This trial is a prospective, single-center, randomized, double-blind study in patients diagnosed with esophageal cancer who post EPG are treated with a LE of ω-3 fatty acid or a mixture of LCT/MCT 50%.
2.1 STUDY OBJECTIVES
The main objective of this study is:
- To establish if the endovenous administration of ω-3 fatty-acid fish-oil LE for 5 days in esophagectomized patients is effective in reducing inflammation – measured as seric concentration of Interleukin-6 (IL6) – compared to the administration of LE of LCT/MCT. Additionally, to determine if doses of 0.8 g/kg/d are more effective than doses of 0.4 g/kg/d in the normalization of IL-6.
The secondary objectives aim to determine if the intravenous administration of ω-3 fatty-acid fish-oil LE for 5 days in esophagectomized patients shows differences compared with the administration of LCT/MCT LE with regard to:
- Seric concentration of other inflammatory parameters: C-reactive protein (CRP), tumoral necrosis factor-α (TNF-α), interleukin-10 (IL-10), interleukin-8 (IL-8) and soluble interleukin-2 receptor (sIL‑2R / CD25s). In addition, whether these markers, alone or in combination, show equal or greater efficacy in the measure of the inflammatory response compared to IL-6.
- Postoperative complications: suture dehiscence, chylotorax, pneumonia and other infections.
- Safety, measured as hepatic impairment and alterations in coagulation parameters.
- Nutritional parameters: albumin, prealbumin and lymphocytes.
- Mortality: evaluated at hospital admission and at one year post-surgical intervention.
2.2. STUDY DESIGN
Prospective, unicentric, randomized, double-blinded study in patients with esophageal cancer and esophagectomized by the Ivor-Lewis or McEwan techniques. The study will be carried out in accordance with the good clinical practice in our hospital.
All participants will receive a LE by continuous infusion in addition to EN support for 5 days post-surgery. The standard EN support will be initiated with Impact Neutre® 500ml (a normocaloric, hyperproteic and immunomodulatory diet composed of 3.9g of lipids in each 100ml, 1.8g of MCT/100ml, 0.61 g of ω-6 fatty acids/100 ml and 0.6g of ω-3 fatty acids/100 ml, with a caloric input of 144kcal/100ml daily); it will be initiated at 21 ml/h and titrated to 1500ml daily.
When the body mass index (BMI) is greater than 25, the ideal adjusted body weight will be applied following the formula: “Ideal adjusted body weight = ideal body weight + (actual body weight - ideal body weight) * 0.25 (if BMI 26-30) or *0.5 (if BMI>30)”. Group A will receive a LE mixture of 0.4 g/kg/d of fish-oil and 0.4g/kg/d of LCT/MCT, Group B will receive 0.8 g/kg/d of fish-oil LE and Group C will receive a LE mixture of 0.8 g/kg/d of LCT/MCT 50%.
2.2.1 Study population
Patients diagnosed with esophageal cancer and candidates for EPG by the Ivor-Lewis or MacEwan techniques, and who meet the following inclusion criteria:
- 18 years old or older, any gender and any race.
- Willing and able to give their written informed consent (IC) for the study. If a subject is unable to give written IC, his legal representative may do so in his/her place.
- Having access to the digestive tract.
Patients who meet the following exclusion criteria will not be chosen:
- Hypersensitivity type 1 or idiosyncratic reactions to any of the LE components.
- Pregnant or breastfeeding women.
- Plasmatic triglycerides concentration >3 mmol/L.
- In receipt of chronic treatment with corticosteroids or immunosuppressants in the last month.
- HIV diagnosis.
- Hepatic impairment classified as Child-Pugh grade B (significative functional compromise) or grade C (decompensated disease).
Subject and/or treatment withdrawal criteria:
Patients can voluntarily refuse to continue in the study at any time. In addition, presentation of any adverse effect related to the treatment will lead to a treatment withdrawal and to exclusion from the study.
All patients who present with surgical complications classifiable as grade IV of the Dindo-Clavien classification [18] will be excluded from the study.
2.2.2 Patients recruitment, randomization and allocation
All patients allocated for EPG following medical criteria, and those who meet the inclusion criteria will be candidates to participate in the trial.
The surgical team will be responsible for communicating the possibility of participating in this trial when informed consent is obtained for the surgical intervention. Informed consent for participation in this trial will be collected before randomization.
Subjects will be randomized to three groups (1:1:1) by a pharmaceutical researcher after recruitment by the surgical team:
- Group A will receive 0.4 g/kg/d of fish-oil LE and 0.4g/kg/d of a LE mixture LCT/MCT receiving a total dose of 0.8g/kg/d of LE over 5 days post-surgery,
- Group B will receive 0.8 g/kg/d of fish-oil LE,
- And Group C will receive 0.8 g/kg/d of a LE mixture of LCT/MCT 50%.
This allocation will be blind for all patients and health personnel. The allocation sequence (computer-generated random numbers) will be generated by the pharmaceutical researcher and it will be performed by randomized blocks permutated with the block size defined at random. In the first step, blocks of size 3 with possible sequences ABC, ACB, CAB and CBA, and size 6 will be defined. In a second step the clusters will be randomized, and in a third step the sequences will be randomized within the blocks. This method ensures that the groups are balanced throughout the study, and that the researcher cannot predict the sequence. The pharmaceutical researcher will be responsible for patient assignation to the corresponding intervention group, and will also assign a numbered patient identification code for each patient in the trial. The composition of the emulsion administered to each patient will only be known by: the pharmaceutical researcher responsible for clinical trials, the pharmaceutical researcher who will validate its conduct, and the personnel who will conduct it.
2.2.3 Number of participants subjects and trial duration:
Recruitment will last a total of 24 months from the approval date. Each subject will participate in the trial for a year post-surgical intervention.
On the basis of the results obtained and as referenced by Furukawa et al [19] (a study of the values of IL6 in esophagectomized patients who received PN with ω-6 fatty acids or without lipids), and considering that the effect of administration of fish-oil emulsion (with ω-3 fatty acids) will be similar to the non-administration of ω-6 fatty acids, a sample size of 33 patients is estimated for 80% of potency and 5% of α error with 10% of anticipated losses.
2.3 STUDY VARIABLES
The main variable of this study is the variation of seric concentration levels of IL6 at randomization and on Days 1, 3, 5, 21 post surgery in esophagectomized patients receiving fish-oil LE parenterally for 5 days compared with those receiving LCT/MCT LE.
The secondary variables will examine whether intravenous administration of fish-oil LE instead of LCT/MCT for 5 days leads to differences from randomization and on Days 1, 3, 5 and 21 post-randomization regarding to:
- Seric concentrations of inflammatory markers: CRP, TNF-α, IL-10, IL-8 and sIL‑2R / CD25s.
- Morbidity measured as postoperative complications: suture dehiscence, chylotorax, pneumonia and other infections.
- Safety measured as hepatic impairment (total bilirubin, alanin-aminotranspherase, aspartate-amino transpherase, gammaglutamil transpherase, alkaline phosphatase) and alteration in coagulation parameters (International Normalized Ratio, prothrombin time, platelet count).
- Nutritional parameters: albumin, prealbumin and lymphocytes.
- Mortality measured for a year after surgical intervention.
2.4 TREATMENTS USED IN THE TRIAL
Research Drugs
The fish-oil emulsion employed in the study is commercialized as Omegaven®, and the mixture emulsion of LCT/MCT is commercialized as Lipofundina®
Lipids emulsions will be prepared at the Pharmacy Department with the same aseptic conditions used for PN (in a laminar flow cabinet). They will be delivered ready for administration in a multilayer bag, and will be stored and conserved in accordance with the normal procedures of the department of Pharmacy. The double blind will be facilitated by the identical galenic presentation of the LE.
Emulsions will be dispensed when the trial recipe used in the Universitary Hospital of Bellvitge is finalized.
Others concomitant treatments
During this trial both the patient's usual medication and any support medication needed during admission will be maintained as usual.
2.5 DATA COLLECTION
Demographic, pharmacological, clinical and analytical data
Demographics, clinical and analytical data generated following normal clinical practice will be collected and recorded in the Data Collection Logbook (DCL).
Demographic data: age, gender, body weight, height and BMI will be recorded.
Pharmacological data: any adjuvant chemotherapy received by a patient after trial treatment will be recorded specifying the treatment scheme.
Analytical data:
- Inflammatory parameters: values of IL-6, CRP, TNF-α, IL-10, IL-8 y CD25 on Days 0, 1, 3, 5 and 21 post surgery will be recorded. These values have been selected according to what is reported in the literature in similar studies [19-25]. Also, these same values will be recorded pre-operatively at the time surgical intervention is indicated to show the patient’s baseline inflammatory status.
- Nutritional parameters: albumin, prealbumin and lymphocytes at the time surgical intervention is indicated and on Days 0, 1, 3, 5 and 21.
- Hepatic parameters: total bilirubin, alanin-aminotranspherase, aspartat aminotranspherase, gammaglutamil transpherase and alkaline phosphatase at the time surgical intervention is indicated and on Days 0, 1, 3, 5 and 21.
- Safety: INR, prothrombin time and platelet count at the time surgical intervention is indicated and on Days 0, 1, 3, 5 and 21.
The total number of blood extractions per patient will be 6.
Clinical data: the following data will be recorded:
- Post-surgery complications such as chylothorax, dehiscence, pneumonia and other infections.
- Mortality: from the day of surgery to one year following surgery.
- Nutritional support: the amount of EN received by each patient will be recorded to determinate total calories administered.
Quantification of cytokines:
- Sample collection: Samples will be centrifugated at 700xg an hour post-extraction. Samples will be aliquoted and stored frozen at -80ºC until analysis (1 year). Cytokine values will be determined by Enzyme-Linked ImmunoSorbent Assay (ELISA).
2.6 RESPONSE ASSESSMENT
2.6.1 Statistical analysis:
Descriptive statistics will be employed for all collected variables data, such as baseline values for inflammatory, nutritional, hepatic and safety parameters, in frequency tables. For continuous variables, statistical descriptions will be used (n, average, standard deviation, value range and median), meanwhile grouped percentages will be used for categorical variables.
The main objective is to establish the difference between basal values of inflammatory parameters and values at Day 5 post randomization, and to assess differences between Days 1, 3 and 21. The secondary objectives are to establish the difference between basal values of morbidity, safety and nutritional parameters and those values at Day 5 post randomization.
Significance will be calculated using Student t-test for matching data or Wilcoxon-test (non-parametric test) depending on whether normality can be assumed or not. To establish the differences among the 3 groups for the same period of time, Student’s t-test (parametric test) or Mann Whitney U test (non-parametric test) will be used, depending on whether normality can be assumed or not. For categorical variables, the chi-square test or the Fisher test will be used when necessary.
The significance level will be established with a 95% confidence interval (CI). Data will be processed with SPPS v 19.
2.7. ADVERSE EVENTS NOTIFICATION
All serious adverse events, regardless of their causal relation, will be reported to the study monitor immediately, sending a fax to +34932607884, in a maximum of 1 working day. According to articles 43 and 44 of the RD1090/2015, which regulates clinical trials in Spain, and in accordance also with sections 25 to 27 from the regulatory document concerning implementation of normal clinical trials (6th version, May 2008), the monitor will be responsible for communicating every serious and unexpected adverse event to the competent Health Authorities. http://www.aemps.es/actividad/invClinica/ensayosClinicos.html
2.8. MONITORING
Monitoring tasks will be carried out by a monitoring company hired for this purpose. The person responsible for monitoring this study will have access to any clinical data required for the conduct of the trial and to all interim results. There will be four monitor-auditing visits that will take place at the beginning of the study prior to the first patient recruitment, two during recruitment of patients, and when the follow-up of the last patient is finished, which means the end of the study. The monitor will be responsible for communicating any adverse events to the health authorities.