EAL

ONC: Branched Chain Amino Acids (2006)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To investigate the effect of Aminoleban EN on patients undergoing hepatic resection for hepatocellular carcinoma (HCC).

Inclusion Criteria:

All patients, from October 1994 - September 1996, undergoing hepatic resection with curative intent for HCC which developed in a cirrhotic liver.

Exclusion Criteria:

Excluded from Study Group: any patients undergoing palliative resection (n=2) and benign modular hyperplasia (n=2).
Excluded from Control Group: any patients undergoing palliative resection (n=1) and/or having adenoma (n=1)

Description of Study Protocol:

Recruitment

All patients, from October 1994 - September 1996, undergoing hepatic resection with curative intent for HCC which developed in a cirrhotic liver.

Design

Study group received 1 package of Aminoleban EN three times a day in addition to a diet of 40 grams pro/day + 6300 KJ/day (for a total of 80 g pro and 8946 KJ per day) for a twelve week course.

Control groups was given a diet of 80 grams protein and 6300 KJ per day for a twelve week course.

Compliance

Both groups of patients were seen by a dietitian at each follow-up, with the aid of diet diaries, to determine compliance with either the experimental or control regimen.

Blinding used (if applicable)

The surgeon responsible for the subsequent management of the post-hepatectomy patient was blinded to the randomization.

Statistical Analysis

Parametric, non-parametric, and categorical data analyzed by Student's t-test, Mann-Whitney U-test, and Chi-squared test, respectively
Survival rates were calculated by the Kaplan-Meier method and analysed by analysis of variance with repeated measures
The effect of Aminoleban was included as a between-subject factor
P values of < 0.05 considered statistically significant
SPSS for Windows 6.0 used for calculations

Data Collection Summary:

Timing of Measurements

Variables were recorded pre-operatively, weekly after operation for 4 weeks, and then monthly for up to 1 year. Compliance was checked on each follow-up.

Dependent Variables, measured through timely blood tests

Hemoglobin
Platelet
White cell count
Potassium
Urea
Creatinine
Total protein
Alkaline phosphatase
Alanine transferase
Sodium
Albumin
Bilirubin
Prothrombin time
Activated partial thromboplastin time

Independent Variables

1 package of Aminoleban EN given three times daily (total of 40 grams)

Composition of Aminoleban: 50 grams per packet consisting of valine (1.6 g), leucine (2.0g), and isoleucine (1.9g), complemented by other amino acids, various minerals, and 14 vitamins; in addition, 6.5 g gelatin hydrolysate, 3.5 g of rice oil, and 31.05 g dextrin.

Description of Actual Data Sample:

Initial N: study group n=21; control group n=23

Attrition (final N): study group n=14; control group n=18

Age: study group: 51.5 +/- 10.8; control group: 53.3 +/- 12.8

Ethnicity: unknown

Other relevant demographics: comparable in terms of sex, age, Child-Pugh grading and the extent of liver resection.

Anthropometrics: no significant difference in terms of Karnofsky performance score and anthropometric measures (weight, mid-arm circumference and triceps skin fold)

Location: Japan

Summary of Results:

Significant Blood Results; ANOVA with repeated measures

Variables	Time	Time and group	Group (Significant differences in favor of study group)
Hemoglobin	< 0.001	0.70	0.02
Sodium	< 0.001	0.44	0.008
Bilirubin	< 0.001	0.39	0.007
Albumin	< 0.001	0.67	0.045
Prothrombin Time	0.001	0.41	0.098, NS
Activated partial thromboplastin time	0.17	0.23	0.12, NS

Complications	Study	Control
Minor
Fever	9	7
Urinary Tract infection	1	1
Chest infection	1	2
Wound infection	4	5
Chest effusion	2	3
Major
Primary hemorrhage	1	1
Reactionary hemorrhage	1	0
Secondary hemorrhage	1	0
Upper gastrointestinal bleeding	1	1
Infected ascites	3	1
Persistent chest effusion	8	10
Liver failure	3	4

Additional Findings:

No significant difference in symptoms of malaise, anorexia, nausea, vomiting, itchiness, abdominal distension, abdominal pain, diarrhea, coffe-ground emesis, passage of tarry stools, and ankle swelling
No significant difference in ascites, ankle edema, and encephalopathy
Study group had a shorter hospital stay, median of 10 days, compared to 16.5 days for the control group

Mortalities/Drop-out Rates:

Study group, 7 mortalities:

3 patients died from coagulopathy with liver failure on the 6th, 10th and 12th postoperative days
1 patient died from subphrenic collection and chest infection with respiratory failure on the 25th postoperative day
3 patient were found to have liver recurrence on follow-up 1 year, 1 year and 2 months, and 2 years.

Control group, 5 mortalities:

1 patient died from liver failure with postoperative complications of bile leak and sepsis
1 patient died from liver failure 3 years after operation
3 patients died of recurrence at 3 months, 4 months, and 8 months after operation respectively

Author Conclusion:

"A 12-week course of Aminoleban EN is beneficial for patients with HCC who undergo curative hepatic resection. It helps to maintain a higher hemoglobin and sodium level. It can also improve the liver function as reflected by the higher albumin and lower bilirubin. There is no adverse effect in terms of morbidity, mortality, survival, and recurrence."

Author noted that in the study group, four patients died after intitiation of therapy within a 30-day period as compared to only one patient in the control group. There may be a possibility of adverse effects due to Aminoleban.

Authors Suggestions for Future Studies:

Compare the 3-month and 12-month regime

To estimate the mortality in the series, a sample size of nearly 500 patients is needed.

Funding Source:

Industry:

Otsuka Pharmaceuticals

Pharmaceutical/Dietary Supplement Company:

Reviewer Comments:

This is a well-constructed study which shows promise for the role of BCAA in patients with HCC. However, future studies should consider a larger sample size and be able to provide similar findings outside of the manufacturers funding.

Positives:

* Nutrition intake was monitored closely by a dietitian to maintain the experimental and control regimens

*Well-matched study population in terms of demographics and anthropometrics

Limitations:

* The control group consumed approximately 646 kJ energy less than the study group.

* Small sample size

* Ethnicity of group never stated

* Acknowledging that the present study was sponsored by Otsuka Pharmacuetical Company, Tokyo, Japan. This is the manufacturer of Aminoleban EN, the branch-chained amino acids.

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	Yes
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
2.	Was the selection of study subjects/patients free from bias?		Yes
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	???
3.	Were study groups comparable?		Yes
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	Yes
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	Yes
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	Yes
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	Yes
4.	Was method of handling withdrawals described?		N/A
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	Yes
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	Yes
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
5.	Was blinding used to prevent introduction of bias?		Yes
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	Yes
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	Yes
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	N/A
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	Yes
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		???
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	Yes
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	N/A
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	Yes
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	Yes
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	No
	6.6.	Were extra or unplanned treatments described?	No
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	???
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	Yes
7.	Were outcomes clearly defined and the measurements valid and reliable?		Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	Yes
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.7.	Were the measurements conducted consistently across groups?	Yes
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	Yes
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	N/A
9.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
10.	Is bias due to study's funding or sponsorship unlikely?		???
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	No