Kobashi 2006

Methods	Randomised trial comparing supplements (branched chain amino acids) to no supplements in outpatients with cirrhosis and hepatocellular carcinoma. Geographical location Japan. Paper published 2006
Participants	Inclusion criteria: Cirrhotic patients with hepatocellular carcinoma. Exclusion criteria: None cited. 233 patients (159 men/74 women, mean age 69).
Interventions	Intervention group received nutritional supplement (Commercial supplement [Amionleban® ‐ 40.5 gm protein (18.3 gm BCAA), 630 kcal/day); Controls did not receive supplement. Duration therapy three years.
Outcomes	Mortality, appearance hepatic encephalopathy. Quality of life information collected but not presented in usable format.
Category of study	Supplements/Medical.
Sample size calculation	Not reported if done.
Full paper or abstract only	Abstract.
Notes	Data for mortality and hepatic encephalopathy obtained at poster presentation by RK; numbers of hepatic encephalopathy episodes presented as total, and, for purposes of meta‐analysis, assumed to be one per patient. Request for further information sent via e‐mail to Dr Kobashi on September 19, 2011 (hkobashi@md.okayama‐u.ac.jp); email address failed. Letter via US mail sent same day (Department of Gastroenterology and Hepatology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan). Response received via e‐mail (kobashi0584@gmail.com) informing us 1) that randomisation performed with computer software by study center, 2) that, while no formal mechanism in place to provide concealment of allocation, the assignment was accomplished by fax from the study center, 3) that a sample size was calculated (but no number provided), 4) that there were no significant differences between the 2 groups as for age, sex, viral markers (HBV or HCV), serum ammonia, total bilirubin, prothrombin‐time, BTR, ascites, or Child‐Pugh class, but serum albumin was significantly lower and encephalopathy significantly higher in the BCAA group, and 5) that the trial was not funded (unclear what he meant, but possibly by industry). He also informed us that both ascites and encephalopathy were present in 31 patients at the beginning of the trial and newly occurred in 54 but that he did not have any data regarding how many had resolution of either during the trial, that 9 patients developed bleeding during the trial, that the serum bilirubin levels in the treated/control arms was 1.29 (0.77 SD)/1.15 (0.078 SD), there were no infections, that quality of life data were obtained (and he sent a spread sheet with numerical scores but no standard deviations), and that no data were obtained regarding costs, lengths of stay, nutritional outcomes, or adverse events. An email was sent back to Dr Kobashi on October 14, 2011, inquiring about the exact sample size calculation, the numbers in each group who had new ascites and encephalopathy, how many in each arm bled, and whether the bilirubin values were baseline or end of study values. On October 17, Dr Kobashi replied with data regarding ascites (16/100 versus 27 [+ 1 pleural effusion]/102 developed it, 3/19 versus 7/12 with ascites deteriorated, but no information provided regarding numbers with ascites who improved), encephalopathy (12/108 versus 16/113 developed it, and no apparent worsening in the 11/1 individuals who had it at the beginning, but no data regarding improvement in this small group of patients), and bleeding (7 [4 varices, 2 without endoscopy, 1 biliary]/5 [2 varices, 3 gastric ulcers] had bleeding, but the 2 without endoscopy and 1 with biliary bleeding were excluded). Also informed us that trial was not funded. While the mortality data was noted on the poster to be not significant, the analyses indicated that the 95% confidence interval did not overlap the line of equivalence; a subsequent e‐mail was sent to him and he responded that the numbers that RK had copied were correct. Dr Kobashi also informed us that the trial has not been published in full paper form to date for the following reason: "Sorry to say we have not yet published the full paper of this study. I have some difficulties in the authorship, and the priority for the full authorship of this study belongs to another person (my colleague)." He indicated that this other investigator has some reason not to publish it in a full paper.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	See comment in notes.
Allocation concealment (selection bias)	Low risk	See comment in notes.
Blinding (performance bias and detection bias) All outcomes	High risk	Not blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Outcomes of all 233 patients at point in time reported.
Selective reporting (reporting bias)	Low risk	Mortality and morbidity outcomes reported.
Other bias	Low risk	See comment in notes re: funding.
Intent to treat analysis	Low risk	All patients accounted for.
Baseline imbalance?	High risk	No data provided in abstract; data from email indicated that most characteristics similar, but BCAA group had lower albumin and more encephalopathy (suggesting that there was an imbalance in the degree of illness between the two groups).
Early stopping?	Unclear risk	Information from author indicated that he estimated need for 150 to 200 patients per group, but statistician did do sample size calculation. However, do not know what the exact number was and < 150 in each arm.