Types of studies

All RCTs and quasi‐RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth, or other predictable methods) of interventions whereby fatigue was reported as an outcome (either primary or secondary outcome).

Types of participants

Types of interventions

We will consider any intervention affecting levels of fatigue in patients on dialysis. Studies will be included if fatigue is reported as an outcome.

• Pharmacological treatment (including but not limited to): psychostimulants (amphetamines, modafinil, armodafinil, methylphenidate, pemoline), amantadine, corticosteroids (dexamethasone, prednisone, methylprednisolone), donepezil, antidepressants (selective serotonin reuptake inhibitors, paroxetine), anxiolytics, ESAs, human growth hormone, TNF inhibitor, acetylsalicylic acid, megestrol acetate, alfacalcidol and intravenous levocarnitine

• Non pharmacological treatment (including but not limited to): nutrition (lean body mass, albumin, diet), therapeutic exercise (sleep hygiene, yoga, exercise), alternative and complementary medicine (acupressure, Chinese herbal medicine and acupuncture), psychosocial (psychotherapy, psycho‐education e.g. cognitive restructuring, coping strategies, stress management), educational (goal‐setting, providing information/advice on symptom management/nutrition).

Any mode, frequency, prescription, and duration of therapy, will be considered. The intervention may be administered at any time or day (i.e. dialysis or non‐dialysis days), and in clinical or non‐clinical settings.

Types of outcome measures

We will use time points of measurements as reported by investigators, as well as assess outcome measures at the end of the treatment.

Electronic searches

We will search the Cochrane Kidney and Transplant Register of Studies through contact with the Information Specialist using search terms relevant to this review. The Register contains studies identified from the following sources:

1. Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)

2. Weekly searches of MEDLINE OVID SP

3. Handsearching of kidney‐related journals and the proceedings of major kidney conferences

4. Searching of the current year of EMBASE OVID SP

5. Weekly current awareness alerts for selected kidney and transplant journals

6. Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Studies contained in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE based on the scope of Cochrane Kidney and Transplant. Details of these searches, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available in the "Specialised Register" section of information about Cochrane Kidney and Transplant.

See Appendix 1 for search terms used in strategies for this review.

Searching other resources

1. Reference lists of review articles, relevant studies and clinical practice guidelines.

2. Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies.

Selection of studies

The search strategy described will be used to obtain titles and abstracts of studies that may be relevant to the review. The titles and abstracts will be screened independently by two authors. Two authors will independently assess retrieved abstracts, and if necessary the full text, of these studies to determine which studies satisfy the inclusion criteria.

Data extraction and management

Data relating to study design (RCT, quasi‐RCT), participant characteristics (e.g. age, gender, dialysis vintage, comorbidities), interventions (pharmacological, non‐pharmacological) and outcomes (as described above) will be extracted and organised using the software Review Manager 5.4 (RevMan2014). The two authors will independently carry out data extraction using a standard data extraction form. Studies reported in non‐English language will be translated before assessment. Where more than one publication of a study exists, the publications will be grouped together and the report with the most complete data will be included in the meta‐analyses. Where relevant outcomes are only published in earlier versions these data will be used. Any discrepancy between published versions will be highlighted. Any further information required from the original author will be requested by written correspondence and any relevant information obtained in this manner will be included in the review. Disagreements will be resolved by consensus in consultation with a third author.

Assessment of risk of bias in included studies

The following items will be independently assessed by two authors using the risk of bias assessment tool (Higgins 2011) (see Appendix 2).

• Was there adequate sequence generation (selection bias)?

• Was allocation adequately concealed (selection bias)?

• Was knowledge of the allocated interventions adequately prevented during the study?

  • Participants and personnel (performance bias)

  • Outcome assessors (detection bias)

• Were incomplete outcome data adequately addressed (attrition bias)?

• Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?

• Was the study apparently free of other problems that could put it at a risk of bias?

Measures of treatment effect

For dichotomous outcomes (e.g. adverse events, cardiovascular event, death) results will be expressed as risk ratio (RR) with 95% confidence intervals (CI). Where continuous scales of measurement are used to assess the effects of treatment (e.g. depression, fatigue), the mean difference (MD) will be used, or the standardised mean difference (SMD) if different scales have been used.

Unit of analysis issues

Dealing with missing data

Any further information required from the original author will be requested by written correspondence (e.g. emailing the corresponding author) and any relevant information obtained in this manner will be included in the review. Evaluation of important numerical data such as screened, randomised patients as well as intention‐to‐treat, as‐treated and per‐protocol population will be carefully performed. Attrition rates, for example drop‐outs, losses to follow‐up and withdrawals will be investigated. Issues of missing data and imputation methods (for example, last‐observation‐carried‐forward) will be critically appraised (Higgins 2011).

Assessment of heterogeneity

We will first assess the heterogeneity by visual inspection of the forest plot. We will quantify statistical heterogeneity using the I² statistic, which describes the percentage of total variation across studies that is due to heterogeneity rather than sampling error (Higgins 2003). A guide to the interpretation of I² values will be as follows:

• 0% to 40%: might not be important

• 30% to 60%: may represent moderate heterogeneity

• 50% to 90%: may represent substantial heterogeneity

• 75% to 100%: considerable heterogeneity.

The importance of the observed value of I² depends on the magnitude and direction of treatment effects and the strength of evidence for heterogeneity (e.g. P‐value from the Chi² test, or a confidence interval for I²) (Higgins 2011).

Assessment of reporting biases

If possible, funnel plots will be used to assess for the potential existence of small study bias (Higgins 2011).

Data synthesis

Data will be pooled using the random‐effects model but the fixed‐effect model will also be used to ensure robustness of the model chosen and susceptibility to outliers.

Subgroup analysis and investigation of heterogeneity

We will report the results of our findings separately focusing on fatigue. Data will be pooled using the random‐effects model but the fixed‐effect model will also be used to ensure robustness of the model chosen and susceptibility to outliers. Adverse effects will be tabulated and assessed with descriptive techniques, as they are likely to be different for the various interventions used. Where possible, the risk differences with 95% CI will be calculated for each adverse effect, either compared to no treatment or to another agent.

Based on available data, we will perform the following subgroup analyses:

• Age: < 18 years versus ≥ 18 years; ≥ 18 years and < 64 years versus ≥ 64 years

• Gender: female versus male

• Risk of bias: high versus low (versus unclear) (allocation concealment, blinding of outcome assessors, incomplete outcome data)

• Indication: studies targeting fatigue versus reporting fatigue

• Intervention type: pharmacological versus non‐pharmacological

• Presence of comorbidities: CVD (yes versus no), diabetes (yes versus no), hypertension (yes versus no), depression (clinical diagnosis versus none)

• Fatigue outcome measures used: validation data available versus de novo

• Dialysis type: PD versus HD

• Dialysis vintage: < 5 years versus ≥ 5 years

Sensitivity analysis

We will perform sensitivity analyses in order to explore the influence of the following factors on effect size:

• Repeating the analysis excluding abstract‐only publication

• Repeating the analysis excluding industry‐funded studies

• Repeating the analysis taking account of risk of bias (allocation concealment)

• Repeating the analysis excluding any very long or large studies to establish how much they dominate the results.