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ONC: Dietary Supplements and Medical Food Supplements Containing Fish Oil (2013)

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:
To compare the effect of an oral supplement with 2.2 grams of eicosapentaenoic acid (EPA) with a supplement that was isocaloric, with the same amount of protein and antioxidants on weight gain, body composition, overall dietary intake, and quality of life in pancreatic cancer patients with cachexia.
Inclusion Criteria:

Unresectable pancreatic cancer, confirmed in any one of the following ways:

  • Histologically
  • With firm radiological findings
  • With operative diagnosis

Plus:

  • Lost 5% or more of pre-illness stable weight over previous six months
  • Karnofsky Performance Score (KPS) > 60
  • A life expectancy > 2 months
  • Written informed consent

The ethics committees for human research of the participating centers approved the protocol.  Procedures were followed in accordance with the International Committee for Harmonization, Good Clinical Practices and the Helsinki Declaration.

Exclusion Criteria:
  • Surgery, endoscopic stenting, radiotherapy, or chemotherapy in the previous 4 weeks
  • Active medical conditions including major gastrointestinal disease, chronic renal failure, uncontrolled diabetes or human immunodeficiency virus (HIV)
  • Body mass index (BMI) > 30 kg/m2
  • Received medication within the previous 90 days that could modulate metabolism or weight; in particular, patients using fish oil or omega-3 fatty acids providing > 200 mg/day of EPA or one capsule of fish oil/day in the previous 90 days
Description of Study Protocol:

Recruitment

International, multicenter trial.  Patients were recruited from 12 study sites in Australia, Belgium, Canada, Italy, Netherlands, and United Kingdom. 

Design

Randomized, double-blind, controlled trial.

Blinding used

  • Patients were randomized at enrollment in permutation blocks of two using a sequential series of numbered sealed envelopes containing computer generated random assignments.  Randomization envelopes were opened by a third party who shipped the oral supplement directly to the patients' homes. 
  • Patients, investigators, and study personnel were blinded to the treatment group allocation. 
  • Experimental and control study products were packaged identically and not distinguishable from each other.

Intervention

Intervention is for the patients to receive a high protein, calorie dense liquid supplemental control product OR an experimental product that is identical with the exception of added EPA and antioxidants.

Each 237 mL can of experimental and control product contained:

  • 310 calories
  • 16 grams of protein
  • 6 grams of fat

Each can of experimental product contained 1.1 grams of EPA and 2524 IU vitamin A, 75 IU vitamin E, 105 mg vitamin C and 17.5 ug selenium (to prevent the peroxidation of polyunsaturated fatty acids (PUFA)).

Control product DID NOT contain EPA or extra antioxidants.

Each participant was required to consume 2 cans of supplement per day.

Statistical Analysis

Planned Analyses

  • Intent to treat analysis (includes dropouts and non-compliance)
  • Continuous variables analyzed with two-sample t-test or Wilcoxon signed rank test, as appropriate
  • Categorical variables analyzed using Chi-square or Fisher's exact test, as appropriate

Additional Analyses

  • Post-hoc analysis conducted due to high level of non-compliance with intervention (patients consumed less than 2 cans of supplement/day)
  • Paired t-test or Wilcoxon signed rank test, as appropriate, for within group comparisons
  • Correlation product moment analysis for additional within group comparisons
  • Analysis of covariance and Pearson correlation coefficient for experimental and control groups separately
  • Wilcoxon signed rank test to examine correlation between amount of experimental product consumed and specific outcomes
  • Kaplan-Meier (survival analysis) method to examine patient survival from date of enrollment

If p-value < 0.05, then results were considered to be statistically significant.

 

 

Data Collection Summary:

Timing of Measurements

Initial assessment (self-report), baseline, 4 weeks and 8 weeks

Dependent Variables

Initial assessment, self-reported

  • Height
  • Pre-illness stable weight
  • Duration of weight loss

Baseline, 4 weeks and 8 weeks

  • Weight without shoes and light clothing on spring balance scales
  • Body composition assessed using a multiple frequency bioelectrical impedance analyzer
  • Total body water calculated with equations validatedin surgical patients.  Lean body mass calculated from total body water assuming lean tissue has 73% water
  • Dietary intake using 3-day food diaries with Total intake = oral supplement consumption + spontaneous food intake
  • EPA in plasma phospholipids using gas chromatography
  • Quality of life measured using two self-administered questionnaires:  1.  EuroQolEQ-5D and 2.  European Organization for Research and Treatment of Cancer QLQ-C30
  • Karnofsky Performance Score (KPS)

Independent Variables

Each participant required to consume 2 cans of oral supplement per day. 

Each 237 mL can of experimental and control supplement contained:

  • 310 calories
  • 16 grams of protein
  • 6 grams of fat

Each can of experimental supplement contained 1.1 grams of EPA, 2524 IU vitamin A, 75 IU vitamin E, 105 mg vitamin C and 17.5 ug selenium (to prevent peroxidation of polyunsaturated fatty acids)

Control supplement did not contain EPA or extra antioxidants.

 

 

Description of Actual Data Sample:

 

Initial N: 200 (Experimental group (E) = 95 (41 females, 54 males); Control group (C) = 105 (49 females, 56 males))

Attrition (final N): 110 (50 E and 60 C)

Age: mean of E = 67; mean of C = 68

Ethnicity: Not stated.

Other relevant demographics: Not stated.

Anthropometrics:  The two groups were comparable for all variables including age, sex, histological proof of disease, stage of disease, usual weight, pancreatic enzyme supplementation, and baseline characteristics.  However, 52% of the E group and 41% of the C group had stage IV disease, respectively.

Location:  International multicenter study with 12 sites in Australia, Belgium, Canada, Italy, Netherlands, and United Kingdom

 

Summary of Results:

Results for 100 of the 110 patients at 8 weeks:

  • Supplement intake for E and C groups averaged 1.4 cans/day.
  • Both supplements equally effective in halting weight loss (Change in weight E: -0.25 kg/month and Change in weight C:  -0.37 kg/month; p = 0.74).
  • No significant difference between groups for supplement intake (p = 0.63) , change in meal (p = 0.24) or total dietary intake (p = 0.16).
  • Significant increase in total (meals plus supplement) dietary intake (E:  15 g protein/day (p <0.001) and 224 kcal/day (p = 0.001); C:  6 g protein/day (p = 0.036) and 68 kcal/day (p = 0.098).

Other findings:

  • E and C groups had high levels of EPA at baseline (14%) suggesting undisclosed prior supplementation with n-3 fatty acids.  At weeks 4 and 8, 18% of C group had high EPA levels and 26% of E group had little or no elevation of EPA.
  • No significant difference in duration of survival between E and C groups (p > 0.05).

Due to non-compliance, correlation analysis done separately for each group:

  • Significant dose-response relationship between supplement intake and weight (p < 0.001) and LBM (p = 0.036) in E group.  No significant correlation in C group (p > 0.05)
  • Significant association between plasma EPA and LBM gains (p = 0.043) in E group.  No significant association in C group (p > 0.05).
  • Significant association between 8-week plasma EPA and increases in weight (p < 0.001) and LBM (p = 0.001) in the E group.  No significant association in C group (p > 0.05).
  • Intake of experimental supplement correlated with improved QOL (EQ5Dindex) (p = 0.01).  Intake of control supplement not correlated with improved QOL (p = 0.77).
  • Weight gain significantly associated with improved QOL (EQ5Dindex measured) in E group (p < 0.001).  Weight gain not significantly associated with improved QOL in C group (p = 0.59).
Author Conclusion:
  • No clear advantage at the mean dose taken (1.4 cans/day) from the n-3 enriched, specialized protein and energy dense oral supplements for patients with advanced cancer cachexia.
  • Enrichment with n-3 fatty acids did not provide a therapeutic advantage and that both supplements were equally effective in stopping weight loss.
  • Post hoc dose-response analysis suggests that if taken in sufficient quantity, only the n-3 fatty acid enriched energy and protein dense supplement results in net gain of weight, lean tissue, and improved QOL.

Limitations:

  • Variety of compliance issues that may have biased study results. 
  • Mean intake of the supplement (1.4 cans/day) did not supply the suggested therapeutic dose (2.1 g/day) of EPA.

Project support:

Abbott Laboratories, Chicago, IL, USA

Conflict of interest:

AC Voss is an employee of the Ross Products Division, Abbott Laboratories.

Funding Source:
University/Hospital: Royal Infirmary
Reviewer Comments:

A potentially useful study that must consider efforts to facilitate patient compliance in future work.  Although researchers determined that no clear advantage existed for patients taking the mean dose taken (1.4 cans/day), post hoc dose-response analysis suggests that if taken in sufficient quantity, only the n-3 fatty acid enriched energy and protein dense supplement results in net gain of weight, lean tissue, and improved QOL.

Subject non-compliance and use of post-hoc analysis suggest that the findings may not be due to the supplement and they are not generalizable.  Nonetheless, the data are suggestive, encouraging more research

Limitations: 

  • No information about the ethnicity/race of patients.
  • Assessment of EPA sources from food were not recorded.
  • Too many statistical tests.
  • Need more information about why both groups consumed an average of 1.4 cans of supplement.

 

 

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? Yes
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")? N/A
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? Yes
  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.) 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? 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? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? N/A
  6.6. Were extra or unplanned treatments described? N/A
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? N/A
  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? ???
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? Yes