Other Amino Acids
Citation:
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:
Does supplementation with Beta-hydroxy-Beta-methylbutyrate (HMB), L-arginine and L-glutamine reverse or stabilize muscle loss in cancer cachexia thus increasing total body weight and lean body mass?
Inclusion Criteria:
- Patients with advanced solid tumors (stage IV)
- Documented weight loss greater than 5%
- Prognosis of 3 months or greater survival
- Chemotherapy and radiation therapy were acceptable during study
Exclusion Criteria:
- Patients taking megace, corticosteroid analogues, or omega-3 fatty acids or their cogeners
- Patients who had received total parenteral nutrition in the previous three months
- Weight loss less than 5%
- Prognosis of less than 3 months survival
- Patients without advanced solid tumors
Description of Study Protocol:
- 49 patients with cancers were recruited and screened from Reno, Nevada, Las Vegas, Nevada, and from Manhasset, New York
Design
- Conducted at three study sites between January 1999 and May 2000 for a total of 24 weeks
1. Prior to initiation of study:
- Informed consent obtained from each patient
- Health history and demographic data were obtained
- Each patient had undergone a physical examination
- Blood was drawn
- Body weight and initial body composition were measured
- Questionnaires were filled out regarding quality of life, adverse events, and dietary intake
2. During study:
- Questionnaires regarding quality of life, adverse events and dietary intake were repeated every four weeks: week 4,8,12,16,20, and 24 weeks during the study
- Body weight and body composition were measured every four weeks for 24 weeks
3. Nutritional supplements were randomly assigned to each patient within each study site:
- Treatment group received mixture containing 3 grams of HMB (calcium salt), 14 grams of L-glutamine, and 14 grams of L-arginine daily (Juven; Metabolic Technologies, Inc., Ames, Iowa)
- Control group received a nutrient mixture similar to the nitrogen content of the treatment group: L-alanine (11 grams), L-glutamic acid (1.75 grams), L-glycine (6.10 grams), and L-serine (4.22 grams)
- Each supplement was mixed with 240 cc of water and was isonitrogenous at 7.19 grams nitrogen a day and isocaloric at 180 calories a day.
- Supplements were provided in individual dose packets. Patients were advised to take two doses a day. Each dose was mixed with 240 cc of water.
4. Measurements
- Certified scale was used and calibrated daily with certified weights
- Body composition was evaluated by Bioelectrical Impedance Analysis(Body Composition Analyzer, BIA-101S; RJL Systems, Clinton Township, Michigan; and Body Composition Analyzer, model 310e; Biodynamics, Seattle, Washington)
- In a subset of subjects, additional measurements of body composition using air displacement plethysmography were made. (Bod Pod; LMI, Concord, California)
Blinding used
- Random assignment of nutritional supplements to each patient using computer generated random numbers prior to the start of the study in a double-blind fashion
- Each supplement had a tangy orange flavor and was provided in plain white foil packets
- Each dose supplied in a separate packet was provided a subject number
Intervention
- 3 grams of HMB (calcium salt), 14 grams of L-arginine, 14 grams of L-glutamine provided daily to treatment group
- 11 grams of L-alanine, 1.75 grams of L-glutamic acid, 6.10 grams of L-glycine, and 4.22 grams of L-serine provided daily to control group
Statistical Analysis
- Repeated measure analysis of variance model (ANOVA, SAS Institute, Cary, North Carolina) was used in the comparison of body composition data and questionnaire data regarding quality of life, emotional state, and dietary intake
- Last value carried forward procedure was used to analyze the intent-to-treat analysis
- Linear and quadratic contrasts were used for the repeated measures ANOVA.
- Cochran-Mantel-Haenszel test determined statistical differences between supplements
- Adverse events questionnaires were analyzed as catagorical data
Data Collection Summary:
Timing of Measurements
- Questionnaires regarding quality of life, adverse events and dietary intake were repeated every four weeks: week 4, 8, 12, 16, 20, and 24 weeks during the study
- Body weight and body composition were measured every four weeks for 24 weeks
Dependent Variables
- Weight measured by certified scale
- Body composition (Fat Free Mass and Fat Mass) evaluated by Bioelectrical Impedance Analysis (and additional measurements in a subset of patients by Bod Pod)
- Age
- Sex
- Prior Involuntary weight loss
- Quality of Life
- Adverse events
- Dietary intake (ESHA Research, The Food Processor, Nutrition and Fitness Software, version 7.3, 1998)
Independent Variables
- 3 grams of HMB, 14 grams of L-arginine, and 14 grams of L-glutamine provided to treatment group
Control Variables
- Nutrient mixture provided to control group matched the nitrogen content of the treatment group with the non-essential ammino acids L-alanine , L-glutamic acid, L-glycine and L-serine
Description of Actual Data Sample:
Initial N: N=49 (35 male/14 female), 25 patients were randomized to the control group and 24 were randomized to the HMB/Arg/Gln group.
Attrition (final N):
- 17 patients withdrew from the study prior to their first 4-week follow-up visit (11 control; 6 HMB/Arg/Gln)
- Total of 32 patients met the criteria for statistical analysis. Of the 32 patients, 14 patients (10 male, 4 female) consumed the control supplement and 18 patients (15 male, 3 female) consumed the HMB/Arg/Gln mixture
- During 24 week study period, an additional 23 patients withdrew for various reasons
- 9 patients completed the entire 24-week protocol (2 control; 7 HMB/Arg/Gln)
Age: 65.9 years old
Ethnicity: Not specified
Other relevant demographics:
- Cancer diagnosis included breast, carcinoid, head and neck, colon, lung, ovarian, pancreatic, prostate, stomach, liver, uterine, ball bladder.
Anthropometrics
- Initial body weight, initial percent fat mass, and antecedent weight loss were similar in the control and the treatment group
Location:
- Cancer patients were recruited and screened from three different locations: Reno, Nevada, Las Vegas, Nevada, and Manhasset, New York.
Summary of Results:
Table 1 Patient Characteristics
|
Variables |
Control (recruited) |
Control group (4-week follow-up) |
Treatment Control (12-week follow-Up) |
HMB/Arg/Gln (recruited) |
HMB/Arg/Gln (4-week follow-up) |
HMB/Arg/Gln (12-week follow-up) |
|
Age |
66.1 (2.1) |
67.4 (2.4)
|
66.0 (2.1) | 65.9 (2.0) | 64.3 (2.4) |
66.0 (2.3) |
|
Sex (M/F)
|
16/9 | 10/4 | 6/1 | 19/5 | 15/3 | 9/0 |
|
Weight (kg)
|
59.2 (2.3) | 60.6 (3.6) | 58.9 (1.7) | 63.7 (2.4) | 65.7 (3.0) |
72.4 (1.7) p<0.05 |
|
Fat (%)
|
18.3 (1.5) | 17.0 (2.0) | 18.7 (1.3) | 17.7 (1.7) | 18.8 (1.8) | 17.2 (1.6) |
| Prior involuntary weight loss(%) | 16.7 (1.5) | 15.8 (2.0) | 19.0 (2.2) | 14.2 (1.2) | 14.4 (1.6) |
11.7 (1.0) p<0.05 |
| Cancer Diagnosis | ||||||
|
Breast
|
1 |
0 |
0 | 1 | 1 |
0 |
|
Carcinoid
|
1 | 1 | 0 | 1 | 1 | 0 |
|
Head/Neck
|
3 | 3 | 2 | 0 | 0 | 0 |
|
Colon
|
5 | 1 | 0 | 8 | 7 | 4 |
|
Lung
|
4 | 3 | 1 | 2 | 1 | 1 |
|
Ovarian
|
2 | 1 | 0 | 0 | 0 | 0 |
|
Pancreatic
|
4 | 1 | 1 | 4 | 3 | 1 |
|
Prostate
|
2 | 1 | 0 | 5 | 3 | 3 |
|
Stomach
|
2 | 2 | 2 | 1 | 1 | 0 |
|
Liver
|
1 | 1 | 1 | 1 | 1 | 0 |
|
Uterine
|
0 | 0 | 0 | 1 | 1 | 0 |
|
Gall Bladder
|
0 |
0 |
0 | 1 | 0 |
0 |
- Patient Characteristics
- Prior to first four week follow up, 32 patients met the criteria for statistical analysis: 14 patients consumed the control supplement and 18 patients consumed the HMB/Arg/Gln supplement
- Nine patients completed 24 week protocol
- Lower drop out rate in the HMB/Arg/Gln group as compared to the control group throughout the length of the study
- Baseline calorie intakes after 3 day dietary recall were 1,864 kcals per day and 79 grams of protein per day in the control group and 1,441 calories per day and 66 grams of protein per day in the treatment group. They were not statistically different.
- After four weeks, calorie and protein intake increased in the control group (2,169 calories/Day and 94.5 grams of protein/Day) but were maintained in the HMB/Arg/Gln group(1,478 calories/Day and 62 grams of protein/Day). (excluding calories and protein provided by supplementation with control supplement or HMB/Arg/Gln supplement)
- Protein intakes for both groups were greater than 0.8 grams of protein/kilogram/Day. Calorie intake for HMB/Arg/Gln group was below 30 calories/kilogram/Day.
Table 2
Effect of HMB, L-Arg, and L-Gln supplementation on health status assessed by Short Form-36 Health Survey in cancer cachexia patients
|
Scale |
Control Weeks screen |
4 |
12 |
24 |
HMB/Arg/Gln Weeks Screen |
4 |
12 |
24 |
|
Physical Functioning |
41.5 |
56.2
|
59.1 | 56.2 | 44.6 | 43.5 | 47.7 |
49.4 |
|
Role Physical
|
20.4 | 11.2 | 12.7 | 15.1 | 4.6 | 13.8 | 14.4 | 16.1 |
|
Bodily Pain
|
42.5 | 45.4 | 45.2 | 46.5 | 39.9 | 53.0 | 46.7 |
42.1 |
|
General Health
|
45.5 | 33.6 | 35.9 | 37.6 | 48.3 | 43.4 | 43.5 | 40.8 |
| Vitality | 35.4 | 36.5 | 34.3 | 34.6 | 32.4 | 37.0 | 36.4 |
33.8
|
|
Social Functioning
|
45.3 | 61.2 | 62.3 | 66.0 | 33.7 | 47.3 | 52.2 | 49.7 |
|
Role-emotional
|
47.1 |
34.5 |
28.4 | 26.9 | 41.8 | 43.3 | 49.4 |
37.0 |
|
Mental Health
|
63.9 | 72.2 | 65.4 | 66.3 | 63.6 | 63.8 | 66.4 | 65.3 |
Above data are presented as mean score (%) for the health status category at baseline and follow up visits at 4, 12 and 24 weeks.
2. Body Composition Outcome
At four weeks supplementation, HMB/Arg/Gln treatment group gained 0.95 +/- 0.66 kg of weight as compared to the control group who lost 0.26 +/- 0.78 kg of weight
- Measurements by BIA indicated that the HMB/Arg/Gln treatment group had significant gain in fat-free mass(FFM)
- Subset of patients who underwent body composition analysis by air displacement plethysmograpy (Bod Pod) confirmed significant changes in FFM as measured by BIA.
- At 24-weeks of supplementation, HMB/Arg/Gln group gained 2.27 +/- 1.17 kg of body weight. Weight gain was significantly different from baseline weight (p=0.06).
- At 24-weeks of supplementation, the control group gained 0.27 +/- 1.39 kg and this weight gain was not significantly different from the baseline weight (p=0.84).
- During 24-week period, there was no significant difference in fat mass change between HMB/Arg/Gln goup and the control supplemented group.
3. Safety of HMB/Arg/Gln supplementation was assessed using questionnaires and by evaluating serum chemistries and hematologic indices.
- Questionnaires
- One questionnaire evaluated safety in relation to the gastrointestinal tract, respiratory tract, hearing system, eyesight, muscular skeletal system, neurologic system and energy level
- Drop out rate was higher in the control supplemented group as compared to the HMB/Arg/Gln group
- Adverse events questionnaires showed that difference in drop out rates was not due to adverse event
- Quality of life questionnaires (Short Form-36 Health Survey and Functional Assessment Health Survey) concluded no changes in physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, or mental health. No changes in social well-being, relationship with doctor, emotional well-being or functional well-being. HMB/Arg/Gln group showed a decresed physical well being as compared to control group.
- Serum Chemistries and hematologic indices
- Evaluated at baseline and at 12 weeks.
- No changes in liver functions: total bilirubin, alkaline phosphatase, lactate dehydrogenase, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, gamma-glutamyl-transferase and iron
- No changes in renal function or electrolytes: serum glucose, potassium, creatinine, and calcium
- At 12 weeks, no difference in total protein, albumin, globulin, prealbumin, triglycerides, total cholesterol
- Though not statistically different, HMB/Arg/Gln group showed 11% increase in serum prealbumin as compared with a -15% decrease in the control group.
- At 12-weeks, serum levels of sodium, blood urea nitrogen, uric acid, and phsophorous were increased (p<0.05) in the HMG/Arg/Gln group as compared with decreased levels in the control group
- Hematologic indices indicated no changes between two groups from baseline to 12 weeks.
Author Conclusion:
- First double-blind, randomized and controlled study to show increase in fat free mass with amino acid supplementation(B-hydroxy-B-methlbutyrate, L-arginine, and L-glutamine) in Stage IV cancer patients with cancer cachexia as compared to controls receiving similar calorie and protein supplementation.
- Increase in fat free mass was shown by BIA and air displacement plethysmorgraphy (ADP) and methods were strongly correlated in this study.
Funding Source:
| Government: | NIH | ||
| Industry: |
|
Reviewer Comments:
Limitations:
- Heterogeneous patient population of stage IV cancer patients
- Patients receiving various treatment modalities with chemotherapeutic agents
- Small sample size
- Timing of intervention not indicated
- Compliance to intervention not mentioned
- Cancer cachexia was limited to 5% weight loss-unclear if this was within one month time
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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? | No | |
| 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? | Yes | |
| 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? | ??? | |
| 4.5. | If diagnostic test, was decision to perform reference test not dependent on results of test under study? | Yes | |
| 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.) | ??? | |
| 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? | N/A | |
| 6. | Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? | Yes | |
| 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? | No | |
| 6.5. | Were co-interventions (e.g., ancillary treatments, other therapies) described? | N/A | |
| 6.6. | Were extra or unplanned treatments described? | Yes | |
| 6.7. | Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? | Yes | |
| 6.8. | In diagnostic study, were details of test administration and replication sufficient? | N/A | |
| 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? | No | |
| 10.1. | Were sources of funding and investigators' affiliations described? | Yes | |
| 10.2. | Was the study free from apparent conflict of interest? | No | |