REDOXS

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A Randomized Trial of Supplemental Parenteral
Nutrition in Under and Over Weight Critically
Ill Patients The TOP UP Trial October 17th
2011 Study Sponsor Dr. Daren Heyland Project
Leader Rupinder Dhaliwal Project Assistant
Roger Leung Clinical Evaluation Research Unit
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Protocol Version March 28th 2011
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Background Objectives
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• Point prevalence survey of nutrition practices in
  ICUs around the world conducted Jan. 27, 2007
• Enrolled 2772 patients from 158 ICUs over 5
  continents
• Included ventilated adult patients who remained
  in ICU gt72 hours

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What study patients actually received?

• Average Calories in all groups
• 1034 kcals and 47 gm of protein
• Result
• Average caloric deficit in Lean Pts
• 7500kcal/10days
• Average caloric deficit in Severely Obese
• 12000kcal/10days

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ICU patients are not all created equalshould we
expect the impact of nutrition therapy to be the
same across all patients?
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TOP UP Trial Hypothesis
Increased early energy and protein delivery with
PNEN to underweight (BMI lt 25) and obese (BMI
35) critically ill patients will result in
improved survival at 60 day versus standard EN
alone
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Objectives

• Perform an initial multi-center pilot study in
  Canada,USA, France Belgium in 160 patients to
  demonstrate feasibility
• Assuming feasibility, large-scale 2000 patient
  multi-center, multinational trial will be
  undertaken

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Study Design
Randomized Trial (unblinded)
EN only
Primary Outcome
Stratified by Site BMI Med vs Surg On EN
ICU patients
R
BMI lt25
60-day mortality
BMI gt35
Fed enterally
EN plus supplemental PN for 7 days
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Objectives Pilot Study

• Primary Aim
• Difference in the calories and protein received
  between the control and intervention groups
• Estimate recruitment rate
• Evaluate the safety, tolerance, and logistics
  around providing supplemental PN in the study
  population, e.g.
• To ensure adequate glycemic control in both
  groups
• To ensure other metabolic consequences of the
  feeding strategies are minimized
• To establish adequate compliance with study
  protocols and completion of case report forms.
• Secondary Aims
• Explore the effect of differential intake of
  protein/energy on muscle mass and muscle
  function.

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OutcomesPilot study

• Primary outcome 60 day mortality
• Secondary outcomes
• ICU (28 day) mortality
• Hospital mortality
• Duration of mechanical ventilation
• Duration of stay (ICU and hospital)
• Development of ICU-acquired infections
• Multiple organ dysfunction (SOFA and PODS)
• Functional status, HR QOL at 3 6 months
• Muscle Function Tests

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Study Overview
Imp Manual p 9
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Pilot Study Participating Sites

• Target 160 patients from 9 institutions
• Royal Alexandra Hospital, Edmonton (Jim
  Kutsogiannis)
• University of Alberta Hospital, Edmonton (Dean
  Karvellas)
• University of Colorado, US (Paul Wischmeyer )
• Erasme University Hospital, Brussels (Jean
  Charles Preiser)
• Hôpitaux Universitaires, Strasbourg, France
  (Michael Hasselmann)
• Grey Nuns Hospital, Edmonton (Dan Stollery)
• University of Wisconsin (Ken Kudsk)
• University of Vermont (Renee Stapleton)
• Oregon Health Sciences University (Robert
  Martindale)

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TOP UP Teamwork
Site Investigator Regulatory Inclusion/exclusion
criteria ICU infection adjudication SAE reporting
Nurse Adjust EN PN hourly Product
Reconstitution?
Pharmacist Checking allocation Dispensing Logs
Dietitian Dosing Calculation Optimizing
nutrition Monitoring Adequacy
Study Coordinator Regulatory Screening/Randomizat
ion Pharmacy communication Data collection Study
intervention monitoring Collaboration with SI SAE
reporting Protocol Violation reporting
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Role of Site Investigator
Delegation of Authority Patient EligibilityICU
Infection adjudicationSAE identification/assessme
nt Investigator Confirmation
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Delegation of Authority Logs
Imp Manual p 11,12

• The Investigator should maintain a list of
  appropriately qualified persons
• to whom the investigator has delegated
  significant trial-related duties
• (ICH section 4.1.5)
• Completed Log to be sent to CERU before start of
  trial

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Inclusion Criteria
Imp Manual p 13, CRFs

• 1) Mechanically ventilated adult patients (18
  years old)
• 2) Expected to remain mechanically ventilated for
  more than 72 hours
• 3) On enteral nutrition or expected to initiate
  enteral nutrition within 48
• hours from ICU admission
• Interpret 48 hrs as 7 days due to
  exclusion criteria 4
• 4) BMI lt 25 or gt35 based on pre-ICU actual or
  estimated dry weight

If using estimated weight/height, you may add a
buffer of ? 1 for BMI after rounding
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Exclusion Criteria
Imp Manual p 14, CRFs

• gt48 hours from admission to ICU to time of
  consent (any ICU)
• Not expected to survive an additional 48 hours
  from screening evaluation
• 3. Lack of commitment to full, aggressive care
  (anticipated withholding or withdrawing
  treatments in the first week but isolated DNR
  acceptable)

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Exclusion Criteria
Imp Manual p 14, CRFs

• 4. Patients with an absolute contraindication to
  EN deemed to require PN for the first 7 days of
  ICU admission (e.g. GI obstruction or no GI
  tract access for any reason)
• 5. Already at goal rate of Enteral Nutrition at
  screening evaluation (at 60 target rate and no
  evidence of intolerance i.e. high GRVs)

What about patients that have not been challenged
with EN?
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To enrol the right type of patient
AS A GUIDELINE if patient has not been challenged
with EN
?

• is NOT at risk for EN intolerance

• is at risk for EN intolerance

Refer to list of risk factors for GI intolerance
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Risk Factors for EN Intolerance
Imp Manual p 15

• High APACHE Scores (gt25)
• On more than 1 pressor, or increasing doses of
  pressors
• Receiving continuous infusion of narcotics
• High NG/OG output (gt 500 mls over 24 hrs)
• Recent surgery involving esophagus, stomach or
  small bowel OR peritoneal contamination with
  bowel contents
• Pancreatitis
• Multiple GI investigations
• Recent history of diarrhea/ C.difficile
• Surgical patients with future ORs planned
• Abdominal Aortic Aneurysm (emergency vascular
  surgery)

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Imp Manual p 15
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Exclusion Criteria
Imp Manual p 14, CRFs

• Patients already receiving PN on admission to ICU
  (does NOT refer to those that received PN in
  hospital prior to this acute episode of illness)
• Patients with diabetic ketoacidosis or non
  ketotic hyperosmolar coma
• Pregnant or lactating patients
• 9. Patients with clinical fulminant hepatic
  failure (see definition)
• 10. Dedicated port of central line not
  available
• Known allergy to study nutrients (soy, egg or
  olive products)
• Enrolment in another industry sponsored ICU
  intervention study (co- enrollment in
  academic studies will be considered on a case by
  case basis)

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Eligibility confirmation
Document in the medical chart or Sign worksheet
by MD and keep as source
Prompted at time of Pre randomization
Refer to Consent Training Slides
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Infection AdjudicationSite Investigator to make
determination of a newly acquired infection
based on antibiotic and microbiology data
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Infection Adjudication
CRS/REDCAP manual p 21-27
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Suspicion of ICU Infection Antibiotics
CRFs p 40, 41

• Is this antibiotic prescribed for prophylaxis?
• Is this a substitute for an antibiotic previously
  ordered for an infection that occurred within 72
  hrs of admission to ICU?

NO to both
YES to either
Clinical Suspicion of Infection Need
adjudication by Site Investigator/MD Delegate
No adjudication needed
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Suspicion of ICU Infection Microbiology
CRFs p 42, 43

• Is this organism a manifestation of an
  infection that occurred within the first 72 hrs
  of admission?

NO
YES
Clinical Suspicion of Infection Need
adjudication by Site Investigator/MD Delegate
Indicate if Relapse/Recurrent OR Persistent
infection
No adjudication needed
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Infection Adjudication REDCAP
CRS/REDCAP Manual p 24

• This is a newly acquired infection
• This is NOT a newly acquired infection
• This is a previously adjudicated infection

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Infection Adjudication

• Site Investigator will need
• Access to view the Infection Adjudication table
  on REDCAP (Research Coordinator to show this)
• Appendix 9 Categories of Infection
• Appendix 10 Definitions of No Newly Acquired
  Infection
• Medical Chart
• Refer to CRS/REDCAP Manual pages 21-27 for step
  by step process

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SAE Identification and Reporting
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SAE Identification
Imp Manual p 38-49

• A serious adverse event is any untoward medical
  occurrence that at any dose,
• Results in death
• Is life threatening (the subject was at
  immediate risk of death from the event
• Results in persistent or significant
  disability/incapacity
• Requires in patient hospitalization possibly
  related to the use of the study materials
• Prolongs of hospitalization.
• Is a congenital anomaly or birth defect
• Is an important medical event that may
  jeopardize the patient and may require medical or
  surgical intervention to prevent one of the
  outcomes listed above medically important
  condition

An unexpected adverse event is that event that is
NOT expected due to the progression of the
underlying disease or co-morbid illnesses.  
Adverse Event must be serious and unexpected to
be reported
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SAE Reporting (to CERU)
Imp Manual p 40
Must be done on electronic data capture system
and faxed to CERU
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Imp Manual p 42-44
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Imp Manual p 45-48
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Imp Manual p 45-48
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Imp Manual appendix J
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SAE Reporting to Regulatory Bodies
If SAE is related, CERU will report to Regulatory
bodies, Sites and Baxter within 7 days (fatal) or
15 days (non fatal)
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Investigator Confirmation
CRS/REDCAP Manual p 30
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Study Groups
Imp Manual p 17
Name of Group Intervention
Supplemental PN EN (enteral nutrition) plus Olimel
EN only EN
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Dosing Procedures (both groups)

• Dosing of the intervention will depend upon the
  energy and protein needs of the patient
• To be determined by the dietitian/MD

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Protein and Calorie needs
Protocol, Imp Manual p 25
Guidelines for Dosing of Protein and Energy Based
on BMI

• Upon enrolment, the dietitian/MD will
• Calculate prescribed energy and protein intake as
  per standard practice
• 2. Ensure that minimum energy and protein
  needs are met as follows

Minimum Energy Minimum Protein
BMIlt25 25 kcals/kg actual wt 1.2 g/kg actual wt
BMI 35 20 kcals/kg ABW 1.2 g/kg Obesity-ABW
Obesity-adjusted Body weight IBW actual
weight IBW x 0.25, where IBW is ideal body
weight (BMI of 25)
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Prescribed Volume
Imp Manual p 25

• 3. Determine the prescribed volume for EN (or
  study PN, or EN study
• PN) in mls/24 hrs to meet the prescribed
  energy and protein needs
• MUST use enteral formula of 1.2 ? 0.2 kcal/ml
• Meet protein needs over energy needs
• 4. Determine the hourly rate of EN (or study PN,
  or EN study PN)
• (assume PN 1
  Kcal/ml)

Must be done asap after randomization
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Study Tools
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Other considerationsPropofol

• Propofol calories to be factored into assessment
  of caloric needs, only as per discretion of
  dietitian/MD

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Enteral Nutrition (both groups)
Imp Manual p 17

• Enteral Nutrition to start as per usual practice
  (patient stabilized, NG/Feeding tube in place)
• Standard enteral nutrition formula 1.0 to 1.4
  kcals/ml
• (hypercaloric formulas not allowed)
• NO protein supplements (for 7 days)
• NO probiotics (for 7 days)
• NO glutamine supplements (for 7 days)
• Start at 25 ml/hr and increase every 4 hrs as
  tolerated until goal rate
• Discontinue when the feeding tube comes out
• Refer to Enteral Nutrition Algorithm Paired
  Feeding Algorithm appendices C F

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Trace Elements and Multivitamins
Imp Manual p 18

• DO NOT add to the PN solution
• If patient does not receive EN and is dependant
  on PN for gt48 hrs,
• IV supplementation is recommended
• Suggested guidelines
• Standard doses of multivitamins
• 5 mg zinc
• 1 mg copper
• 0.5 mg manganese
• 10 mg chromium
• 60mcg selenium.
• use commercially available trace element
  solutions

doses can be adjusted at discretion of the
medical team
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Dietitian

• Determine Energy/protein needs (prescribed
  Volume)
• Follow Canadian Clinical Practice Guidelines
  Assist with data collection
• Baseline Nutrition Assessment
• Daily EN monitoring
• Daily PN monitoring (non study PN)

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Baseline Nutrition
CRFs p 12-13
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CRFs p 20-21,23
Daily EN Monitoring
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CRFs p 22, 24
Daily PN Monitoring (non study PN)
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CRFs p 3
Study Days and Data Collection
Data MUST be collected according to calendar day
as described below Do NOT collect data according
to your flow sheet unless it runs from
0700-0700
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Supplemental PN group
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Olimel N9E (5.7)
Imp Manual p 17,18
Amino acids

• 3-in-1 PN solution that contains glucose, lipid
  emulsion and an amino acids
• Blend of desirable lipids olive oil, soybean oil
  (ratio 80/20)
• Alpha-tocopherol/moderate PUFA,
• better vitamin E status
• less lipid peroxidation.
• Protein and energy content of Olimel N9E enables
  the maintenance of an adequate nitrogen/energy
  balance
• 1 Litre bags, provided by Baxter

Dextrose
Lipid emulsion
Spike insertion site
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Olimel N9E (with electrolytes)
Product monograph
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Olimel N9E
Imp Manual p 18

• Once reconstituted, will be a milky color
• Unmixed product store between 15 to 30 degrees
  C. Do not
• Freeze. Once reconstituted, use immediately
• If pre-activation occurs at time of delivery, do
  not use and
• report to Baxter

Dedicated Central line needed, piggybacking with
other lines not recommended unless standard
practice for PN at your site
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When to start Olimel?
Imp Manual p 19

• Start as soon as central line access
• Preferably within 2 hrs of randomization

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Paired Feeding
Imp Manual p 19-20

• Enteral and parenteral solutions provided
  continuously over 24 h
• Rate of PN depends upon rate of EN
• Adjust PN hourly so that EN PN target rate as
  determined by dietitian/MD
• Initiate PN study solution at 25 ml/hr (or
  faster) and advance by 25 ml q 4 hrs to target
  rate as tolerated
• Monitor blood sugars and electrolytes every 4 hrs
  as needed
• Do not advance PN/EN if BS, K, Phosp, Mag
  becoming more abnormal (ranges as per your local
  site)
• .

To reach the target combined rate by EN plus PN
within 24 hrs from randomization
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Imp Manual appendix F
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Sample MD orders (Supplemental Group)
Imp Manual p 24
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Duration of Study Intervention
Imp Manual p 20
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Before or at 7 days Supplemental Group
Imp Manual p 19
Duration of intervention ICU admission to 7
days post randomization
If d/c from ICU to ward prior to 7 days
If in ICU PN indicated, use Olimel If out of
ICU PN indicated, use standard PN

• Continue study PN until
• 50 goal rate until day 7 OR
• until patient tolerating adequate
• po intake, whatever happens first
• NO daily titration needed

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Use of Non Study Parenteral Nutrition
Imp Manual p 20

• If parenteral nutrition is truly indicated
• In ICU use Olimel until study day 28 maximum
• When on floor after ICU use standard PN

Both groups If non study PN received before 7
days
PROTOCOL VIOLATION Report to CERU asap
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EN only group
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Enteral Nutrition
Imp Manual p 17-18

• Enteral Nutrition to start as per usual practice
  (patient stabilized and NG/Feeding tube in place)
• Standard enteral nutrition formula
• 1.0 to 1.4 kcals/ml
• (hypercaloric formulas not allowed)
• NO protein supplements (for 7 days)
• NO probiotics (for 7 days)
• NO glutamine supplements (for 7 days)
• Start at 25 ml/hr (or and increased every 4 hrs
  as tolerated until goal rate
• Discontinue when the feeding tube comes out
• Refer to Enteral Nutrition Algorithm

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Imp Manual appendix C
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Before or at 7 days EN only group
Imp Manual p 21
Duration of intervention ICU admission to 7
days post randomization
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Both groups

• EN only
• Supplemental PN group

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Trace Elements and Multivitamins
Imp Manual p 18

• DO NOT add to the PN solution
• If patient does not receive EN and is dependant
  on PN for gt48 hrs,
• IV supplementation is recommended
• Suggested guidelines
• Standard doses of multivitamins
• 5 mg zinc
• 1 mg copper
• 0.5 mg manganese
• 10 mg chromium
• 60mcg selenium.
• use commercially available trace element
  solutions

doses can be adjusted at discretion of the
medical team
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Co-interventions
Imp Manual p 18

• Follow Canadian Nutrition Guidelines
• Glycemic Control Protocol
• Daily sedation vacations
• Sepsis management guidelines
• Daily trials of weaning from mechanical
  ventilation

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Investigational Product

• Dispensing Storage

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Pharmacy

• For most sites, the pharmacy may only be involved
  in the initial receipt of the Olimel.
• The Research Coordinator/delegate will therefore
  be responsible for the following
• storage of Olimel
• dispensing of Olimel (including addition of
  labels)
• completion of dispensing and accountability logs
  
• sending temp logs to CERU monthly
• maintenance of inventory and destruction of the
  expired/unused product

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Central Randomization System
CRS/REDCAP Manual p 12

• Upon randomization, Research Coordinator will
  be notified of the study group
• the patient has been randomized to

EN only or EN Supplemental PN
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Supplemental PN
Imp Manual p 22-23

• For day 1
• Research Coordinator to obtain hourly rate of
  infusion from dietitian/MD
• Prepare enough 1 litre bags of the
  
• investigational product to last one day
• Example Dietitian/MD has determined that the
  hourly rate is 65 ml/hr
• the total volume needed for 1 day would be 65 X
  24 1536 mls.
• The pharmacist /delegate is to prepare 2 X 1
  Litre bags of the product.
•  
• In order to prevent running out of product before
  the bag
• change time, you may need to send 2 X 1 litre
  bags on day 1
•  

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Supplemental PN

• For Subsequent days
• The Research Coordinator to determine how much
  enteral nutrition the patient is anticipated to
  tolerate and will prepare enough Olimel
  accordingly.
•  
• Example
• 1. Goal rate 65 ml/hr
• 2. Patient tolerating 25 ml/hr well today (or
  expected to)
• 3. Prepare enough product for remaining volume
  40 ml/hr X 24 960 mls 1 X 1 litre bag
•  

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Olimel in overpouch
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• After removing pouch, check the Oxygen indicator 

Black
Light yellow brown
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Check non permanent seals

• Confirm the integrity of the bag and of the
  non-permanent seals.
• Use only if the bag is
• not damaged, if the non-permanent seals are
  intact (i.e. no mixture of
• the contents of the three compartments)
• if the amino acids solution and the glucose
  solution are clear, colourless
• practically free of visible particles, and
• if the lipid emulsion is a homogeneous liquid
  with a milky appearance

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1. Ensure that the product is at room temperature
when breaking the non- permanent seals2. After
removing overpouch, manually roll bag from hanger
side down
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Continue rolling the bag until all non permanent
seals are broken ½ way
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Solution turns milky showing that the seals are
broken (1/2 way)
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Mix well by inverting the bag 3 times
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Solution will turn to a milky color is ready to
hang
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Labels
Imp Manual p 23
Study The TOP-UP Study ID NCT01206166 Olimel
N9E   PARENTERAL USE ONLY   Canadian Sponsor
Dr. Daren Heyland Clinical Evaluation Research
Unit, Kingston General Hospital, 76 Stuart St,
Kingston, ON K7L 2V7     Randomization
_________ Patient ID ________________ Patient
Name _____________   Directions Run at
maximum goal rate of XX ml/hr and titrate down as
enteral feeds increase.   Storage Room
temperature Expiration 24 hrs
Unblinded labels Appx 3 x 5 size Generate
and attach 1 label for outside of reconstituted
bag Labels must be placed on extra bags needed
for after hours (expiration date and time must be
recorded..by RN)
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Imp Manual appendix D
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Imp Manual appendix E
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Nursing Procedures
Imp Manual p 26
Training Slides available on Reconstitution of
Olimel www.criticalcare nutrition.com
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Overview of steps and timelines
Screen patient Eligible patient (checked by MD)
Research Coordinator obtains consent Randomizes
patient on CRS Dietitian determines dosing of
calories and protein Writes sample entry Note in
chart Facilitates Medical Orders in chart
48 hrs 2 hrs from admission
Research Coordinator/Pharmacist dispenses product
for patient
Research Coordinator informs RN Patient started
on intervention
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Muscle Function Tests
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Weekly U/Sounds
Imp Manual p 28-30, CRFs 32-33

• Why?
• To assess Muscle Layer Thickness (MLT) of the M.
• vastus intermedius and M. rectus femoris
• When?
• Weekly PLUS within 72 hrs of CT Scan
• Whom?
• To be done by site investigator or designated
  clinician (RN specialist, R Coordinator, RN,
  fellow)
• How?
• Refer to Ultrasound Procedure pages 28-39 Imp
  Manual

Volunteer U/S training records must be submitted
to CERU
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Abdominal/Pelvic CT Scan
CRF p 34-35

• Why?
• Assess muscle mass (at 3rd lumbar vertebrae) as a
  predictor of
• lean tissue mass
• When?
• CT Scans done 1-2 days prior or after ICU
  admission and all
• subsequent scans
• Whom?
• Research Coordinator to retrieve scans of
  previously done CTs and
• obtain copies and send DE-IDENTIFIED to
  University of Waterloo
• How?
• CT Images already performed for clinical reasons
• Not to be done for the study if not clinically
  indicated

Mourtzakis M et al Critical Care Canada Forum,
2009.
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Hand Grip Strength
Imp Manual p 31

• Why?
• To assess the physical strength
• When?
• ICU discharge
• Whom?
• To be done by the Research Coordinator
• How?
• On a patient that is awake and attentive, upright
  with elbow at 90 degrees
• Using a hand dynamometer (Jamar) on dominant
  hand, three readings (sustained 5 sec, rest for
  15 sec between)
• REFER TO HAND GRIP STRENGTH TEST MODULE (SLIDES)

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6 Minute Walk Test
Imp Manual p 32-34

• Why?
• One time measure of functional status of patients
• When?
• Prior to hospital discharge
• Whom?
• To be done by the Research Coordinator
• How?
• Calculate the total distance walked by patient in
  6 minutes.
• On a patient that is able to walk, need a long
  corridor (30 metres)
• Patients with recent unstable angina are excluded
• Ensure that the patient is safe, chair nearby
• Worksheets, specific instructions, script
  provided

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CRF page 36,37
Rehab Practices
Need to get from physio, RN flowsheet or RN
(daily)
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Research Coordinator Procedures
Imp Manual

• Consent (Training Module)
• Training of nurses
• Data Collection
• Protocol Violations

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Case Report Forms
CRFs Oct 17th 2011
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CRS/REDCAP Manual Oct 17th 201l
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Resources online
www.criticalcarenutrition.com
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