Bellinghieri 1983.

Study characteristics
Methods	Study design Cross‐over RCT Study dates Duration of follow‐up: 8 weeks Time frame: not reported
Participants	Study characteristics Setting: not reported Country: Italy Inclusion criteria: patients on HD 3 times/week (4 hours each dialysis); affected by an almost constant presence of cramps for at least 6 months during HD; experienced asthenia immediately afterwards and during the interval between one session and another Exclusion criteria: not reported Baseline characteristics Number (analysed/randomised): intervention group (not reported/7); control group (not reported/7) Mean age ± SD (years): overall (49 ± 4) Sex (M/F): intervention group (4/3); control group (5/2) Dialysis type: HD Mean dialysis vintage ± SD (years): overall (1.9 ± 0.3) Comorbidities CVD: not reported Diabetes: not reported Hypertension: not reported Depression (clinician diagnosis): not reported
Interventions	Intervention classification Pharmacological intervention Indication: study targeting fatigue Intervention group L‐carnitine (oral): 2 g/day Control group Placebo Co‐interventions Not reported
Outcomes	Outcomes reported Fatigue outcome measures used: validation data available Asthenia: evaluated every 15 days (Appendix 3) Cramps: evaluated every 15 days (Appendix 3) Blood samples for carnitine determination in muscle and serum (free carnitine, acetylcarnitine): assessed pre‐ and post‐treatment Laboratory tests (red and white cells, HCT, calcium, potassium, triglyceride, cholesterol, lipoprotein): assessed pre and post‐treatment Death: assessed until the end of treatment
Notes	Additional information Funding: Sigma‐Tau, Pomezia Conflicts of interest/disclosures: not reported Trial registration identification number: not applicable A priori published protocol: not reported
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Sequence generation methods were not reported in sufficient detail to permit judgement
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment was not reported in sufficient detail to permit judgement
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "Double‐blind study." Comment: Although the author reported that the study used a double‐blind design, information about blinding of participants and investigators were not clearly stated
Blinding of outcome assessment (detection bias) All outcomes	High risk	Quote: "Objective examination of asthenia consisted in making the patient flex the knees with the trunk in upright position for different intervals (exercise A) and walk repeatedly up band down three steps (exercise B). Asthenia was scored as slight if fatigue appeared at less than 60 sec of exercise A and at less than 30 ascents and descents during exercise B, intense at less than 15 sec of exercise A and at less than 10 ascents and descents of exercise B. Moderate degree of asthenia was between the two extremes. The exercises were performed immediately after and between haemodialysis. In the latter case the patients did the exercises at home and recorded the results." Comment: The outcomes were assessed with an appropriate measure, without differences between groups. However, subjective measures were used, it was not stated whether outcomes were assessed without knowledge of treatment allocation, and knowledge of treatment assignment may have influenced reporting. Participant beliefs about the superiority/inferiority of either intervention could have influenced their assessment of the outcome, but there was no evidence that this was likely. All outcomes that should be addressed (fatigue, cardiovascular disease, death and vascular access) were not reported. However, objective and subjective outcomes were assessed
Incomplete outcome data (attrition bias) All outcomes	High risk	The number of patients who completed the study was not clearly stated for the first phase. It was unclear if there was evidence that the results were not biased by missing outcome data
Selective reporting (reporting bias)	High risk	Information about the protocol and the statistical analysis plan were not reported. It was not reported if multiple eligible outcome measurements (scales and time points) were pre‐specified. It was unclear if the reported approach to analysing this outcome was pre‐specified or influenced by the results. Fatigue at the end of treatment was not reported in a format that was extractable for meta‐analysis (cross‐over study: data related to the first period were not reported). All outcomes that should be addressed (fatigue, cardiovascular disease, and death) were not reported
Other bias	High risk	No data were available to assess the possible imbalance between groups. Funding (pharmaceutical company) could influenced the data analysis and conflicts of interest were not reported