Akizawa 2002.

Study characteristics
Methods	Study design Parallel RCT Study dates Duration of follow‐up: 4 weeks Study duration: not reported
Participants	Study characteristics Setting: not reported Country: Japan Inclusion criteria: undergoing maintenance HD 3 times/week (4 hours/dialysis session) and complicated orthostatic hypotension defined by SBP drop of ≥ 15 mm Hg after standing, as well as subjective symptoms of fatigability, malaise/weakness, dizziness and light‐headed feeling Exclusion criteria: patients with narrow‐angle glaucoma; severe hypertension; liver disorder; haemorrhagic complications; heart disease or peripheral vascular disorders Baseline characteristics Number (analysed/randomised): intervention group 1 (48/51); intervention group 2 (46/49); control group (47/49) Mean age ± SD (years): intervention group 1 (61.5 ± 11.0); intervention group 2 (63.5 ± 12.4); control group (61.1 ± 11.5) Sex (M/F): overall (71/78); intervention group 1 (30/21); intervention group 2 (22/27); control group (19/30) Dialysis type: HD Mean dialysis vintage ± SD (years): intervention group 1 (5.6 ± 20.2); intervention group 2 (6.1 ± 19.8); control group (6.9 ± 20.0) Comorbidities CVD: not reported Diabetes: intervention group 1 (27/51); intervention group 2 (19/49); control group (19/49) Hypertension: not reported Depression (clinician diagnosis): not reported
Interventions	Intervention classification Pharmacological intervention Indication: study targeting fatigue Intervention group 1 L‐DOPS (oral): 400 mg Intervention group 2 L‐DOPS (oral): 200 mg Control group Placebo (oral) Co‐interventions Concomitant use of antihypertensive or vasopressor drugs was permitted if they had been used prior to the initiation of the trial, but without a change of dose During HD, a minimum amount of fluid replacement was provided if patients developed hypertensive symptoms, and postural changes, such as lifting the lower extremities, were allowed as needed During the study period, HD conditions and dry weight were kept constant
Outcomes	Outcomes reported Fatigue outcome measures used: validation data available Changes in SBP and DBP: measured before and after standing (assessed during 4 times points while changes in BP after standing were assessed after 2 and 4 weeks) Symptoms related to orthostatic hypotension questionnaire: fatigability, malaise/weakness, physical disturbing on standing up, dizziness on standing up, bad feeling, sleep disorder (Akizawa 2002) Light‐headed feeling: recorded before and after HD Coldness of limbs: recorded before and after HD Adverse events: assessed until week 4 Laboratory tests: including blood cell count, blood chemistry, chest X‐ray and ECG (assessed before and after the trial) Pulse rate: recorded before and after HD
Notes	Additional information Funding: Sumitomo Pharmaceuticals Co., Ltd provided L‐DOPA 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 design." Comment: Although the author reported that the study used a double‐blind design, information about blinding of participants and investigators was not clearly stated
Blinding of outcome assessment (detection bias) All outcomes	High risk	Quote: "Eight subjective symptoms related to orthostatic hypotension (fatigability, malaise/weakness, physical disturbing on standing up, dizziness on standing up, bad feeling, sleep disorder) were monitored through doctor's questions, based on notebooks kept by the patients. The severity of each symptom was separately assessed using a 4‐point rating scale, i.e. severe (daily activities were greatly disturbed by the symptom), moderate (daily activities were disturbed by symptoms), mild (patients were aware of the symptoms, but daily activities were not disturbed), and asymptomatic (there was no symptom at all and patients were not bothered by any symptoms)." Comment: Fatigue was 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. However, objective and subjective outcomes were assessed
Incomplete outcome data (attrition bias) All outcomes	High risk	Quote: "Of the 149 patients, 5 were excluded from efficacy assessment due to missing blood pressure data, and 3 were also excluded because L‐DOPS therapy was discontinued within 2 weeks of the trial. A total of 141 patients (400 mg group 48 patients, 200 mg group 46 patients, and placebo group 47 patients) were thus subjected to efficacy assessment." Comment: 48/51 participants in intervention group 1 (400 mg L‐DOPS), 46/49 participants in intervention group 2 (200 mg L‐DOPS) and 47/49 participants in the control group (placebo) completed the study (> 5% lost to follow‐up, whit differences between groups). In addition, some analyses were reported on a lower number of participants
Selective reporting (reporting bias)	High risk	Information about the protocol and the statistical analysis plan was 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 reported in a format that was not extractable for meta‐analysis. All outcomes that should be addressed (fatigue, cardiovascular disease, and death) were not reported
Other bias	High risk	There was no evidence of different baseline characteristics or different non‐randomised co‐interventions between groups. Funding (pharmaceutical company) could influence the data analysis, and conflicts of interest were not reported.