0 mg/dL at baseline screening.

Exclusion Criteria

1. Prior history of gout, nephrolithiasis, stroke, or chronic kidney disease.

2. Presentation of urine pH ≤ 5.0 or uric acid crystalluria on urine analysis at baseline screening.

3. Subject who showed febrile condition or have any sort of unstable and hopeless disorders.

4. Subjects on following medications undergo 4 weeks of wash-out period, and then not co-administered at all over study duration: co-enzyme Q, creatine, daily vitamin E 50 IU or more, and daily vitamin C 300 mg or more.

5. Presence of psychiatric or cognitive impairment by which interrupt to carry out the whole process of the study.

• Minimum Eligible Age: 19 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Yonsei University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Department of Neurology, Yonsei University College of Medicine

Seoul, Seou, South Korea

Countries

South Korea

Other Identifiers

4-2017-0990

Identifier Type: -

Identifier Source: org_study_id