Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess evidence from randomised controlled trials (RCTs) on the efficacy and safety of treatment with riluzole for patients with PD.
Background
Description of the condition
Parkinson's disease (PD) is a neurodegenerative disorder that is usually classified as a movement disorder. Prevalence rates range from 57 to 371 per 100,000 worldwide and peak between the ages of 70 and 79 years (Lang 1998; Strickland 2004; Twelves 2003). The most obvious clinical features are motor related and include tremor, rigidity, slowness of movement and postural instability. PD is generally acknowledged to result from progressive loss of dopaminergic neurons in the substantia nigra, specifically the ventral portion of the pars compacta (Davie 2008). Levodopa is regarded as the most effective treatment and has been widely used for over 30 years (National Collaborating Centre 2006). However, levodopa‐induced motor fluctuations and dyskinesias present major problems in the treatment of patients with PD.
Description of the intervention
Drugs with potential neuroprotective effects are needed for patients with PD as well as existing symptomatic treatments. For instance, mitochondrial enhancement (e.g. coenzyme Q10 and creatine) may be beneficial for patients with PD (Liu 2014). Riluzole is the only drug that has been approved in most countries for the treatment of a neurodegenerative disease (amyotrophic lateral sclerosis) with prolonged median survival (Miller 2007). The neuroprotective effects of riluzole have been demonstrated in animal models of neurodegenerative diseases such as PD and Huntington's disease (HD) (Douhou 2002; Schiefer 2002). Concerning the symptomatic effects, riluzole seemed to improve the symptoms and reduce chorea scores with protecting grey matter volume loss and increasing the production of neurotrophins for patients with HD (Bonelli 2007; Squitieri 2009).
How the intervention might work
The mechanism of action of riluzole is unknown. Mitochondrial dysfunction has been found to play a role in the pathogenesis of PD at early stages (Liu 2011). The deficit of energy increases vulnerability to glutaminergic stimulation and contributes to the neurodegenerative process in PD (Beal 1998). Also, in PD, neuronal activity in the subthalamic nucleus, , which is in charge of projecting to the internal segment of the globus pallidus via the neurotransmitter glutamate, is strengthened (Stefani 2005). Therefore, the glutamate antagonist riluzole may be beneficial for patients with PD. In addition, augmentation of the synaptic efficacy of striatal ionotropic glutaminergic receptors contributes to the appearance of dyskinesias (Chase 2004); this could be relieved by riluzole through the modulation of excitatory glutaminergic transmission in striatal spiny neurons (Bibbiani 2005).
Why it is important to do this review
Although levodopa is used as the first‐line agent in the treatment of PD, levodopa‐induced dyskinesias (LIDs) can be seen in about 40% of patients with PD treated with levodopa for five years (Van Gerpen 2006). In addition to potentially improving motor function in patients with PD, riluzole may prevent LIDs (Merims 1999). It is still unknown that if riluzole can prolong median survival in PD. Therefore, the efficacy of riluzole for patients with PD should be determined. Several randomised controlled clinical trials have already been conducted. However, no systematic review in the current peer‐reviewed literature focuses on the use of riluzole for patients with PD.
Objectives
To assess evidence from randomised controlled trials (RCTs) on the efficacy and safety of treatment with riluzole for patients with PD.
Methods
Criteria for considering studies for this review
Types of studies
We included parallel‐group RCTs focused on riluzole versus placebo or active comparator for patients with PD.
Types of participants
We included patients diagnosed with idiopathic PD at any stage given stable antiparkinson medications or no medical intervention at the time of entry into the study. We applied no limitations in gender or age.
Types of interventions
Comparisons of riluzole versus no riluzole that allowed other treatments to be given provided they were the same in both groups. The no riluzole group might be placebo controlled or open controlled.
Comparisons of riluzole versus other active treatments (pharmacological or non‐pharmacological) subdivided by type of active intervention. Again an open comparison or a blinded comparison (i.e. placebo for each active agent) might be performed.
Types of outcome measures
The efficacy outcomes included symptomatic and neuroprotective effects. We analysed efficacy outcomes reported at the end of treatment or during follow‐up. While we analysed safety outcomes reported during the treatment period.
Primary outcomes
Efficacy
The change in score measured by the scales for motor function, e.g. (Unified Parkinson's Disease Rating Scale (UPDRS)‐III.
Safety
The number of participants with adverse effects (AEs).
Secondary outcomes
Changes in score on other UPDRS subscales (UPDRS‐I; UPDRS‐II; UPDRS‐IV; Hoehn and Yahr Staging and Schwab‐England ADL scale).
Survival.
Quality of life scales (such as 39‐Item Parkinson's Disease Questionnaire, Parkinson's Disease Questionnaire Short Form, Parkinson's Disease Quality of Life Questionnaire, Parkinson's Impact Scale, and Scales for Outcomes in Parkinson's Disease‐Psychosocial).
Number of participants with motor complications (e.g. motor fluctuations, dyskinesias, any motor complications (fluctuations or dyskinesias)).
Number of withdrawals from treatment due to severe AEs.
Search methods for identification of studies
Electronic searches
We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (31 January 2017), MEDLINE (1966 to 31 January 2017), EMBASE (1980 to 31 January 2017), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to 31 January 2017), PsycINFO (1840 to 31 January 2017), Chinese databases such as the China Biological Medicine Database (CBM‐disc) (1979 to 31 January 2017) and the China National Knowledge Infrastructure (CNKI) (1979 to 31 January 2017) and the Database of Abstracts of Reviews of Effects (DARE) (31 January 2017).
The search strategy for MEDLINE through Ovid Gateway was shown in Appendix 1 and adapted for the other databases.
To identify further published, unpublished and ongoing trials, we searched the trials registers in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) (e.g. ClinicalTrials.gov (http://www.clinicaltrials.gov/), World Health Organization (WHO) International Clinical Trials Registry Platform (http://apps.who.int/trialsearch/).
Searching other resources
In addition, we:
searched reference lists of reviews and retrieved articles for additional studies;
searched conference proceedings from the previous three years for relevant studies, including World Congress of Neurology, World Congress on Parkinson's Disease and Related Disorders, International Congress of Parkinson's Disease and Movement Disorders and International Congress on Non‐Motor Dysfunctions in Parkinson's Disease and Related Disorders;
contacted authors of trials to ask for additional information when necessary; and
contacted relevant pharmaceutical companies for information on trials of riluzole.
We applied no language limitations for the search, and tried to obtain translations of articles when necessary.
Data collection and analysis
Selection of studies
Two review authors (LJ, WL) independently screened titles and abstracts of citations produced by the literature search to determine whether the inclusion criteria were met and obtained the full text of potentially relevant studies. Two review authors (LJ, WL) independently evaluated eligibility and assessed the methodological quality of these studies. Disagreements were resolved by discussion or by consultation with an independent party if necessary.
Data extraction and management
Two review authors (LJ, WL) independently extracted eligible data from published reports onto standardised forms and cross‐checked them for accuracy. We used checklists to independently record details, including methods of generating a randomisation schedule; methods of concealing allocation; blinding of assessors; completion of intention‐to‐treat analyses; reporting of adverse events and drop‐outs for all reasons; important imbalances in prognostic factors; characteristics of participants (sociodemographic and related clinical information); interventions provided (medications and non‐pharmacological interventions); and outcomes measured. We resolved disagreements regarding inclusion by discussion or by consultation with an independent party if necessary.
Assessment of risk of bias in included studies
Two review authors (LJ, WL) independently assessed the risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved disagreements by discussion or by consultation with a third party. We assessed risk of bias according to the following domains.
Random sequence generation.
Allocation concealment.
Blinding of participants and personnel.
Blinding of outcome assessment.
Incomplete outcome data.
Selective outcome reporting.
Other bias.
We assessed the risk of bias for each domain as high, low or unclear and provided information from the study report together with a justification for our judgement in the 'Risk of bias' tables.
Measures of treatment effect
We expected RCTs to measure both dichotomous data and continuous data. We expressed continuous data as mean differences (MDs) or as standardised mean differences (SMDs) if studies did not use the same scales to measure outcomes. All effect measures were presented with 95% confidence intervals (CIs). For dichotomous outcomes, we calculated risk differences with 95% CIs, when there were no events in either group. For time‐to‐event variables, we would express the intervention effect as a hazard ratio.
Unit of analysis issues
We planned to deal with unit of analysis issues according to recommendations provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Dealing with missing data
According to the intention‐to‐treat (ITT) principle, all randomly assigned participants should be included. We considered different scenarios (best‐case and worst‐case) to account for missing data and ran ITT analyses by imputing missing data.
Assessment of heterogeneity
We tested heterogeneity using the I² statistic (Higgins 2011) and determined whether significant heterogeneity was present. We considered I² values over 50% as suggestive of substantial heterogeneity but took care to consider the direction and magnitude of effects.
Assessment of reporting biases
We planned to use a funnel plot to examine potential publication bias if more than 10 studies were found. However, there were only 3 studies included.
Data synthesis
If a sufficient number of comparable studies were available, we carried out meta‐analyses using a random‐effects model. When studies used survival data analysis, if estimates of log hazard ratios and standard errors could be obtained, we planned to combine them using the RevMan generic inverse variance method. If substantial heterogeneity between studies prevented combining of outcome data, we provided a descriptive summary of results.
Subgroup analysis and investigation of heterogeneity
We planned to analyse subgroups of studies categorised by stage of PD (participants with early or later PD) and by dosage and duration of riluzole treatment. We planned to use the Chi² test to examine the significance of differences between subgroups. However, we did not perform subgroup analyses due to the limited available data.
Sensitivity analysis
We planned to undertake sensitivity analyses to assess the robustness of results using fixed‐effect versus random‐effects models and the inclusion or exclusion of studies at high risk of bias in any domains of 'Risk of bias' tables. We would have examined potential sources of methodological heterogeneity. When total number of AEs rather than the number of patient with AEs were available, the assumption that all events were in separate patients was considered with sensitivity analysis that all events were in one patient.
Acknowledgements
The review authors would like to acknowledge the help provided by the Cochrane Movement Disorders Group.
Appendices
Appendix 1. MEDLINE search strategy through Ovid Gateway
1.Parkinson$.tw.
2.exp Parkinsonian Disorders/
3.1 or 2
4.Riluzole/
5.Riluzole.tw
6.2‐Amino‐6‐trifluoromethoxybenzothiazole.tw
7.Rilutek.tw
8.or/4‐6
9.randomized controlled trial.pt.
10.controlled clinical trial.pt.
11.randomized controlled trials/
12.random allocation/
13.double?blind method/
14.single?blind method/
15.clinical trial.pt.
16.exp clinical trials/
17.clin$ with trial$.tw.
18.random$.tw.
19.exp research design/
20.or/9‐21
21.limit 20 to animal
22.limit 20 to human
23.21 and 22
24.21 not 23
25.20 not 24
26. 3 and 8 and 25
What's new
Last assessed as up‐to‐date: 31 January 2017.
| Date | Event | Description |
|---|---|---|
| 31 August 2017 | Amended | The protocol was withdrawn because it does not meet the current methodological standards of The Cochrane Collaboration |
Contributions of authors
Liu J and Wang L formulated the idea and developed the basis for the review.
The manuscript was completed by Liu J and corrected by Wang L.
Liu J and Wang L will be in charge of updating the review.
Declarations of interest
None known.
Notes
The protocol does not meet the current methodological standards of The Cochrane Collaboration.
Withdrawn from publication for reasons stated in the review
References
Additional references
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