Fukuda 2015.

Study characteristics
Methods	Study design Parallel RCT Study dates Duration of follow‐up: 12 weeks Time frame: March to August 2008
Participants	Study characteristics Setting: multicentre (4 dialysis centres in the Osaka district in Japan) Country: Japan Inclusion criteria: 30 to 70 years; treated for ESKD for at least 1 year with afternoon HD 3 times/week; patients who had been taking vitamins before recruitment were included after a washout phase of at least 2 weeks Exclusion criteria: active malignant tumour; pregnancy; lactation Baseline characteristics Number (analysed/randomised): intervention group (87/103); control group (86/99) Mean age ± SD (years): intervention group (55.6 ± 10.0); control group (56.2 ± 8.9) Sex (M/F): intervention group (71/16); control group (72/15) Dialysis type: HD Mean dialysis vintage ± SD (years): intervention group (10.6 ± 8.26); control group (11.0 ± 7.74) Comorbidities CVD: not reported Diabetes: intervention group (21/87); control group (21/87) Hypertension: not reported Depression: not reported
Interventions	Intervention classification Pharmacological intervention Indication: study targeting fatigue Intervention group Active treatment (containing vitamin B1, vitamin B2, niacin, vitamin B6, vitamin B12, folic acid, vitamin C, carnitine, coenzyme Q10, naive galacto‐oligosaccharide, and zinc) Control group Placebo Co‐interventions Not reported
Outcomes	Outcomes reported Fatigue outcome measures used: validation data available Changes in the acute and chronic fatigue 4‐point VAS: assessed at 0, 4, and 12 weeks Anxiety and depression Loss of attention and memory Pain Fatigue Overwork Autonomic imbalance Sleep problems Infection HRQoL KDQOL‐SF 36: assessed at 0, 4, and 12 weeks Physical functioning Role‐physical Bodily pain Role‐emotional General health Vitality Social functioning Mental health Symptoms of the kidney‐disease‐specific (symptoms/problems, effects of kidney disease, burden of kidney disease, work status, cognitive function, sleep, quality of social interaction Non‐halted reported (social support, dialysis staff encouragement, patients satisfaction) Serum ACTH Immunoradiometric assay: assessed at weeks 0, 4, and 12 Cortisol and α‐melanocyte‐stimulating hormone: assessed at weeks 0, 4, and 12 Nonfasting blood (including lipid and inflammation parameters) Radioimmunoassay: assessed at weeks 0, 4, and 12 Human herpes virus 6 and 7 reactivation Determined in saliva by polymerase chain reaction: assessed at weeks 0 and 12 Numbers of viral DNA copies Determined in saliva by polymerase chain reaction: assessed at weeks 0 and 12 Autonomic function Determined via measurement of beat‐to‐beat variation by using acceleration plethysmography Adverse events: assessed until the end of treatment Serious adverse events: assessed until the end of treatment Hospitalisation: assessed until the end of treatment Laboratory data (including white blood cell, Hb, platelets, albumin, AST, ALT, LDH, creatinine, sodium, potassium, calcium, phosphorous, iron, glucose, cholesterol, HDL, CRP; triglycerides): assessed at weeks 0, 4, and 12
Notes	Additional information Funding: this study was partly supported by grants from the Asahi Kasei Kuraray Medical Cooperation, 21st Century COE Program and Grant‐in Aid for Scientific Research (C) (KAKENHI‐24500826) by Ministry of Education, Culture, Sports, Science and Technology (Japan), and grants from Health Labour Sciences Research Grant (Comprehensive Research on Disability Health and Welfare [24163001]), Japan. Tsutomo Tabata, Mikio Okamura, Tomoyuki Yamanaka, Shigeki Okada, Sumio Hirata, Yasuyoshi Watanabe and Yosiki Nishizawa received research grants from the Asahi Kasei Kuraray Medical Cooperation, but the sponsors were not involved in the design, execution, analysis, or reporting of the results of this study Conflicts of interest/disclosures: nutritional drink and placebo products were prepared by the Asahi Kasei Kuraray Medical Corporation. Other authors declare no conflict of interests Trial registration identification number: UMIN 000001055 A priori published protocol was published
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomisation by means of a computer‐generated random number table (1:1) was to either the nutritional drink, or matching placebo in accordance with the minimization method with three factors (sex, age, each of four dialysis centre); one drink was taken by patients after each dialysis session under the supervision of a nurse." Comment: Computer generation is considered as low‐risk of bias. No imbalance between intervention groups was apparent
Allocation concealment (selection bias)	Unclear risk	Quote: "Originally assigned code numbers were kept in closed envelopes within the coordinating centre." Comment: It was not reported if envelopes were numbered and opaque. No imbalance between intervention groups was apparent
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The patients and attending physicians were blinded to the treatment. [...] All study investigators, medical staff, statistician and participants were blinded to the randomisation procedure and treatment assignments." Comment: A double‐blind study was considered as low risk of bias
Blinding of outcome assessment (detection bias) All outcomes	High risk	Quote: "The safety of the intervention and scientific integrity of the study were supervised by an independent data and safety monitoring board located at the Center for Drug & Food Clinical Evaluation, Osaka City University Hospital, Osaka, Japan (coordinating centre)." Comment: The outcomes were assessed with an appropriate measure, without differences between groups. However, subjective measures were used. 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. It was not clearly stated if the independent data and safety monitoring was blinded to the treatment assigned. However, subjective and objective outcomes were reported. It was not stated if the independent data safety and monitoring board was blinded to the treatment allocation
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Quote: "172 patients (86 in each group) completed the study. [...] One participant withdrew consent before the randomisation and a total of 202 patients [Inoue Hospital, Suita, Japan (n = 72); Ohno Memorial Hospital, Osaka, Japan (n = 54); Okada Clinic, Osaka, Japan (n = 31); Shirasagi Hospital, Osaka, Japan (n = 46)] were included in the trial and were randomly assigned to one of the two treatment arms. Of the 202 participants, six in the nutritional drink group and two in the placebo group did not receive allocation. Four participants in the nutritional group and two in the placebo group did not receive allocation because they withdrew consent. Two participants in the nutritional drink group did not receive allocation because of hospitalisation or changing the time of dialysis from afternoon to morning. Ten participants in each group discontinued intervention (in the nutritional group, 4 withdrew consent and 6 experienced adverse effects; in the placebo group, 1 withdrew consent, 1 was hospitalised, 5 experienced adverse effects, 2 changed the time of dialysis from afternoon to morning, and 1 had unknown reasons). Finally, 68 patients in Inoue Hospital, 43 in Ohno Memorial Hospital, 24 in Okada Clinic, and 39 in Shirasagi hospital completed the intervention. One patient was excluded from the final analysis because of changing the hospital visit date from a weekday to the weekend." Comment: Figure 1 reported that no patients were lost to follow‐up. However, 87/103 participants in the intervention group and 86/99 participants in the control group were analysed. 0/103 participants in the intervention group and 1/99 participants in the control group were excluded from the analyses (ITT)
Selective reporting (reporting bias)	High risk	Protocol was published. Fatigue was reported in accordance with a pre‐specified analysis plan, using multiple eligible outcome measurements (scales, time points). Fatigue was reported in a format that was extractable for meta‐analysis. All outcomes that should be addressed (fatigue, cardiovascular disease, and death) were not reported
Other bias	Low risk	There was no evidence of different baseline characteristics, or different non‐randomised co‐interventions between groups. Funding was not involved in the design, execution, analysis, or reporting of the results of this study. The study seemed to be free from other source of bias