The study was sponsored and funded by Baxter Healthcare, manufacturer/Licensee of OliClinomel N4. ProScribe was used in compliance with global guidelines for good publication practice.

For this prospective, randomized, multicenter, active-controlled, parallel-group investigational trial, the Ethics Committees of Shanghai Sixth People&#8217;s Hospital approved the study protocol.
1. Patient recruitment and enrollment
<ol>
	<li>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.</li>
	<li>Randomize enrolled subjects to one of the two study treatments (olive-oil-based 3CBsor soybean-oil-based CoBs), based on the randomization schedule.
	<ol>
		<li>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).</li>
		<li>Do not blind the data management personnel, biostatistician, and/or the personnel at the central laboratory for the assignment of study treatment.</li>
	</ol>
	</li>
	<li>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. 
	&#8203;NOTE: For this study, the study treatment assignment was delegated to the site pharmacist.</li>
	<li>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.
	<ol>
		<li>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.</li>
	</ol>
	</li>
</ol>
2. Study population
<ol>
	<li>Inclusion criteria
	<ol>
		<li>Enroll subjects into the study if all the following criteria are met:
		<ol>
			<li>Ensure that the subject is male or female aged 18 to 80 years.</li>
			<li>Ensure that the subject is inpatient but hospitalized for fewer than 14 days prior to enrollment in the study.</li>
			<li>Ensure that the subject requires PN because enteral nutrition was not feasible, inadequate, or inadvisable</li>
			<li>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.</li>
		</ol>
		</li>
	</ol>
	</li>
	<li>Exclusion criteria
	<ol>
		<li>Exclude subjects from the study if any of the following criteria are met:
		<ol>
			<li>Exclude if the patient has a life expectancy of fewer than 6 days from the start of study treatment, as determined by the investigator.</li>
			<li>Exclude if the patient has established hypersensitivity to the individual constituents of any of the study treatments.</li>
			<li>Exclude if the patient has used forbidden medications (e.g., glucocorticosteroids or antitumor chemotherapeutic agents) within 30 days prior to enrollment in the study.</li>
			<li>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) &#62;4x upper limit of normal (ULN), aspartate aminotransferase (AST) &#62;4x ULN; total serum bilirubin &#62;2x ULN; history of human immunodeficiency virus infection</li>
			<li>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 &#62;2x ULN or &#62;4.52 mM (&#62;400 mg/dL).</li>
			<li>Exclude patients with severe hyperglycemia; serum glucose levels &#62;20 mM (&#62;360 mg/dL); and with clinically relevant abnormalities of plasma electrolytes, such as sodium (&#60;130 mM or &#62;150 mM), potassium (&#60;3.0 mM or &#62;5.5 mM), magnesium (&#60;0.70 mM or &#62;1.10 mM), calcium (&#60;2.0 mM or &#62;3.0 mM), or phosphorus (&#60;0.96 mM or &#62;1.62 mM).</li>
			<li>Exclude pregnant and lactating patients.</li>
			<li>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.</li>
			<li>Exclude for any reason, as per the investigator&#8217;s opinion, that renders the subject unsuitable for the trial.</li>
		</ol>
		</li>
	</ol>
	</li>
	<li>Removal of patients from therapy or assessment
	<ol>
		<li>Discontinuation of study treatment/early release from study
		<ol>
			<li>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).</li>
			<li>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 &#60;5 full days of post-surgery study treatment).</li>
		</ol>
		</li>
		<li>Withdrawal from study
		<ol>
			<li>Withdraw the patient if the patient did not continue to fulfill the inclusion or exclusion criteria.</li>
			<li>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</li>
			<li>Withdraw the patient if the patient voluntarily withdrew consent/authorization for the study</li>
			<li>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</li>
		</ol>
		</li>
	</ol>
	</li>
</ol>
3. Method and clinical parameters
<ol>
	<li>Efficacy Assessments
	<ol>
		<li>Assess the primary efficacy outcome measure of the serum prealbumin level on day 5. 
		NOTE: Secondary efficacy parameters included:
		<ol>
			<li>Time for preparation of the study treatment (Table 1)</li>
			<li>Duration to achieve tolerability of oral nutrition</li>
			<li>Infectious complication</li>
			<li>Length of hospitalization</li>
			<li>Nutrition markers: Albumin and fatty acids (including linoleic, oleic acid, arachidonic acid, and eicosapentaenoic acid)</li>
			<li>Infection and inflammatory markers: Including procalcitonin, C-reactive protein, interleukin-6, and intercellular adhesion molecule-1</li>
			<li>Oxidative stress markers: Including malondialdehyde and F2-isoprostane</li>
			<li>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)</li>
		</ol>
		</li>
		<li>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).</li>
		<li>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.</li>
		<li>Collect 2-3 mL of blood per sample. If the test was performed 4 hours after collection, store the blood in the 4 &#176;C refrigerator.</li>
		<li>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 &#176;C refrigerator. Take an aliquot from the urine collection and transfer it to a central laboratory for analysis of efficacy parameters.</li>
	</ol>
	</li>
	<li>Safety assessments 
	NOTE: The safety assessments in this study included:
	<ol>
		<li>Adverse events and SAEs</li>
		<li>Vital sign assessment and physical examination findings, including body weight and injection-site rating by the investigator</li>
		<li>Clinical laboratory assessments: Hematology, serum chemistry, urinalysis, and other required laboratory assessments by the investigator</li>
	</ol>
	</li>
</ol>
4. Study treatments
<ol>
	<li>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.
	<ol>
		<li>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).</li>
		<li>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.</li>
		<li>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.</li>
		<li>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.</li>
		<li>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.</li>
		<li>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.</li>
		<li>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.</li>
		<li>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.</li>
	</ol>
	</li>
	<li>Contraindicated medications and therapies
	<ol>
		<li>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.</li>
		<li>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.</li>
		<li>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).</li>
		<li>Allow the use of dextrose-containing IV solutions for maintenance of fluid status from randomization until the study treatment is discontinued.</li>
	</ol>
	</li>
	<li>Acceptable medications and therapies
	<ol>
		<li>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.</li>
		<li>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.</li>
		<li>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.</li>
	</ol>
	</li>
</ol>
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).
<ol>
	<li>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.</li>
	<li>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.</li>
	<li>Use analysis of variance (ANOVA) to compare continuous data, and use the chi-square test/Fisher&#39;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.</li>
	<li>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.</li>
	<li>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.</li>
	<li>Use the Kruskal-Wallis test to analyze differences between treatment groups to determine the preparation time of the study treatment (days 1 to 5).</li>
	<li>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.</li>
	<li>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&#39;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.</li>
	<li>Complete statistical analyses using statistical analysis software. A p-value &#60;0.05 was considered to be statistically significant.</li>
</ol>

<ol>
	<li>Jeejeebhoy, K. N. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Parenteral+nutrition+in+the+intensive+care+unit.">Parenteral nutrition in the intensive care unit.</a> Nutrition Reviews. 70 (11), 623-630 (2012).</li><li>Simmer, K., Rakshasbhuvankar, A., Deshpande, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Standardised+parenteral+nutrition.">Standardised parenteral nutrition.</a> Nutrients. 5 (4), 1058-1070 (2013).</li><li>Vanek, V. W., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A.S.P.E.N.+position+paper:+Clinical+role+for+alternative+intravenous+fat+emulsions.">A.S.P.E.N. position paper: Clinical role for alternative intravenous fat emulsions.</a> Nutrition in Clinical Practice. 27 (2), 150-192 (2012).</li><li>Singer, P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=ESPEN+guidelines+on+parenteral+nutrition:+Intensive+care.">ESPEN guidelines on parenteral nutrition: Intensive care.</a> Clinical Nutrition. 28 (4), 387-400 (2009).</li><li>Calder, P. C., Jensen, G. L., Koletzko, B. V., Singer, P., Wanten, G. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Lipid+emulsions+in+parenteral+nutrition+of+intensive+care+patients:+Current+thinking+and+future+directions.">Lipid emulsions in parenteral nutrition of intensive care patients: Current thinking and future directions.</a> Intensive Care Medicine. 36 (5), 735-749 (2010).</li><li>Umpierrez, G. E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+double-blind,+randomized+clinical+trial+comparing+soybean+oil-based+versus+olive+oil-based+lipid+emulsions+in+adult+medical-surgical+intensive+care+unit+patients+requiring+parenteral+nutrition.">A double-blind, randomized clinical trial comparing soybean oil-based versus olive oil-based lipid emulsions in adult medical-surgical intensive care unit patients requiring parenteral nutrition.</a> Critical Care Medicine. 40 (6), 1792-1798 (2012).</li><li>Jia, Z. Y., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Safety+and+efficacy+of+an+olive+oil-based+triple-chamber+bag+for+parenteral+nutrition:+A+prospective,+randomized,+multi-center+clinical+trial+in+China.">Safety and efficacy of an olive oil-based triple-chamber bag for parenteral nutrition: A prospective, randomized, multi-center clinical trial in China.</a> Nutrition Journal. 14, 119 (2015).</li><li>Tetzlaff, J. M., Moher, D., Chan, A. W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Developing+a+guideline+for+clinical+trial+protocol+content:+Delphi+consensus+survey.">Developing a guideline for clinical trial protocol content: Delphi consensus survey.</a> Trials. 24 (13), 176 (2012).</li><li>Glasser, S. P., Howard, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Clinical+trial+design+issues:+At+least+10+things+you+should+look+for+in+clinical+trials.">Clinical trial design issues: At least 10 things you should look for in clinical trials.</a> Journal of Clinical Pharmacology. 46 (10), 1106-1115 (2006).</li><li>Ruikar, V. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Interactive+voice/Web+response+system+in+clinical+research.">Interactive voice/Web response system in clinical research.</a> Perspectives in Clinical Research. 7 (1), 15-20 (2016).</li><li>Kulkarni, P. M., Meadows, E. 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The authors have nothing to disclose.

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&#8217; 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...

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 (&#969;-6 polyunsaturated fatty acid [&#969;-6 PUFA]), which is mainly proinflammatory. Experimental data suggest that &#969;-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 (&#969;-9 monounsaturated fatty acids, [&#969;-9 MUFAs]), have a neutral response on the immune system3,4. Substituting soybean-oil-based &#969;-6 PUFAs with olive-oil-based &#969;-9 MUFAs can make the PN safe and further widen its clinical application5,6. 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.

a clinical trial assessing the safety, efficacy, and delivery of olive-oil-based three-chamber bags for parenteral nutrition

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.

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 ...

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

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.

Limited evidence exists to precisely estimate efficacy and safety differences between parenteral nutrition (PN) prepared using olive-oil-based ...

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10.6K Görüntüleme.  Shanghai Jiao Tong University Affiliated Sixth People's Hospital. Bu protokol, gelecekteki birden fazla merkez, odacıklı oda-çanta için bir şablon sağladı. Protokol, gelecekteki araştırmalar için pratik bir model sağlamak için denge ve etkinlik, klinik manevra kabiliyeti ile imzalandı. Bu yöntem, özellikle üçlü oda torbaları için, ebeveynlik ve tıbbi beslenme çalışmaları için bir referans olarak kullanılabilir.Tuhaflığı tasarlamak ve uygulamak zordur. Benzer bir protokole başvuru belki de bu alana ilk kez giren biri iç...

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

Testing the Efficacy of Pharmacological Agents in a Pericardial Target Delivery Model in the Swine

To date, many pharmacological agents used to treat or prevent arrhythmias in open-heart cases create undesired systemic side effects. For example, antiarrhythmic drugs administered intravenously can produce drops in systemic pressure in the already compromised cardiac patient. While performing open-heart procedures, surgeons will often either create a small port or form a pericardial cradle to create suitable fields for operation. This access yields opportunities for target pharmacological delivery (antiarrhythmic or ischemic preconditioning agents) directly to the myocardial tissue without undesired side effects.
We have developed a swine model for testing pharmacological agents for target delivery within the pericardial fluid. While fully anesthetized, each animal was instrumented with a Swan-Ganz catheter as well as left and right ventricle pressure catheters, and pacing leads were placed in the right atrial appendage and the right ventricle. A medial sternotomy was then performed and a pericardial access cradle was created; a plunge pacing lead was placed in the left atrial appendage and a bipolar pacing lead was placed in the left ventricle. Utilizing a programmer and a cardiac mapping system, the refractory period of the atrioventricular node (AVN), atria and ventricles was determined. In addition, atrial fibrillation (AF) induction was produced utilizing a Grass stimulator and time in AF was observed. These measurements were performed prior to treatment, as well as 30 min&#160;and 60 min&#160;after pericardial treatment. Additional time points were added for selected studies. The heart was then cardiopleged and reanimated in a four chamber working mode. Pressure measurements and function were recorded for 1 hr after reanimation. This treatment strategy model allowed us to observe the effects of pharmacological agents that may decrease the incidence of cardiac arrhythmias and/or ischemic damage, during and after open-heart surgery.

We have developed a swine model for the target delivery of pharmacological agents within the pericardial space/fluid. Using this approach, the relative benefits of administered agents on induced atrial fibrillation, relative refractory periods and/or ischemic protection can be investigated.

To date, many pharmacological agents used to treat or prevent arrhythmias in open-heart cases create undesired systemic side effects. For example, ...

Phosphorus-31 Magnetic Resonance Spectroscopy: A Tool for Measuring In Vivo Mitochondrial Oxidative Phosphorylation Capacity in Human Skeletal Muscle

Skeletal muscle mitochondrial oxidative phosphorylation (OXPHOS) capacity, which is critically important in health and disease, can be measured in vivo and noninvasively in humans via phosphorus-31 magnetic resonance spectroscopy (31PMRS). However, the approach has not been widely adopted in translational and clinical research, with variations in methodology and limited guidance from the literature. Increased optimization, standardization, and dissemination of methods for in vivo 31PMRS would facilitate the development of targeted therapies to improve OXPHOS capacity and could ultimately favorably impact cardiovascular health. 31PMRS produces a noninvasive, in vivo measure of OXPHOS capacity in human skeletal muscle, as opposed to alternative measures obtained from explanted and potentially altered mitochondria via muscle biopsy. It relies upon only modest additional instrumentation beyond what is already in place on magnetic resonance scanners available for clinical and translational research at most institutions. In this work, we outline a method to measure in vivo skeletal muscle OXPHOS. The technique is demonstrated using a 1.5 Tesla whole-body MR scanner equipped with the suitable hardware and software for 31PMRS, and we explain a simple and robust protocol for in-magnet resistive exercise to rapidly fatigue the quadriceps muscle. Reproducibility and feasibility are demonstrated in volunteers as well as subjects over a wide range of functional capacities.

Phosphorus-31 Magnetic Resonance Spectroscopy: A Tool for Measuring In Vivo Mitochondrial Oxidative Phosphorylation Capacity in Human Skeletal Muscle

This work demonstrates the feasibility of an in vivo phosphorus-31 magnetic resonance spectroscopy (31PMRS) technique to quantify mitochondrial oxidative phosphorylation (OXPHOS) capacity in human skeletal muscle.

Skeletal muscle mitochondrial oxidative phosphorylation (OXPHOS) capacity, which is critically important in health and disease, can be measured in vivo ...

Optimized LC-MS/MS Method for the High-throughput Analysis of Clinical Samples of Ivacaftor, Its Major Metabolites, and Lumacaftor in Biological Fluids of Cystic Fibrosis Patients

Defects in the cystic fibrosis trans-membrane conductance regulator (CFTR) are the cause of cystic fibrosis (CF), a disease with life-threatening pulmonary manifestations. Ivacaftor (IVA) and ivacaftor-lumacaftor (LUMA) combination are two new breakthrough CF drugs that directly modulate the activity and trafficking of the defective CFTR-protein. However, there is still a dearth of understanding on pharmacokinetic/pharmacodynamic parameters and the pharmacology of ivacaftor and lumacaftor. The HPLC-MS technique for the simultaneous analysis of the concentrations of ivacaftor, hydroxymethyl-ivacaftor, ivacaftor-carboxylate, and lumacaftor in biological fluids in patients receiving standard ivacaftor or ivacaftor-lumacaftor combination therapy has previously been developed by our group and partially validated to FDA standards. However, to allow the high-throughput analysis of a larger number of patient samples, our group has optimized the reported method through the use of a smaller pore size reverse-phase chromatography column (2.6 &#181;m, C8 100 &#197;; 50 x 2.1 mm) and a gradient solvent system (0-1 min: 40% B; 1-2 min: 40-70% B; 2-2.7 min: held at 70% B; 2.7-2.8 min: 70-90% B; 2.8-4.0 min: 90% B washing; 4.0-4.1 min: 90-40% B; 4.1-6.0 min: held at 40% B) instead of an isocratic elution. The goal of this study was to reduce the HPLC-MS analysis time per sample dramatically from ~15 min to only 6 min per sample, which is essential for the analysis of a large amount of patient samples. This expedient method will be of considerable utility for studies into the exposure-response relationships of these breakthrough CF drugs.

Ivacaftor and ivacaftor-lumacaftor combination are two new CF drugs. However, there is still a dearth of understanding on their PK/PD and pharmacology. We present an optimized HPLC-MS technique for the simultaneous analysis of ivacaftor and its major metabolites, and lumacaftor.

Defects in the cystic fibrosis trans-membrane conductance regulator (CFTR) are the cause of cystic fibrosis (CF), a disease with life-threatening ...

Preparation of Peripheral Blood Mononuclear Cell Pellets and Plasma from a Single Blood Draw at Clinical Trial Sites for Biomarker Analysis

Analysis of biomarkers in peripheral blood is becoming increasingly important in clinical trials to establish proof of mechanism to evaluate effects of treatment, and help guide dose and schedule setting of therapeutics. From a single blood draw, peripheral blood mononuclear cells can be isolated and processed to analyze and quantify protein markers, and plasma samples can be used for the analysis of circulating tumor DNA, cytokines, and plasma metabolomics. Longitudinal samples from a treatment provide information on the evolution of a given protein marker, the mutational status and immunological landscape of the patient. This can only be achieved if the processing of the peripheral blood is carried out effectively in clinical sites and samples are properly preserved from the bedside to bench. Here, we present an optimized general-purpose protocol that can be implemented at clinical sites for obtaining PBMC pellets and plasma samples in multi-center clinical trials, that will enable clinical professionals in hospital laboratories to successfully provide high quality samples, regardless of their level of technical expertise. Alternative protocol variations are also presented that are optimized for more specific downstream analytical methods. We apply this protocol for studying protein biomarkers against DNA damage response (DDR) on X-ray irradiated blood to demonstrate the suitability of the approach in oncology settings where DDR drugs and/or radiotherapy have been practiced as well as in preclinical stages where mechanistic hypothesis testing is required.

This protocol details clinically implementable preparation of high quality PBMC and plasma biosamples at the clinical trial site that can be used for translational biomarker analysis.

Analysis of biomarkers in peripheral blood is becoming increasingly important in clinical trials to establish proof of mechanism to evaluate effects of ...

Direct Drug Delivery to Kidney via the Renal Artery

There is a need for directed injections to enable increased and specific renal exposure for efficient evaluation of drug targets in the renal research field. Accumulation of drugs in certain organs may give rise to adverse and unwanted effects, depending on the nature of injectate. To minimize spillover and/or accumulation in other tissues, the herein described method directs the formulation into the renal artery bloodstream by inserting a catheter in the infra renal aorta, just below where it branches into the renal artery, resulting in the kidney as first reached organ and distributing of formulation throughout the kidney.
This manuscript provides a detailed description of the method, as well as its challenges and difficulties. It guides the experimenter to become skillful with this type of microsurgery that requires accuracy under sterile conditions. Speed is crucial for minimizing the ischemia and practicing the procedure will increase the chance of successful injections without adverse effects. By modulating the time between injection and reperfusion as well as the injected volume, the risk of spillover to other organs is mitigated. 
Note that this technique is suitable for single dosing strategies.

This manuscript describes a method for targeted delivery to a single kidney via a catheter placed in the infrarenal abdominal aorta in the mouse.

There is a need for directed injections to enable increased and specific renal exposure for efficient evaluation of drug targets in the renal research ...

Predicting Prognosis in Acute Heart Failure Using Phase Angle &amp; BIVA Z-Scores

Clinical Application of Phase Angle and BIVA Z-Score Analyses in Patients Admitted to an Emergency Department with Acute Heart Failure

Acute heart failure is characterized by neurohormonal activation, which leads to sodium and water retention and causes alterations in body composition, such as increased body fluid congestion or systemic congestion. This condition is one of the most common reasons for hospital admission and has been associated with poor outcomes. The phase angle indirectly measures intracellular status, cellular integrity, vitality, and the distribution of spaces between intracellular and extracellular body water. This parameter has been found to be a predictor of health status and an indicator of survival and other clinical outcomes. In addition, phase angle values of &lt;4.8&#176; upon admission were associated with higher mortality in patients with acute heart failure. However, low phase angle values may be due to alterations-such as the shifting of fluids from an intracellular body water (ICW) compartment to an ECW (extracellular body water) compartment and a concurrent decrease in body-cell mass (which can reflect malnutrition)-that are present in heart failure. Thus, a low phase angle may be due to overhydration and/or malnutrition. BIVA provides additional information about the body-cell mass and congestion status with a graphical vector (R-Xc graph). In addition, a BIVA Z-score analysis (the number of standard deviations from the mean value of the reference group) that has the same pattern as that of the ellipses for the percentiles on the original R-Xc graph can be used to detect changes in soft-tissue mass or tissue hydration and can help researchers compare changes in different study populations. This protocol explains how to obtain and interpret phase angle values and BIVA Z-score analyses, their clinical applicability, and their usefulness as a predictive marker for the prognosis of a 90-day event in patients admitted to an emergency department with acute heart failure.

Author Spotlight: Unveiling Prognostic Indicators in Heart Failure - The Role of Phase Angle and Bioelectrical Impedance Analysis 

In this protocol, we explain how to obtain and interpret phase angle values and bioelectrical impedance vectorial analysis (BIVA) Z-score obtained by bioelectrical impedance in patients with acute heart failure admitted to the Emergency Department and their clinical applicability as a predictive marker for the prognosis of a 90-day event.

Acute heart failure is characterized by neurohormonal activation, which leads to sodium and water retention and causes alterations in body composition, ...

Developing an Exercise Program for Rheumatoid Arthritis Patients

Evaluation of Changes in Hydration and Body Cell Mass with Bioelectrical Impedance Analysis after Exercise Program for Rheumatoid Arthritis Patients

Rheumatoid arthritis (RA) is a debilitating disease that can result in complications such as rheumatoid cachexia. While physical exercise has shown benefits for RA patients, its impact on hydration and body cell mass remains uncertain. The presence of pain, inflammation, and joint changes often restrict activity and make traditional body composition assessments unreliable due to altered hydration levels. Bioelectrical impedance is a commonly used method for estimating body composition, but it has limitations since it was primarily developed for the general population and does not consider changes in body composition. On the other hand, bioelectrical impedance vectorial analysis (BIVA) offers a more comprehensive approach. BIVA involves graphically interpreting resistance (R) and reactance (Xc), adjusted for height, to provide valuable information about hydration status and the integrity of the cell mass.
Twelve women with RA were included in this study. At the beginning of the study, hydration and body cell mass measurements were obtained using the BIVA method. Subsequently, the patients participated in a six-month dynamic exercise program encompassing cardiovascular capacity, strength, and coordination training. To evaluate changes in hydration and body cell mass, the differences in the R and Xc parameters, adjusted for height, were compared using BIVA confidence software. The results showed notable changes: resistance decreased after the exercise program, while reactance increased. BIVA, as a classification method, can effectively categorize patients into dehydration, overhydration, normal, athlete, thin, cachectic, and obese categories. This makes it a valuable tool for assessing RA patients, as it provides information independent of body weight or prediction equations. Overall, the implementation of BIVA in this study shed light on the effects of the exercise program on hydration and body cell mass in RA patients. Its advantages lie in its ability to provide comprehensive information and overcome the limitations of traditional body composition assessment methods.

Author Spotlight: Implementation of BIVA for Analyzing Disease Risk Factors in Patients with Low Body Cell Mass 

This protocol assesses alterations in hydration and body cell mass status using bioelectrical impedance vectorial analysis following a dynamic exercise program designed for patients with rheumatoid arthritis. The dynamic exercise program itself is detailed, highlighting its components focused on cardiovascular capacity, strength, and coordination. The protocol details steps, instruments, and limitations.

Rheumatoid arthritis (RA) is a debilitating disease that can result in complications such as rheumatoid cachexia. While physical exercise has shown ...

Therapeutic Efficacy of Small Needle Knife Therapy in Treating Frozen Shoulder

Clinical Efficacy of Small Needle Knife Therapy on Stage I-II Frozen Shoulder

Frozen shoulder is a kind of aseptic inflammatory disease of the shoulder caused by strain, trauma, and other reasons, resulting in shoulder joint pain and limited function. The protocol presented here demonstrates the operation of a small needle knife in treating frozen shoulders, including patient management, material preparation, positioning, operation, and postoperative care. The purpose of this protocol is to relieve the pain and functional limitations and improve the living ability of patients with frozen shoulders. In our study, 76 stage I-II frozen shoulder patients who met the inclusion criteria were randomly divided into a control group and a treatment group (n=38). Patients in the control group received functional exercise, while the treatment group received small needle knife therapy with functional exercise. The visual analogue scores (VAS), the Constant and Murley scores (CMS), and the thickness of the coracohumeral ligament (CHL) under ultrasound were evaluated. After small needle knife therapy, the VAS score was significantly lower in the treatment group (5.11 &plusmn; 0.89) than in the control group (5.49 &plusmn; 0.65; t=-2.065, p&lt;0.05); the CMS score was significantly higher in the treatment group (64.72 &plusmn; 4.78) than in the control group (60.97 &plusmn; 6.00; t=2.947, p&lt;0.05); the CHL thickness was significantly decreased in the treatment group (2.38 &plusmn; 0.36) than in the control group (2.57 &plusmn; 0.42; t=-2.117, p&lt;0.05). These results indicate that the small needle knife significantly relieved the pain symptoms, improved the shoulder function, reduced the CHL thickness, and improved the quality of life and, therefore, had significant therapeutic efficacy in stage I-II frozen shoulder patients.

Author Spotlight: Treating Frozen Shoulder with Small Needle Knife Therapy 

The protocol presented here describes the detailed operation method and proves the effectiveness of a small needle knife in the treatment of frozen shoulders.

Frozen shoulder is a kind of aseptic inflammatory disease of the shoulder caused by strain, trauma, and other reasons, resulting in shoulder joint pain ...

Assessing Strength Exercise Volume and Its Impact on Insulin Sensitivity in Obesity

Randomized Controlled Trial to Study the Acute Effects of Strength Exercise on Insulin Sensitivity in Obese Adults

An acute session of strength exercise (SE) ameliorates insulin sensitivity (IS) for several hours; however, the effects of SE volume (i.e., number of sets) have not been studied thoroughly. Although it is intuitive that some SE is better than none, and more is better than some for the improvement of IS, high-volume sessions might be challenging for diseased populations to complete, especially obese adults, for whom even a brisk walk can be challenging. This protocol details a randomized clinical trial to assess the acute effects of SE on IS in obese adults. The inclusion criteria are body mass index &#62;30 kg/m2, central obesity (waist circumference &#62;88 cm and &#62;102 cm for women and men, respectively), and age &#62;40 years. Participants will be familiarized with the SE (7 exercises targeting major muscle groups) and then will perform three sessions in a randomized order: session 1 - high-volume session (3 sets/exercise); session 2 - low-volume session (1 set/exercise); session 3 - control session (no exercise). Diet will be controlled the day before and on the day of the sessions. Sessions will be completed at night, and an oral glucose tolerance test will be performed the next morning, from which several indexes of IS will be derived, such as the area under the curve (AUC) of glucose and insulin, the Matsuda index, the Cederholm index, the muscle IS index, and the Gutt index. Based on pilot studies, we expect ~15% improvement in IS (insulin AUC, and Matsuda and Cederholm indexes) after the high-volume session, and ~8% improvement after the low-volume session compared to the control session. This study will benefit individuals who find high-volume SE sessions challenging but still aim to improve their IS by investing 1/3 of their time and effort.

Author Spotlight: Exploring the Impact of Reduced Resistance Exercise Volume on Metabolic Health 

This study describes a randomized controlled trial protocol aiming at assessing the acute effects of strength exercise volume on insulin sensitivity in obese individuals.

An acute session of strength exercise (SE) ameliorates insulin sensitivity (IS) for several hours; however, the effects of SE volume (i.e., number of ...

Assessing the Efficacy of Cranial Electrical Stimulation in Fibromyalgia

A Randomized, Sham-Controlled Trial of Cranial Electrical Stimulation for Fibromyalgia Pain and Physical Function, Using Brain Imaging Biomarkers

Fibromyalgia is a chronic pain syndrome that presents with a constellation of broad symptoms, including decreased physical function, fatigue, cognitive disturbances, and other somatic complaints. Available therapies are often insufficient in treating symptoms, with inadequate pain control commonly leading to opioid usage for attempted management. Cranial electrical stimulation (CES) is a promising non-pharmacologic treatment option for pain conditions that uses pulsed electrical current stimulation to modify&#160;brain function via transcutaneous electrodes. These neural mechanisms and the applications of CES in fibromyalgia symptom relief require further exploration.
A total of 50 participants from the Atlanta Veterans Affairs Healthcare System (VAHCS) diagnosed with fibromyalgia were enrolled and then block-randomized into either a placebo plus standard therapy or active CES plus standard therapy group. Baseline assessments were obtained prior to the start of treatment. Both interventions occurred over 12 weeks, and participants were assessed at 6 weeks and 12 weeks after treatment initiation. The primary outcome investigated whether pain and functional improvements occur with the application of CES. Additionally, baseline and follow-up resting state functional connectivity magnetic resonance imaging (rs-fcMRI) were obtained at the 6-week and 12-week time points to assess for clinical applications of neural connectivity biomarkers and the underlying neural associations related to treatment effects.
This is a randomized, placebo-controlled trial to determine the efficacy of CES for improving pain and function in fibromyalgia and further develop rs-fcMRI as a clinical tool to assess the neural correlates and mechanisms of chronic pain and analgesic response.

Author Spotlight: Methodologies and Advancements of Chronic Pain Management Research

The current study is a randomized, placebo-controlled trial to determine the efficacy of cranial electrical stimulation (CES) for improving pain and function in fibromyalgia and further develop resting functional connectivity magnetic resonance imaging (rs-fcMRI) as a clinical tool to assess the neural correlates and mechanisms of chronic pain and analgesic response.

Fibromyalgia is a chronic pain syndrome that presents with a constellation of broad symptoms, including decreased physical function, fatigue, cognitive ...