Inosine for multiple sclerosis
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effectiveness and safety of inosine to modify disease course and prognosis in people with multiple sclerosis.
Background
Description of the condition
Multiple sclerosis (MS) is an autoimmune, chronic inflammatory demyelinating disease of the central nervous system (CNS) that primarily affects people aged from 20 years to 50 years (Miller 2012). MS is the leading cause of non‐traumatic disability in young adults in many countries (Pugliatti 2006). An updated report by the Multiple Sclerosis International Federation showed that the estimated number of people with MS worldwide increased from 2.1 million in 2008 to 2.3 million in 2013 (MSIF 2013). The global median prevalence of MS has increased from 30 (in 2008) to 33 per 100,000 (in 2013) (MSIF 2013). While MS is present in all regions of the world, its prevalence varies from 2.1 and 2.2 per 100,000 (Sub‐Saharan Africa and East Asia respectively) to 140 and 108 per 100,000 (North America and Europe respectively) (MSIF 2013). MS is two to three times more prevalent in women than men (Golden 2017). MS imposes a huge economic burden on the healthcare system and society with an average annual cost of USD 41,133 (adjusted by purchasing power parity) per patient (Kolasa 2013).
The aetiology of MS is not clear. The underlying causes include genetics and environmental factors such as infections (Ascherio 2007; Compston 2002). While locations of attacks can differ, few clinical features are disease‐specific. Major systems involved in MS include motor, sensory, visual and autonomic (Compston 2008). There are four clinical courses of MS: relapsing‐remitting MS (RRMS) (85%): secondary progressive MS (SPMS) (which evolves from an initial course of RRMS); primary progressive MS (PPMS) (10%); and progressive‐relapsing MS (PRSM) (5%) (Lublin 1996).
The prognosis of MS is variable, hard to predict and depends on the disease subtype, the individual's sex and age, and the severity of demyelinating lesions (Weinshenker 1994). In a population‐based series of 806 people with RRMS, the median time from disease onset to requiring aids for walking, bed bound status and death was roughly 15, 26 and 41 years respectively (Scalfari 2010). After 25 years from onset, 80% of people with RRMS may convert to SPSM (Scalfari 2010). Furthermore, people with MS have a statistically significant increase in mortality compared with the general population, with a reduction of life expectancy of between 7 years and 14 years (Scalfari 2013).
At present, there is no cure for MS. The main aims of current treatments are to hasten recovery from acute attacks of MS, reduce the risk of relapse, and prevent the occurrence of disability. High dose corticosteroid treatment after acute attacks can hasten relapse recovery (Filippini 2000; Howard 2016). However, there is insufficient evidence that corticosteroid treatment delays progression of long‐term disability or prevents new attacks in people with MS (Ciccone 2008; Filippini 2000; Howard 2016). Studies have shown that disease‐modifying therapies such as interferon beta can reduce the risk of relapse and delay disability progression (Filippini 2013; Tramacere 2015). At present, there is no treatment available that can comprehensively halt disease progression or regenerate damaged nerves. Alternative MS therapies are needed to expand the current treatment repertoire.
The successful use of inosine has been reported to reduce magnetic resonance imaging activity and prevent disease progression in an uncontrolled clinical trial in participants with MS (Spitsin 2001). A non‐randomised clinical trial including 64 MS participants showed that inosine can reduce relapse rates and delay progression of disease measured on the Expanded Disability Status Scale (EDSS) (Toncev 2006). A randomised, double‐blind trial also showed that oral administration of inosine can decrease the number of gadolinium‐enhanced lesions and improve the disease measured on the EDSS (Markowitz 2009). However, benefits of inosine for MS were not confirmed in subsequent studies (Gonsette 2010; Muñoz 2015).
Description of the intervention
Uric acid, the end product of purine metabolism in humans, is an antioxidant. It is a potent scavenger of peroxynitrite, which can cause a variety of potentially toxic chemical changes in tissue (Beckmann 1994). Studies have shown that uric acid may have a protective effect against degenerative neurological diseases such as Parkinson's disease and amyotrophic lateral sclerosis (Abraham 2014; Jesús 2013; Shen 2013). Treatment of experimental allergic encephalomyelitis mice with uric acid has been reported to elicit strong, dose‐dependent therapeutic effects (Hooper 1998). Meta‐analyses have showed that serum uric acid levels were lower in people with MS than healthy people in control arms (Liu 2012; Wang 2016). Studies have also showed that serum uric acid levels were lower in people with clinically‐active MS compared to those whose MS was clinically inactive (Liu 2012; Wang 2016).
How the intervention might work
Oral administration of uric acid does not increase serum uric acid levels because it is degraded in the gut. Oral administration of inosine to people with MS can increase uric acid levels both in serum and cerebrospinal fluid (Koprowski 2001). As a precursor of uric acid, inosine is a low‐molecular weight molecule that participates in a wide variety of intracellular biochemical processes. Inosine confers anti‐inflammatory effects by inhibiting the production of several pro‐inflammatory cytokines (Haskó 2000; Marton 2001). A study demonstrated that inosine is a potent activator of axon outgrowth in the central nervous system (Benowitz 1998). Inosine has also demonstrated protective effects on ischaemic brain damage and spinal cord injuries in rats (Liu 2006; Shen 2005). On the other hand, as a naturally occurring purine, inosine appears to be non toxic to humans, even when ingested at high doses (Williams 1990).
Why it is important to do this review
There have been no systematic reviews to date focusing on inosine for people with MS. A systematic review of the existing evidence is warranted to evaluate the effectiveness and safety of inosine for people with MS.
Objectives
To assess the effectiveness and safety of inosine to modify disease course and prognosis in people with multiple sclerosis.
Methods
Criteria for considering studies for this review
Types of studies
We will include all relevant randomised controlled trials (RCTs), irrespective of publication status or language. We will include data from the first phase of included cross‐over trials.
Types of participants
People with a confirmed diagnosis of multiple sclerosis (MS) according to published criteria (McDonald 2001; Polman 2005; Polman 2011; Poser 1983) regardless of age, sex, degree of disability, duration, type and course of the disease. All concomitant treatments will be accepted.
Types of interventions
We will evaluate trials independent of dosage, route of administration, frequency of administration and duration of treatment.
Comparisons include: inosine versus placebo or no intervention; inosine plus approved treatments (such as beta interferon) versus placebo or no intervention plus approved treatments.
Types of outcome measures
The outcome measures per se will not form part of the exclusion criteria for this review.
Primary outcomes
Benefit
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The number of participants who experienced disability progression at one year and after, or at the end of the study. Disability progression is defined as a one‐point increase in the Expanded Disability Status Scale (EDSS) score (Kurtzke 1983) (or a half‐point increase for participants with a baseline score ≥ 5.5) confirmed in the absence of relapse. Other definitions of disability progression reported in the trials will be accepted.
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The number of participants experiencing at least one relapse at one year and after, or at the end of the study. Relapse is defined as the appearance of one or more new symptoms due to MS or the deterioration of pre‐existing symptoms, persisting more than 24 hours in the absence of fever and preceded by a period of stability of at least 1 month (McDonald 2001). Definitions of relapse reported in the trials will be accepted.
Safety profile
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The number of participants experiencing serious adverse events (e.g. major haematological abnormalities) at one year and after, or at the end of the study.
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The number of participants who withdrew or dropped out from the study because of adverse events at one year and after, or at the end of the study.
Secondary outcomes
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The mean change in EDSS at one year and after, or at the end of the study.
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Annualised relapse rate (number of relapses per patient‐year).
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Mean serum uric acid levels at one year and after, or at the end of the study.
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The number of gadolinium‐enhancing T1‐weighted lesions at one year and after, or at the end of the study.
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Quality of life assessed using any validated disease‐specific or generic instruments at one year and after, or at the end of the study.
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The number of participants experiencing any adverse event at one year and after, or at the end of the study.
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The number of participants experiencing urinary tract stones or gout at one year and after, or at the end of the study. Definitions of urinary tract stones or gout reported in the trials will be accepted.
Search methods for identification of studies
Search strategies will be not limited by year of publication, language or publication type.
Electronic searches
The Information Specialist will search the Trials Register of the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group, which, among other sources, contains trials from:
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Cochrane Central Register of Controlled Trials (CENTRAL) (2016, most recent issue);
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MEDLINE (PubMed) (1966 to date);
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Embase (Embase.com) (1974 to date);
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Cumulative Index to Nursing and Allied Health Literature (CINAHL) (EBSCOhost) (1981 to date);
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Latin American and Caribbean Health Science Information Database (LILACS) (Bireme) (1982 to date);
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ClinicalTrials.gov (clinicaltrials.gov); and
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World Health Organization (WHO) International Clinical Trials Registry Platform (apps.who.int/trialsearch).
Information on the Group's Trials Register and details of search strategies used to identify trials can be found in the 'Specialised Register' section within the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group's module.
The keywords that we will use to search for trials for this review are listed in Appendix 1.
We will also search the following Chinese databases:
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The China Biological Medicine Database (CBM) (sinomed.imicams.ac.cn/zh/);
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Wanfang Data (www.wanfangdata.com/);
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The Chinese National Knowledge Infrastructure (CNKI); (epub.cnki.net/grid2008/index/ZKCALD.htm);
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Chinese Science and Technique Journals Database (VIP) (www.cqvip.com/).
Searching other resources
We will:
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handsearch the reference lists of all retrieved articles, texts and other reviews on the topic.
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contact authors of published trials if information reported is incomplete.
Data collection and analysis
Selection of studies
Two review authors (PPN and YY) will independently screen the titles and abstracts of all studies identified by the search strategy for inclusion or exclusion. We will obtain the full text of all potentially relevant studies for further assessment to determine if the study meets the pre‐determined inclusion criteria. Papers assessed in full text that do not meet the inclusion criteria will be listed in the 'Characteristic of excluded studies' table with the reason for exclusion. Any disagreement regarding inclusion/exclusion will be resolved by discussion among the review authors, or by referral to the editorial board of the Cochrane Multiple Sclerosis Group for arbitration if necessary.
Data extraction and management
Two review authors (PPN and YHW) will independently extract data from the selected trials using a standardised data extraction form and enter the data into RevMan software (Review Manager 2014).
We will extract the following information from individual studies:
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study design;
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study setting;
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MS diagnostic criteria;
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inclusion and exclusion criteria;
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methodological quality of studies;
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characteristics of participants;
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details of intervention;
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description of outcomes;
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withdrawals, compliance, length of follow‐up and number of participants followed up; and
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study period and location of study.
Any disagreements will be resolved by discussion among the review authors, or by referral to the editorial board of the Cochrane Multiple Sclerosis Group for arbitration, if necessary.
Assessment of risk of bias in included studies
Two review authors (PPN and YHW) will independently assess the methodological quality of the included studies using the Cochrane 'Risk of bias' tool (Higgins 2011). Random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome and other biases domains will be assessed. We will assign a judgement of low risk of bias, high risk of bias, or unclear risk of bias for each domain. We will report these assessments in the 'Risk of bias' table for each included study. We will rate studies to be of high methodological quality if the risk of bias for all entries is low. We will term these 'high‐quality studies'. We will consider studies as low methodological quality where there is unclear or high risk of bias for one or more entries and will term these as 'low‐quality studies'.
We will resolve any disagreements among review authors arising at any stage by discussion, or by referral to the editorial board of the Cochrane Multiple Sclerosis Group for arbitration, if necessary.
Measures of treatment effect
We will analyse data using RevMan (Review Manager 2014). We will express results for dichotomous outcomes as risk ratios (RRs) with 95% confidence intervals (CIs). We will calculate differences in means or standardised mean differences (SMDs) with 95% CIs for continuous data.
Unit of analysis issues
Data from included studies with non‐standard designs (e.g. cross‐over trials, cluster‐randomised trials) will be managed according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). For example, data from the first phase only will be used for included cross‐over trials. For cluster‐randomised trials, a direct estimate of the required effect measure (e.g. an odds ratio with its CI) that appropriately accounts for the cluster design will be extracted and used for pooling analysis. If the data were not available, analyses that aim to reduce the size of each trial to its effective sample size will be performed (Higgins 2011; Rao 1992).
Dealing with missing data
We will contact the original study authors to request missing data. If data are unavailable, we will use the available data when they can be assumed to be missing at random. If data cannot be assumed to be missing at random, we will undertake sensitivity analyses to impute missing data and compare results for best‐case and worst‐case scenarios.
The intention‐to‐treat (ITT) method will be used whenever possible.
Assessment of heterogeneity
We will assess clinical and methodological heterogeneity by considering the characteristics of participants, interventions, study designs and outcomes.
For each set of studies that are both clinically and methodologically homogenous, we will examine statistical heterogeneity by visual inspection of CI overlap on the forest plot (poor overlap indicating the presence of heterogeneity) and using the Chi² statistic (significance level of 0.1) and the I² statistic (Higgins 2011). We will consider an I² value greater than 50% to indicate substantial heterogeneity.
Assessment of reporting biases
If we are able to pool more than 10 trials, we will assess reporting bias according to the recommendations on testing for funnel plot asymmetry (Egger 1997) as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Data synthesis
We will pool results from clinically similar studies for meta‐analysis if the methods and available data in each study are sufficiently similar to enable pooling. We will use a fixed‐effect meta‐analysis if the I² ≤ 50%. If the I² > 50% we will explore individual trial characteristics to identify potential sources of heterogeneity in pre‐planned subgroup analyses. We will perform meta‐analysis using both fixed‐effect and random‐effects models where there is substantial heterogeneity to assess the choice of model. We will report the most conservative result, if we find non‐identical results between the models.
We will provide descriptive analysis of results if the outcome data from different studies cannot be pooled.
Subgroup analysis and investigation of heterogeneity
If possible, we will undertake subgroup analyses according to:
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doses of inosine;
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degree of disability;
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MS type;
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co‐interventions; and
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study quality.
Sensitivity analysis
We will perform sensitivity analyses by excluding trials of high risk of bias. We will compare results from random‐effects and fixed‐effect models. We will also perform best‐case and worst‐case scenario analyses where missing data can not be assumed to be missing at random.
'Summary of findings' table
We will assess the overall quality of the evidence for the primary outcome using the GRADE system. The Grading of Recommendation, Assessment, Development and Evaluation (GRADE) Working Group developed a system for grading the quality of evidence (Atkins 2004; Guyatt 2008; Guyatt 2011; Schünemann 2006) which takes into account issues not only related to internal validity but also to external validity, such as directness of results. The 'Summary of findings' tables present the main findings of a review in a transparent and simple tabular format. In particular, they provide key information concerning the quality of evidence, the magnitude of effect of the interventions examined and the sum of available data on the following outcomes:
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The number of participants who experienced disability progression at 24 months.
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The number of participants who experienced at least one relapse at 24 months.
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The number of participants who experienced serious adverse events at 24 months.
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The number of participants who withdrew or dropped out from the study because of adverse events at 24 months.
The GRADE system provides the following criteria for assigning grades of evidence.
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High: We are very confident that the true effect lies close to that of the estimate of the effect.
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Moderate: We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
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Low: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect.
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Very low: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect.
Grading is decreased for the following reasons.
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Serious (‐1) or very serious (‐2) study limitation for risk of bias.
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Serious (‐1) or very serious (‐2) inconsistency between study results.
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Some (‐1) or major (‐2) uncertainty about directness (the correspondence between the population, the intervention, or the outcomes measured in the studies actually found and those under consideration in our systematic review).
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Serious (‐1) or very serious (‐2) imprecision of the pooled estimate.
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Strong suspicion of publication bias (‐1).
We will justify all decisions to down grade the quality of studies using footnotes and we will make comments to aid readers' understanding of the review where necessary.
We will create the 'Summary of findings' tables using GRADEpro GDT (GRADEpro GDT 2015).
