Observational Retrospective Analysis Assessing the Influence of Three-Chamber Bags Compared to Hospital Compounded Parenteral Nutrition Bags on Blood Stream Infections
Conditions: Parenteral Nutrition, Blood Stream Infection
Sponsor: Fresenius Kabi

Study Outline 3CBs-001-CNI  
page 1 of 5 Study Outline 3CB-001-CNI, Draft 0.7 2016-05-18  
Study title  
  
 
Observational retrospective analysis assessing the 
influence of three compartment bags (3CBs) 
compared to hospital compounded parenteral 
nutrition bags on blood stream infections  
Study number  
  
 
3CBs-001-CNI (CT.gov ID NCT03284398) 
Study rationale   
PN requirement  
Nutritional support is often needed in critically ill patients with 
parenteral nutrition (PN) required in approx. 15% [Ziegler 
2009]; in most patients requiring PN nutritional needs are met 
by standardized formulations recommended by European and 
US guidelines [Kochevar 2007, Singer 2009].  
  
PN types: compounding vs multichamber bags  
PN solutions are derived from   
  
manual compounding of bags in hospitals with or without 
the use of laminar-air-flow systems as all-in-one solutions   
 
industrial, standardized multi-chamber bags (MCB), e.g. 
SmofKabiven® and Kabiven®.  
  
Complications of PN  
PN is an independent risk factor for catheter-related 
bloodstream infections (BSI) [Beghetto 2005], a common 
cause of morbidity and mortality with substantial healthcare-
related cost.   
BSI rates are strongly influenced by  
 
the delivery system with a significantly higher incidence in 
patients receiving  hospital compounded PN bags compared 
to MCBs [Turpin 2012, Pontes-Arruda 2012]  
 
the type of compounding with automated compounding 
being superior to manual compounding reflected by lower 
BSI  
 
manipulations despite compounding under strict sterile and 
aseptic conditions with an increased risk of errors and 
sepsis [Singer 2009]  
 
addition of nutrients to the PN system on the ward [Turpin 
2014].  
  
Commercially available, standardized MCBs avoid the need of 
compounding, thereby reducing the risk of BSI. Within the 
MCBs, the three chamber bags (3CBs), e.g. SmofKabiven® and 
Kabiven® require least additional manipulations as all three 
main compartments consisting of amino acids, glucose with 
electrolytes, and lipids are pre-filled.   
  
Required data for three chamber PN bags   
To date, there is only scarce evidence showing reduced 
frequency of BSI with three chamber bags such as Fresenius 

Study Outline 3CBs-001-CNI  
page 2 of 5 Study Outline 3CB-001-CNI, Draft 0.7 2016-05-18  
Kabi’s SmofKabiven® and Kabiven® compared to hospital 
compounded PN bags. This information is relevant to provide 
data for the pharmaco-economic model to support the clinical 
and economic values of three-chamber bags.  
  
Hypothesis  
Patients receiving 3CBs experience a significantly lower BSI 
rate compared to patients receiving hospital compounded PN 
bags.   
  
Objectives  
Primary objective  
  
Assess the rates of BSI from the use of 3CBs (e.g.,  
SmofKabiven®, Kabiven®, others) compared to hospital 
compounded bags (HCBs) in patients requiring PN in Spanish 
hospitals  
  
  
      
Secondary objectives  
- 
Determine  the extent of treatment requirement in patients 
receiving 3CBs compared to hospital compounded bags  
- 
Assess mortality rate in patients receiving 3CB compared to 
patients receiving HCBs  
- 
Evaluate the influence of additions made to the PN bags on 
BSI rates  
- 
Assess the effect of manual versus automated compounding 
on BSI rates  
- 
Evaluate the rate of PN-associated adverse events in 
patients receiving 3CBs compared to HCBs, including sepsis, 
organ failure, metabolic impairment, hepatic dysfunction 
and electrolyte imbalance  
- 
Assess the achievement of the nutritional target in patients 
receiving 3CBs compared to HCBs  
    
Investigational sites  
Approximately 10 sites using 3CBs and/or HCBs  
  
Study design  
Retrospective observational data retrieval in a two-step design:  
In step 1, data from 30% of the target patient number will be 
obtained from the investigational sites to evaluate study 
feasibility and perform an interim analysis assessing statistical 
power.In step 2, the study will be continued by documenting 
further 70% of patients if the statistical power is > 60%.  
  
  
Observational drug  
Any PN administered in 3CBs, containing all three major 
macronutrients (glucose, amino acids, lipids)  
  
Comparator  
Hospital compounded PN bags containing all three major 
macronutrients  
  
Patients  
Adult hospitalized patients receiving PN in Spain, treated on 
any ward and by any medical discipline within the hospital 
(intensive care unit, normal ward; surgery, non-surgery)  

Study Outline 3CBs-001-CNI  
page 3 of 5 Study Outline 3CB-001-CNI, Draft 0.7 2016-05-18  
  
  
  
  
Outcome parameters Primary outcome parameter  
• 
BSI only with concomitant antimicrobial treatment (bacteria 
and/or candida), thereby excluding patients with 
contaminations  
  
Secondary outcome parameters  
• 
Rate of peripheral line associated BSI   
• 
Rate of central line associated BSI  
• 
Single organ failure, multiple organ failure  
• 
Mortality   
• 
PN-related adverse events of special interest: metabolic 
impairment (hyperglycemia, hypertriglyceridemia), hepatic 
dysfunction (cholestasis: transaminases, gamma-glutamyl 
transferase, alkaline phosphatase, bilirubin), electrolyte 
imbalance (sodium, potassium, chloride, calcium, 
phosphate, bicarbonate)  
• 
Changes in prealbumin, C-reactive protein  
• 
Achievement of caloric target (hypo-, hyperalimentation)   
• 
Extent of treatment requirement: Hospital length of stay, 
ICU length of stay, antibiotics, antimycotics, vasopressors 
and mechanical ventilation  
  
These parameters will be documented for the multivariate 
analysis - if available - and the discussion. These are not 
outcome parameters:  
• 
Demographic data: gender, age, weight (BMI)  
• 
Admission type: elective, emergency, transferral  
• 
Reason for hospital admission: leading diagnosis  
• 
Reason for ICU admission: surgical, medical, trauma  
• 
Primary disease  
• 
Duration of hospitalization before venous catheter (VC) 
placement and PN  
• 
Type of venous access: central, peripheral  
• 
VC insertion and maintenance according to “Bacteremia 
Zero” protocol  
• 
Type of hospital compounding: automated, manual  
• 
VC related influence: number of VC; number of lumen of 
VC; site of VC placement (jugular, subclavian, femoral); 
insertion of VC in ER, OR, ICU; clinical experience of staff 
placing and handling VC and PN; duration of VC; duration of 
PN and duration between VC placement and PN; SOP for 
hygiene in place (cap, mask, sterile gloves sterile full body 
drape)  
• 
Indication for PN  
• 
Percentage of PN (supplemental PN, total PN)  
• 
Omega-3 fatty acids and glutamine as active ingredients  

Study Outline 3CBs-001-CNI  
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• 
Additions of vitamins, trace elements and/or electrolytes to 
PN bag  
• 
Addition to PN bag made under sterile conditions in the 
pharmacy, or on the ward  
• 
Co-morbidities: cancer, malabsorption, pancreatitis, liver 
failure, renal failure, diabetes, malnutrition (SGA), 
gastrointestinal disorder  
• 
Enteral, oral nutrition, oral nutritional supplements  
• 
Antibiotic and antimycotic treatment (number, duration, 
antibiotic free days)  
• 
Availability of a Nutrition Support Team at the center  
• 
Hospital characteristics: region, teaching status, urban/ 
rural, number of beds  
• 
APR-DRG severity of illness  
• 
APACHE II score or SAPS II score  
 
 
Inclusion criteria   
  
  
General:   
 
Adult patients ≥ 18 years  
 
Hospitalized between 1. January 2014 and 31. December 
2015   
Study-specific:   
 
PN for at least three consecutive days   
 
PN as 3CBs or hospital compounded, containing all three 
major macronutrients  
 
complete medical record regarding treatment information,  
PN administration details and, if applicable, adverse events 
Exclusion criteria  
General  
Prior participation in this study  
  
Study specific   
 BSI at admission to the participating hospital (not 
hospitalacquired), i.e., prior to the 3rd calendar day of 
admission  
where day of admission is calendar day 1  
 Immunosuppression due to concomitanttherapy (e.g.  
immunosuppressive therapy due to transplantation, use of 
glucocorticoids)or disease (e.g. HIV, leukemia)  
 persisting vascular access (port, shunts for dialysis) used 
during PN episode  
 femoral venous placement of central venous line  
 burns (irrespective of severity), extensive skin injuries 
(e.g., Lyell´s disease)  
 chemo-/ radiotherapy during hospital admission period or 
up to 3 months before hospital admission  
 change of PN delivery method during study period, e.g., 
from compounding to 3CBs (change of dosing and/or 
frequency during the observational period is allowed)  
  

Study Outline 3CBs-001-CNI  
page 5 of 5 Study Outline 3CB-001-CNI, Draft 0.7 2016-05-18  
Sample size  
The sample size must allow the comparison of BSI rates 
associated with three chamber bags with those associated with 
hospital compounded bags. Due to the high variability among 
studies reported in the literature, a mean scenario is considered 
based on the incidence of BSI infections reported in Spain 
[Bonet 2005; Aguilella 2012], i.e., an overall incidence of BSI of 
12.3% with a difference between the groups of 3% (± 1.5%).  
Samples size are estimated assuming incidence rates of BSI in 
MCB of 10.8% and 13.8% in hospital compounded PN, 
respectively.   
A sample of 1891 patients per PN type (3782 patients in total) 
is required taking into account a significance level of 0.05, the 
influence of the interim analysis on statistical power, and a 
statistical power of 0.80.  
  
 
 
Statistical analysis  
  
Interim analysis: The study is run in a 2 stage group sequential 
design with an interim analysis (IA) after acquiring 30% of the 
total sample size. This allows a premature discontinuation if BSI 
rates and their difference, i.e., the actual power of the study, are 
substantially lower than planned. The study will be terminated 
after the IA if the conditional power based on the IA results will 
be smaller than 60%.  
  
Final analysis: Baseline demographics, co-morbidities and 
hospitalization characteristics will be reported descriptively by 
means of standard deviations and medians with ranges for 
continuous variables and by counts and percentages for 
categorical variables. Incidence rates for BSI will be reported by 
treatment group.   
Multivariate logistic regression will be used to create a model to 
estimate the risk of BSI. The model will be adjusted for 
covariables as risk factors, potential confounders, baseline 
differences, etc. As variable-selection method correlations will be 
calculated for the rough selection and then backward elimination 
selection will be applied in the logistic regression model with a 
significance level of 10%. The risk of BSI will be reported as 
adjusted odds ratios with 95% confidence limits.  For secondary/ 
further variables multivariate regression models will be used.  
Observation period  
Length of stay at the participating hospital  
  
Planned start and end  Data retrieval for step 1: September 2016 – January 2017  
  
  
  
  
Data retrieval for step 2: March – June 2017  
  
Principal investigator  Juan Carlos Montejo, MD PhD  
Madrid, Spain