A Clinical Trial Assessing the Safety, Efficacy, and Delivery of Olive-Oil-Based Three-Chamber Bags for Parenteral Nutrition

Summary

Here, we present a protocol for a study comparing the efficacy, safety, and delivery of olive-oil-based 3CB and soybean-oil-based CoB formulations in adults requiring parenteral nutrition. The results revealed that olive-oil-based 3CBs is non-inferior and well tolerated compared to soybean formulations.

Abstract

Limited evidence exists to precisely estimate efficacy and safety differences between parenteral nutrition (PN) prepared using olive-oil-based three-chamber bags (3CBs) and soybean-oil-based compounded bags (CoBs) in hospitalized adult patients. We designed a multicenter, randomized, prospective, open-label, noninferiority protocol to compare the efficacy, safety, and distribution of olive-oil-based 3CBs and soybean-oil-based CoB formulations in adult Chinese patients requiring PN during surgical intervention. Subjects were randomized to receive either one of the study treatments using an interactive voice or web-based recognition system in accordance with the randomization code. Randomization was further stratified based on the study site and surgical category. Both treatment groups received similar amounts of calories and protein. In addition, the two study treatments contained a similar composition of the amino-acid component. The only difference between the two PN formulations was the lipid constitution. The duration of administration of study treatments was a minimum of 5 days up to a maximum of 14 days after the surgical procedure. The primary efficacy endpoint was serum prealbumin levels on day 5 of the study. Noninferiority was proved if the anti-log of the lower bound of the 95% confidence interval (CI) of the treatment difference was at least 0.80. Other efficacy measures included treatment preparation time; duration to achieve tolerability of oral nutrition; associated infectious complications; length of hospitalization; and laboratory assessment of markers of nutrition, inflammation, metabolism, and oxidative stress. A total of 458 patients were enrolled in the study. The results showed that olive-oil-based 3CBs were non-inferior to soybean-based CoBs, besides being well tolerated. The infection rate was found to be significantly lower in the olive-oil-based 3CB group. Thus, this study may be used as a reference for future research on lipid emulsion and 3CBs.

Introduction

Parenteral nutrition is an essential component of overall therapy for a wide spectrum of indications, such as major gastrointestinal surgery, transient enteral intolerance, severe burns, coma; or for use in critically ill patients. Improvements in intravenous (IV) nutritional formulations and knowledge advancement regarding the implementation of therapy allow the safe and clinically efficacious administration of IV nutrition. These characteristics are particularly important in a metabolically stressed patient¹.

Parenteral nutrition is commonly administered to patients by mixing nutrients that are compounded in the hospital pharmacy. Compounding total parenteral nutrition solutions from individual components is a multi-step, time-intensive process associated with a greater risk of human error. Recently, triple-chamber bag (3CB) systems have been developed in which individual components are separated by nonpermanent breakable seals. The contents of a 3CB include a glucose solution, an amino-acid solution, a lipid emulsion, with or without electrolytes. Prior to administration, the seal separating the various components of the 3CB is broken, enabling the components of the chambers to be admixed. The advantages offered by the 3CB includes increased physio-chemical shelf life of components, reduction the extent of contamination during preparation, and cutting down on the steps required in the preparation of a PN product².

Lipid emulsion is an important ingredient in a PN formula; it can produce different clinical effects, depending upon the constituent fatty acids. Soybean-oil-based lipid emulsions primarily consist of long-chain linoleic acid (ω-6 polyunsaturated fatty acid [ω-6 PUFA]), which is mainly proinflammatory. Experimental data suggest that ω-6 PUFA-rich lipid emulsions may amplify the inflammatory response during stress and traumatic conditions, as well as increasing the infection rate³. On the other hand, olive-oil-based lipid emulsions, which consist of long-chain oleic acid (ω-9 monounsaturated fatty acids, [ω-9 MUFAs]), have a neutral response on the immune system^3,4. Substituting soybean-oil-based ω-6 PUFAs with olive-oil-based ω-9 MUFAs can make the PN safe and further widen its clinical application^5,6. However, there are limited clinical data in this connection.

Therefore, the present study aims to evaluate the rate of infections in two different lipid emulsions that varied in the content of linoleic acid, in addition to having the primary objective of assessing the safety and efficacy of 3CBs compared to CoBs for delivering PN. The assessment was carried out in adult hospitalized patients scheduled to undergo surgery for whom enteral nutrition was either not possible, inadequate, or inadvisable.

Protocol

For this prospective, randomized, multicenter, active-controlled, parallel-group investigational trial, the Ethics Committees of Shanghai Sixth People’s Hospital approved the study protocol.

1. Patient recruitment and enrollment

1. Recruit patients as per the inclusion criteria specified in the protocol. Seek informed consent from patients and perform screening assessments not more than 3 days prior to the scheduled surgery.
2. Randomize enrolled subjects to one of the two study treatments (olive-oil-based 3CBsor soybean-oil-based CoBs), based on the randomization schedule.
   1. Randomize subjects undergoing surgery who were not scheduled for preoperative PN after a surgical procedure (Figure 1). Randomize subjects undergoing surgery and who were scheduled for preoperative PN prior to the surgery (Figure 2). Randomize subjects who were not scheduled to undergo surgery if they meet the enrollment criteria (Figure 3).
   2. Do not blind the data management personnel, biostatistician, and/or the personnel at the central laboratory for the assignment of study treatment.
3. Unblind the designated pharmacist for the preparation of the study treatment. Enter the blinded data into the database. Reveal the treatment group assignments after the database lock.
   ​NOTE: For this study, the study treatment assignment was delegated to the site pharmacist.
4. Perform the allocation of patient numbers using an interactive voice-recognition system/interactive web-based recognition system (IVRS/IWRS) according to the randomization code contained in the randomization list.
   1. Stratify randomization by study site and surgical category (no surgery, medium-complexity, and high-complexity, i.e. each type of surgery is categorized based on the complexity and the length of surgery) within each study site. In addition, specify the block size in the randomization code algorithm.

2. Study population

1. Inclusion criteria
   1. Enroll subjects into the study if all the following criteria are met:
      1. Ensure that the subject is male or female aged 18 to 80 years.
      2. Ensure that the subject is inpatient but hospitalized for fewer than 14 days prior to enrollment in the study.
      3. Ensure that the subject requires PN because enteral nutrition was not feasible, inadequate, or inadvisable
      4. Ensure that the subject is capable of completing at least 5 days of study treatment and having a functional visible peripheral vein for IV delivery of PN.
2. Exclusion criteria
   1. Exclude subjects from the study if any of the following criteria are met:
      1. Exclude if the patient has a life expectancy of fewer than 6 days from the start of study treatment, as determined by the investigator.
      2. Exclude if the patient has established hypersensitivity to the individual constituents of any of the study treatments.
      3. Exclude if the patient has used forbidden medications (e.g., glucocorticosteroids or antitumor chemotherapeutic agents) within 30 days prior to enrollment in the study.
      4. Exclude patients with a confirmed clinically relevant serious condition that prevents inclusion in the study (e.g., congestive heart failure with New York Heart Association class IV) or severe renal insufficiency without adequate compensation (e.g., hemofiltration, hemodialysis, or peritoneal dialysis), etc. or known chronic active hepatitis, alanine aminotransferase (ALT) >4x upper limit of normal (ULN), aspartate aminotransferase (AST) >4x ULN; total serum bilirubin >2x ULN; history of human immunodeficiency virus infection
      5. Exclude patients with confirmed inborn abnormalities related to the metabolism of amino acids (e.g., phenylketonuria, maple syrup urine disease, homocystinuria, or tyrosinemia, etc.), severe dyslipidemia with triglyceride level >2x ULN or >4.52 mM (>400 mg/dL).
      6. Exclude patients with severe hyperglycemia; serum glucose levels >20 mM (>360 mg/dL); and with clinically relevant abnormalities of plasma electrolytes, such as sodium (<130 mM or >150 mM), potassium (<3.0 mM or >5.5 mM), magnesium (<0.70 mM or >1.10 mM), calcium (<2.0 mM or >3.0 mM), or phosphorus (<0.96 mM or >1.62 mM).
      7. Exclude pregnant and lactating patients.
      8. Exclude patients previously enrolled in the current study, or who participated in a study of any investigational drug or device concurrently or within 30 days before enrollment in this study.
      9. Exclude for any reason, as per the investigator’s opinion, that renders the subject unsuitable for the trial.
3. Removal of patients from therapy or assessment
   1. Discontinuation of study treatment/early release from study
      1. Exclude patients who do not continue to meet the inclusion and exclusion criteria after surgery (assessed either in the recovery room or just after transfer to the surgical ward).
      2. Exclude and consider the patient discontinued if any enrolled patient who, continued the study after surgery, and for whom study treatment was prematurely terminated (i.e., completion of <5 full days of post-surgery study treatment).
   2. Withdrawal from study
      1. Withdraw the patient if the patient did not continue to fulfill the inclusion or exclusion criteria.
      2. Withdraw the patient if the patient experienced an adverse event (AE) or developed an inter-current illness, condition, or procedural complication that would interfere with continued participation
      3. Withdraw the patient if the patient voluntarily withdrew consent/authorization for the study
      4. Withdraw the patient if the patient was found to be in violation of the protocol and for whom the physician deemed it in their best medical interests to terminate involvement in the study

3. Method and clinical parameters

1. Efficacy Assessments
   1. Assess the primary efficacy outcome measure of the serum prealbumin level on day 5.
      NOTE: Secondary efficacy parameters included:
      1. Time for preparation of the study treatment (Table 1)
      2. Duration to achieve tolerability of oral nutrition
      3. Infectious complication
      4. Length of hospitalization
      5. Nutrition markers: Albumin and fatty acids (including linoleic, oleic acid, arachidonic acid, and eicosapentaenoic acid)
      6. Infection and inflammatory markers: Including procalcitonin, C-reactive protein, interleukin-6, and intercellular adhesion molecule-1
      7. Oxidative stress markers: Including malondialdehyde and F2-isoprostane
      8. Metabolism markers: Including urine markers of metabolism (urinary urea nitrogen, urinary 3-methylhistidine); hormonal markers of metabolism (thyroid panel, cortisol, growth hormone, insulin-like growth factor-1 [IGF-1], and testosterone)
   2. Draw venous blood via a peripheral vein in a contralateral appendage from the peripheral IV study treatment administration at the time points indicated in the schedule of assessment (Table 1).
   3. Transfer the samples to a central laboratory for analysis of efficacy parameters. Use EDTA anticoagulant tubes for the hematology test. Use common serum tubes which are free of additives for the serum biochemical and serological tests.
   4. Collect 2-3 mL of blood per sample. If the test was performed 4 hours after collection, store the blood in the 4 °C refrigerator.
   5. Collect urine over a 6-hour period, according to the schedule of assessment (Table 1). Record the collected volume of the urine for the applicable treatment day and store in the 4 °C refrigerator. Take an aliquot from the urine collection and transfer it to a central laboratory for analysis of efficacy parameters.
2. Safety assessments
   NOTE: The safety assessments in this study included:
   1. Adverse events and SAEs
   2. Vital sign assessment and physical examination findings, including body weight and injection-site rating by the investigator
   3. Clinical laboratory assessments: Hematology, serum chemistry, urinalysis, and other required laboratory assessments by the investigator

4. Study treatments

1. Dosage Forms and Administration
   NOTE: For this study, the treatments were intended to provide 25 kilocalories per kilogram per day (kcal/kg/day) using a PN admixture that contained 910 kcal/1.5 L, with a dextrose-to-lipid ratio of 62:38 and 5.4 grams (g) nitrogen/1.5 L. The study treatment was delivered over 12 to 22 hours.
   1. For Treatment A (test treatment) which comprises olive-oil-based 3CBs, use dextrose (D-glucose) solution (final mixed concentration 80 g/L) with calcium (final mixed concentration 2 mmol/L); a middle chamber that contains a solution of 15 amino acids (final mixed concentration 22 g/L), with electrolytes including sodium (final mixed concentration 21 mmol/L),potassium (final mixed concentration 16 mmol/L), magnesium(final mixed concentration 2.2 mmol/L), and phosphate (final mixed concentration 8.5 mmol/L); and a smaller outer chamber that contains a lipid emulsion comprising 80 % olive oil and 20 % soybean oil (final mixed concentration 20 g/L).
   2. For Treatment B (control treatment), use a compounded ternary PN admixture that has the same volume, energy, nitrogen and dextrose-to-lipid ratio as Treatment A. It comprises soybean-oil based CoBs, compound amino acid, and intralipid compounded as a 1.5-L admixture in the pharmacy.
   3. Give each research site a table containing the exact composition of different weights to ensure the consistency of prescriptions. Electrolytes, vitamins, minerals, and trace elements were allowed to be prescribed for addition to either treatment group according to the clinical requirement of different patients.
   4. Administer the treatments through a peripheral IV catheter via a control pump. If the infusion is not possible or inadvisable via peripheral IV due to the integrity of the peripheral vein, infuse the study treatment via a peripherally inserted central catheter or a central IV line. Increase the flow rate gradually during the first hour.
   5. Provide a daily volume of 46.6 mL/h and limit the administer duration between 12-22 h. Gradually increase the flow rate during the first hour (50-100 mL/h at the first hour). Adjust the administration rate considering the dose being administered, the daily volume intake, and the duration of the infusion. Do not increase the rate of intake over 150 mL/h.
   6. Administer the treatments for a minimum of 5 days up to 14 days. On days 1 through 5, administer only the study treatment (i.e., PN). On day 6 and until the end of the study period, allow the addition of liquid oral nutrition to the study treatment in order to meet the calculated daily nutrition requirements.
   7. Stop the study treatment once the subject receives at least 80% of the calculated daily nutrition requirements by the administered liquid oral nutrition or the completion of day-14 study treatment, whichever comes first.
   8. Terminate treatment for patients who met the discontinuation or withdrawal criteria. Upon completion or termination of treatment, perform the end-of-treatment procedures for subjects.
2. Contraindicated medications and therapies
   1. Do not administer additional lipids or amino acids during the clinical trial (from screening through completion of the study treatment period, inclusive), to the study subjects. Do not allow the use of glucocorticosteroids within 30 days prior to enrollment.
   2. Administer glucocorticosteroids during the clinical trial (from enrollment through completion of the study treatment period, inclusive) only if medically necessary. Similarly, do not allow the use of antitumor chemotherapeutic agents, whether for treatment of cancer or for other diseases, within 30 days prior to enrollment.
   3. Administer antitumor chemotherapeutic agents during the clinical trial (from enrollment through completion of the study treatment period, inclusive) only if medically necessary. Record the administered concomitant medications on the case report forms (CRFs).
   4. Allow the use of dextrose-containing IV solutions for maintenance of fluid status from randomization until the study treatment is discontinued.
3. Acceptable medications and therapies
   1. Dilute the medications that need to be delivered via the IV route in saline-based solutions; however, limit the volume to 50 mL per medication if a medication is diluted in a dextrose-containing IV solution.
   2. Record these medications on the CRFs, including details about the type of IV solution used as the diluent. Administer dextrose solutions for the treatment of hypoglycemia, and record details on the CRFs.
   3. Do not restrict the use of other concomitant therapies (e.g., drugs, blood and plasma transfusion products, albumin, and other treatments) if these treatments are commercially available. Maintain a detailed record (including dose and duration) of medical treatments, including vitamins, electrolytes, and trace elements.

5. Statistical methods

NOTE: The assumption for the sample size calculation in this noninferiority trial was made such that the true ratio was 1, the coefficient of variance was 0.5, and the noninferiority margin was 20 %. A sample size of 98 patients per study treatment came out of all the assumptions, providing 90% power to claim noninferiority between groups for the primary efficacy endpoint (i.e., prealbumin levels on day 5).

1. To achieve a total of 400 subjects, required for primary efficacy assessment, randomize approximately 500 subjects. Determine the sample size based on the assumption that up to 20% of the randomized subjects would drop out of the study before the day-5 analysis.
2. As the intention-to-treat (ITT) population is the primary analysis population for demographic and other baseline characteristics, draw statistical inferences for the 2 treatment groups.
3. Use analysis of variance (ANOVA) to compare continuous data, and use the chi-square test/Fisher's Exact test to compare categorical data. In the case of significant imbalances for certain variables, review the results using covariate adjustments and subgroup analyses.
4. Use the analysis of covariance (ANCOVA) model to analyze the log-transformed primary efficacy endpoint. For the stated model, treatment and study site were the main effects and baseline serum prealbumin was the covariate.
5. Test the interaction between the 2 main effects and remove from the model if it was statistically insignificant. Determine the least squared geometric mean ratio of the treatment difference for olive-oil-based 3CBs to soybean-oil-based CoBs, as well as the 2-sided 95% CI.
   NOTE: The primary comparison hypothesis was that olive-oil-based 3CBs were non-inferior to soybean-oil-based CoBs for increasing or maintaining serum prealbumin levels. Noninferiority was ascertained if the anti-log of the lower limit of the 95 % CI of treatment difference was at least 0.80.
6. Use the Kruskal-Wallis test to analyze differences between treatment groups to determine the preparation time of the study treatment (days 1 to 5).
7. Use the Kaplan-Meier method to summarize the time required to achieve tolerability of oral nutrition, and the parameter was compared using a log-rank test. Fatty acids, such as linoleic and oleic acids; infection and inflammatory markers; markers of oxidative stress; markers of nutrition; and markers of metabolism were analyzed in the same fashion as the primary endpoint - using the ANCOVA model with the treatment and study site as the main effects. The least squared geometric mean ratio of the treatment differences for olive-oil-based 3CBs to soybean-oil-based CoBs, as well as the 2-sided 95% CI, was determined.
8. For the safety variables, make statistical comparisons between the two treatment groups. Use the ANOVA method to compare continuous data; use the chi-square test/Fisher's exact test to compare categorical data. Use the Cochran-Mantel-Haenszel test with modified ridit scores to compare the relationship and severity of AEs.
9. Complete statistical analyses using statistical analysis software. A p-value <0.05 was considered to be statistically significant.

Results

Patient Disposition
Out of the 480 patients who gave their consent, a total of 458 patients were enrolled and randomized in the study. The ITT population included all randomized patients, of whom 226 constituted the test group and 232 the control group. The safety population included a total of 453 patients, of whom 222 belonged to the test group and 231 to the control group. The modified intention-to-treat (mITT) population comprised a total of 443 patients, of whom 219 were in the test group and 22...

Discussion

The randomized clinical trial protocol is a multi-purpose document. It not only provides guidance for the conduct of trial to the investigators, but it also makes ethics committees and institutional review boards aware of appropriate measures adopted to protect participants’ safety and interests. A proper design is crucial for the success of a clinical trial. It is often noted that the design of a trial is connected with its successes/failures⁸.

Additionally, sele...