ONC: Glutamine (2006)
Citation:
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:
The purpose of the research was to determine whether supplementation of TPN with glutamine enhances the process of immune reconstitution and improves the mucositis score of patients undergoing high-dose chemotherapy and autologous peripheral blood stem-cell transplantation (aPBSCT) or immunoselected CD34+aPBSCT for hematologic malignancies.
Inclusion Criteria:
- Patients admitted for selected or unselected aPBSCT at the Hematology Department, Catholic University A. Gemelli Hospital, Rome, Italy
- Informed consent obtained from all patients/guardians.
Exclusion Criteria:
Not mentioned.
Description of Study Protocol:
Recruitment
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Study 1: 27 consecutive patients of the Catholic University "A Gemelli" hospital, Rome, Italy, admitted to selected or unselected aPBSCT between October 1998 and August 1999
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Study 2: 21 consecutive patients of the Catholic University "A Gemelli" hospital, Rome, Italy, admitted to selected or unselected aPBSCT beginning in September 1999.
Design
- Study protocol approved by institutional review board
- The trial consisted of two consecutive randomized controlled studies.
Blinding used
- Some study personnel were blinded
- No specific statement on blinding.
Intervention
Study One (October 1998 to August 1999)
- 27 consecutive patients admitted for selected or unselected aPBSCT were randomized to one of two groups:
- Study One Glutamine group, 12 patients
- Received Glamin (Fresenius Kabi), a parenteral amino acid solution containing 20 g free glutamine, 1,000 mL/day, from Day +1 after aPBSCT
- Study One placebo group, 15 patients
- Received a placebo.
- Study One Glutamine group, 12 patients
- Daily parenteral nutrition regimen
- Glutamine group
- Intralipid: 10% (Fresenius Kabi), 500 ml
- Glamin: (Fresenius Kabi), 1,000 ml
- 18 essential and non-essential amino acids
- 30.27 g stable glycil-L-glutamine
- 10.27 g glycine
- 20 g glutamine.
- 33% glucose solution, 1,000 ml
- Hydrosoluble and liposoluble vitamins.
- Placebo group
- Intralipid: 10% (Fresenius Kabi), 500 ml
- Freamine: 8.5% (Fresenius Kabi), 1,000 ml
- 33% glucose solution, 1,000 ml
- Hydrosoluble and liposoluble vitamins.
- Glutamine group
Study Two (Beginning September 1999)
- 21 consecutive patients admitted for selected or unselected aPBSCT were randomized to one of two groups:
- 10 patients (Study Two Glutamine group)
- Received Dipeptiven (Fresenius Kabi), a parenteral solution containing 13.46 g glutamine, 100 mL/day, from Day +1 after aPBSCT.
- 11 patients (Study Two placebo group)
- Received a placebo.
- 10 patients (Study Two Glutamine group)
- Daily parenteral nutrition regimen
- Glutamine group:
- Kabimix 1830 (Fresenius Kabi)
- Dipeptiven (Fresenius Kabi), 100 mL
- Hydrosoluble and liposoluble vitamins.
- Placebo group:
- Kabimix 1830 (Fresenius Kabi)
- Hydrosoluble and liposoluble vitamins.
- Glutamine group:
Interventions for all patients, both studies:
- Prophylactic antibiotics
- Broad-spectrum antibiotics for sustained fever >38° C
- RBC infusions if RBC<8g/dL
- Platelet infusions if platelets <15x109/L
- All blood products were irradiated.
Statistical Analysis
Statistical significance defined as P<0.05
- Analysis of continuous factors: Mann-Whitney U-test
- Multiple comparisons: Kruskal-Wallace
- Post-hoc evaluation: Dunn's test
- Analysis of categorical factors: x2 test.
Data from Study One and Study Two were analyzed separately; then data from both studies was pooled and analyzed to check for consistency.
Data Collection Summary:
Timing of Measurements
- Clinical outcomes were evaluated daily
- Immune recovery was measured by lymphocyte subset analysis at baseline, 15, 30, 60, and 90 days
- Mucositis was assessed daily.
Dependent Variables related to cancer symptoms (for both Study One and Study Two)
- Variable One: Clinical outcomes
- Days of hospitalization (in days)
- Days of non-prophylactic antibiotics (in days)
- Number of days with body temperature >38° (in days).
- Variable Two: Immune recovery
- Lymphocyte subset analysis
- Measured by flow cytometry at baseline, 15, 30, 60, and 90 day.
- Lymphocyte subset analysis
- Variable Three: Severity of mucositis
- Measured daily from day 0 to discharge by Daily Mucositis Score (DMS).
Independent Variables
- Study One: Glamin (Fresenius Kabi), a parenteral amino acid solution containing 20 g free glutamine, 1000 mL/day, from Day +1 after aPBSCT.
- Study Two: Dipeptiven (Fresenius Kabi), a parenteral solution containing 13.46 g glutamine, 100 mL/day, from Day +1 after aPBSCT.
Control Variables
- Study One: Placebo solution.
- Study Two: Placebo solution.
Description of Actual Data Sample:
Initial and Final N (no attrition)
- Study One: N=27
- 12 treatment (five females, seven males)
- 15 placebo (five females, 10 males).
- Study Two: N=21
- 10 treatment (five females, five males)
- 11 placebo (three females, eight males).
Mean Age
- Study One
- Treatment group: 37.5 years
- Placebo group: 47 years.
- Study Two
- Treatment group: 31.5 years
- Placebo group: 49 years.
Ethnicity
- Not mentioned.
Other relevant differences between groups
- There were no significant differences between the Study One and Study Two groups in age, sex, conditioning regimen, and diagnosis.
Location
- Hematology Institute, Catholic University "A Gemelli" Hospital, Rome, Italy.
Summary of Results:
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Study 1 Results
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Study 2 Results
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*Measured as PMNs (polymorphonuclear granulocytes)
Summary of pooled data
- Researchers pooled data from Study One and Study Two. Findings included:
- Glutamine-supplemented patients had a significantly lower DMS on Day 10 (2 vs. 5; P=0.046), Day 11 (2 vs. 5; 0.016), and Day 12 (1.5 vs. 3.5; P=0.041)
- Glutamine-supplemented patient days at peak mucositis score was significantly lower (6 vs. 7; P=0.047)
- Glutamine-supplemented patients had better immune reconstitution:
- Higher number CD4+ cells at Day +15 (106 vs. 59 cells/µg; P=0.016), Day +30 (191 vs. 116 cells/µg; P=0.026).
- There were no other significant differences between the treatment and control groups when pooled data was analyzed.
Author Conclusion:
- Both studies showed that parenteral glutamine supplementation strongly improved immune reconstitution in autologous transplant patients, probably through rapid CD4+ subset reconstitution and the limiting of NK overshoot after transplant.
- Both studies showed that parenteral glutamine supplementation significantly reduced peak mucositis and reduced the duration of mucositis and that the effect was dose-related.
- Study One patients who received 20 g glutamine showed a significantly lower mucositis peak than placebo
- Study Two patients who received 13.46 g glutamine showed a trend toward reduced mucositis peak.
- Reduction of mucositis may result in better compliance with high-dose chemotherapy by reducing infections
- Positive effects of parenteral glutamine supplementation were balanced by much higher costs of parenteral nutrition.
Funding Source:
| University/Hospital: | Hematology Institute |
Reviewer Comments:
- Discussion of blinding was not thorough
- Implementation of the second study was not planned in the original study design
- Both Study One and Study Two showed a large difference in mean age of treatment and control groups, suggesting that positive effects could have been related to difference in age
- Generalizability of study may be limited by small sample of patients who received generally heterogenous conditioning regimens.
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Quality Criteria Checklist: Primary Research
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| 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? | ??? | |
| 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? | 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%.) | N/A | |
| 4.3. | Were all enrolled subjects/patients (in the original sample) accounted for? | Yes | |
| 4.4. | Were reasons for withdrawals similar across groups? | N/A | |
| 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? | ??? | |
| 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? | Yes | |
| 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? | 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? | ??? | |
| 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)? | ??? | |
| 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? | Yes | |
| 10.1. | Were sources of funding and investigators' affiliations described? | Yes | |
| 10.2. | Was the study free from apparent conflict of interest? | Yes | |