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KSR Number: KSRA48313

Treatment of fatigue in amyotrophic lateral sclerosis/motor neuron disease

  • Cochrane Database Syst Rev 2018, 1, CD011005, 10.1002/14651858.CD011005.pub2
  • Full report

Risk of Bias Assessment

Overall summary: Low risk of bias in the review

Bottom Line

Limited evidence suggests that modafil or respiratory exercise may reduce fatigue compared to placebo or usual care in patients with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND); however, these results were very uncertain. Resistance exercise may also improve total functional status and lower extremity function compared to placebo. No methodological concerns were noted. Further high quality research is needed to develop and test effective treatments for fatigue in patients with ALS/MND.

Risk of Bias Assessment

Overall summary Low risk of bias in the review

Low

All domains were considered at low concern.

A. Did the interpretation of findings address all of the concerns identified in Domains 1 to 4? Probably yes
B. Was the relevance of identified studies to the review's research question appropriately considered? Probably yes
C. Did the reviewers avoid emphasizing results on the basis of their statistical significance? Probably yes
Risk of bias in the review Low

Details of Review

Number of studies 4
Number of participants 86
Last search date 5th September 2017
Review type Intervention
Objective To determine the effects of pharmacological and non-pharmacological interventions for fatigue in amyotrophic lateral sclerosis/motor neuron disease.
Population Patients diagnosed with possible, probable or definite amyotrophic lateral sclerosis/motor neuron disease (ALS/MND)
Interventions Any intervention that aimed to reduce fatigue in people with ALS/MND (pharmacological or non-pharmacological)
Comparator Placebo, standard care or a different intervention aiming to reduce fatigue
Outcome Primary outcome: level of fatigue at the end of the follow-up period.

Secondary outcomes: sleepiness, depression, quality of life, functional status or adverse events.
Study design Randomised and quasi-randomised controlled trials.

Results

When modafil was compared to placebo, a single randomised controlled trial (RCT) reported a reduction in fatigue (mean difference [MD] - 11.00, 95% confidence interval (CI) -23.08 to 1.08; 1 study, n=32 participants) and sleepiness (MD -2.00, 95% CI -4.46 to 0.46; 1 study, n=32 participants) for modafil compared to placebo after 4 weeks; however, this result was associated with a large degree of uncertainty. The same study reported no difference in depression severity (MD 0.00, 95% CI -4.38 to 4.38; 1 study, n=32 participants) for modafil compared to placebo after 4 weeks.

When resistance exercise was compared to usual care, a single RCT reported an improvement in total functional status (MD 5.70, 95% CI 1.29 to 10.11; 1 study, n=18 participants) and lower extremity function (MD 5.30, 95% CI 1.82 to 8.78; 1 study, n=18 participants) for resistance exercise compared to usual care after 6 months. However, the same study reported no difference in fatigue (MD -0.2, 95% CI -10.98 to 11.38; 1 study, n=18 participants), mental health (MD -1.70, 95% CI -5.50 to 2.10; 1 study, n= 18 participants), physical role (MD 0.20, 95% CI -1.06 to 1.46; 1 study, n=18 participants), pain (MD -0.10, 95% CI -2.01 to 1.81; 1 study, n=18 participants), general health (MD 0.40, 95% CI -4.32 to 5.12; 1 study, n=18 participants), vitaility (MD 1.60, 95% CI -1.87 to 5.07; 1 study, n=18 participants), social function (MD 0.70, 95% CI -0.97 to 2.37; 1 study, n=18 participants) or emotional role (MD 0.60, 95% CI -0.47 to 1.67; 1 study, n=18 participants) for resistance exercise compared to usual care after 6 months.

When respiratory exercise was compared with sham intervention, a single RCT reported a reduction in depression severity (MD 1.77, 95% CI 0.02 to 3.52; 1 study, n=24 participants) for respiratory exercise compared to sham intervention. The same study also reported a reduction in fatigue levels (MD -9.65, 95% CI -22.04 to 2.73; 1 study, n=24 participants) for respiratory exercise compared with sham intervention; however, this result was associated with a large degree of uncertainty. No difference was reported in sleepiness (MD 0.31, 95% CI -3.48 to 4.10; 1 study, n=24 participants), quality of life (MD 0.77, 95% CI -17.10 to 18.64; 1 study, n=24 participants), overall functional status (MD 0.85, 95% CI -2.16 to 3.85; 1 study, n=24 participants), bulbar functional status (MD -0.39, 95% CI -1.38 to 0.61; 1 study, n=24 participants) or respiratory functional status (MD 0.08, 95% CI -0.25 to 0.41; 1 study, n=24 participants) following respiratory exercise compared to sham intervention.

Full Risk of Bias Assessment

The research objective was clearly stated and appropriate inclusion criteria were defined. No restrictions were reported based on study characteristics or sources of information.

1.1 Did the review adhere to pre-defined objectives and eligibility criteria? Probably yes
1.2 Were the eligibility criteria appropriate for the review question? Probably yes
1.3 Were eligibility criteria unambiguous? Probably yes
1.4 Were all restrictions in eligibility criteria based on study characteristics appropriate (e.g. date, sample size, study quality, outcomes measured)? Probably yes
1.5 Were any restrictions in eligibility criteria based on sources of information appropriate (e.g. publication status or format, language, availability of data)? Probably yes
Concerns regarding specification of study eligibility criteria Low

Literature searches were conducted in CENTRAL via the Cochrane Register of Studies (CRS-Web), MEDLINE, EMBASE, PsycINFO, CINAHL Plus and ERIC databases. In addition the reference lists of the included studies, conference abstracts from International ALS/MND Symposia and trial registries (US National Institutes of Health trials registry, ClinicalTrials.gov (clinicaltrials.gov/) and the World Health Organisation International Clinical Trials Registry Platform (ICTRP; apps.who.int/trialsearch/)) were searched to identify additional studies. The search strategy was reported in full and appeared to be adequate. No restrictions were reported based on date, publication format or language. Three reviewers were independently involved in the study selection and disagreements were resolved by discussion.

2.1 Did the search include an appropriate range of databases/electronic sources for published and unpublished reports? Probably yes
2.2 Were methods additional to database searching used to identify relevant reports? Probably yes
2.3 Were the terms and structure of the search strategy likely to retrieve as many eligible studies as possible? Probably yes
2.4 Were restrictions based on date, publication format, or language appropriate? Probably yes
2.5 Were efforts made to minimise error in selection of studies? Yes
Concerns regarding methods used to identify and/or select studies Low

Two review authors independently extracted the data from the eligible studies using a standardised data extraction form. Sufficient individual study characteristics were extracted to allow for the interpretation of the results. Relevant study results appear to have been extracted. Two review authors independently assessed the risk of bias for each study using the Cochrane ’Risk of bias’ tool, and disagreements were resolved by discussion and consensus,

3.1 Were efforts made to minimise error in data collection? Probably yes
3.2 Were sufficient study characteristics considered for both review authors and readers to be able to interpret the results? Probably yes
3.3 Were all relevant study results collected for use in the synthesis? Probably yes
3.4 Was risk of bias (or methodological quality) formally assessed using appropriate criteria? Yes
3.5 Were efforts made to minimise error in risk of bias assessment? Yes
Concerns regarding methods used to collect data and appraise studies Low

The synthesis appeared include all relevant studies. A narrative synthesis was performed to summarise the findings; this was considered appropriate due to the small number of included studies. The quality of the individual studies was considered in the synthesis.

4.1 Did the synthesis include all studies that it should? Probably yes
4.2 Were all pre-defined analyses reported or departures explained? Probably yes
4.3 Was the synthesis appropriate given the degree of similarity in the research questions, study designs and outcomes across included studies? Probably yes
4.4 Was between-study variation minimal or addressed in the synthesis? Probably yes
4.5 Were the findings robust, e.g. as demonstrated through funnel plot or sensitivity analyses? Probably yes
4.6 Were biases in primary studies minimal or addressed in the synthesis? Yes
Concerns regarding synthesis and findings Low

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