The REDOXS© Study REducing Deaths due to OXidative Stress

A Randomized Trial of Supplemental Parenteral Nutrition in Under and Over Weight Critically Ill Patients:

The TOP UP Trial

April 12th 2012

Study Sponsor: Dr. Daren HeylandProject Leader: Rupinder Dhaliwal

Project Assistant: Roger LeungClinical Evaluation Research Unit

Protocol: Version April 11th 2012

Background & Objectives

• Point prevalence survey of nutrition practices in ICU’s around the world conducted Jan. 27, 2007

• Enrolled 2772 patients from 158 ICU’s over 5 continents

• Included ventilated adult patients who remained in ICU >72 hours

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

ICU patients are not all created equal…should we expect the impact of nutrition

therapy to be the same across all patients?

TOP UP Trial: Hypothesis

Increased early energy and protein delivery with PN+EN to underweight

(BMI < 25) and obese (BMI ≥ 35) critically ill patients will result in improved

survival at 60 day versus standard EN alone

• 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

Objectives

ICU patientsBMI <25 R

EN only

EN plus supplemental PN for 7 days

Randomized Trial (unblinded)

Study Design

Fed enterally

Primary Outcome

60-day mortality

BMI >35

Stratified by:SiteBMI

Med vs SurgOn EN

Objectives: Pilot StudyPrimary 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.

Outcomes: Pilot 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

Study OverviewImp Manual p 9

Pilot Study: Participating Sites

Target: 160 patients from 8 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 Nun’s Hospital, Edmonton (Dan Stollery) University of Wisconsin (Ken Kudsk) Oregon Health Sciences University (Robert Martindale)

PharmacistChecking allocation

DispensingLogs

TOP UP Teamwork

DietitianDosing Calculation

Optimizing nutritionMonitoring Adequacy

Study CoordinatorRegulatory

Screening/RandomizationPharmacy communication

Data collectionStudy intervention monitoring

Collaboration with SISAE reporting

Protocol Violation reporting

Site InvestigatorRegulatory

Inclusion/exclusion criteriaICU infection adjudication

SAE reporting

NurseAdjust EN + PN hourlyProduct Reconstitution?

Role of Site Investigator

Delegation of AuthorityPatient Eligibility

ICU Infection adjudicationSAE identification/assessment

Investigator Confirmation

Delegation of Authority Logs“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

Imp Manual p 11,12

Inclusion Criteria

1) Mechanically ventilated adult patients (≥18 years old)

2) Expected to remain mechanically ventilated for more than 48 hours

3) On enteral nutrition or expected to initiate enteral nutrition within 7

days from ICU admission

4) BMI < 25 or >35 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

Imp Manual p 13, CRFs

Exclusion Criteria

1. >72 hours from admission to ICU to time of consent (your ICU)

2. 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)

4. 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)

Imp Manual p 14, CRFs

Exclusion Criteria

5. Patients with diabetic ketoacidosis or non ketotic hyperosmolar coma

6. Pregnant or lactating patients

7. Patients with clinical fulminant hepatic failure (see definition)

8. Patients with Cirrhosis Child’s Class C Liver Disease (except those on a transplant list or transplantable)

9. Dedicated port of central line not available

10. Known allergy to study nutrients (soy, egg or olive products)

11. Enrolment in another industry sponsored ICU intervention study (co- enrollment in academic studies will be considered on a case by case basis)

Imp Manual p 14, CRFs

Eligibility confirmation

Prompted at time of Pre randomization

Refer to Consent

Training Slides

Infection Adjudication

Site Investigator to make determination of a newly acquired infection based on antibiotic

and microbiology data

Infection AdjudicationCRS/REDCAP manual p 21-27

Suspicion of ICU Infection: Antibiotics

• 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

Clinical Suspicion of Infection

Need adjudication by Site Investigator/MD Delegate

CRFs p 40, 41

YES to either

No adjudication needed

Suspicion of ICU Infection: Microbiology

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

NO

Clinical Suspicion of Infection

Need adjudication by Site Investigator/MD Delegate

YES

Indicate if:Relapse/Recurrent OR

Persistent infection

No adjudication needed

CRFs p 42, 43

Infection Adjudication: REDCAP

This is a newly acquired infection

This is NOT a newly acquired infection

This is a previously adjudicated infection

CRS/REDCAP Manual p 24

Infection Adjudication

Site Investigator will need:1. Access to view the Infection Adjudication table on

REDCAP (Research Coordinator to show this)

2. Appendix 9 Categories of Infection

3. Appendix 10 Definitions of No Newly Acquired Infection

4. Medical Chart

Refer to CRS/REDCAP Manual pages 21-27 for step by step process

SAE Identification and Reporting

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

SAE Identification

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

Imp Manual p XX-XX

SAE Reporting (to CERU)Imp Manual p X

Must be done on electronic data capture

system and faxed to CERU

Imp Manual p XX-XX

Imp Manual p XX-XX

Imp Manual p XX

Imp Manual appendix J

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)

Investigator ConfirmationCRS/REDCAP Manual p 30

Study Groups

Name of Group Intervention

Supplemental PN EN (enteral nutrition) plus Olimel

EN only EN

Imp Manual p X

Dosing of the intervention will depend upon the energy and protein needs of the patient

To be determined by the dietitian/MD

Dosing Procedures (both groups)

Protein and Calorie needs

Minimum Energy Minimum Protein

BMI<25 25 kcals/kg actual wt 1.2 g/kg actual wt

BMI ≥ 35 20 kcals/kg ABW* 1.2 g/kg Obesity-ABW*

Guidelines for Dosing of Protein and Energy Based on BMI

*Obesity-adjusted Body weight= IBW + [actual weight – IBW] x 0.25, where IBW is ideal body weight (BMI of 25)

Upon enrolment, the dietitian/MD will:

1. Calculate prescribed energy and protein intake as per standard practice

2. Ensure that minimum energy and protein needs are met as follows

Protocol, Imp Manual p X

Prescribed Volume

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)

Imp Manual p X

Must be done asap after

randomization

Minimum Energy and Protein calculator

BMI < 25

BMI ≥ 35

1) BMI CalculatorHeight = cm

Weight = kgBMI =

2) Minimum Energy and Protein IntakeIf BMI < 25,

Minimum Energy = kcalMinimum Protein = g

If BMI ≥ 35, Minimum Energy = kcal

Minimum Protein = g

This calculator assumes the height and weight have been estimated and automatically allows for a buffer of 1 BMI.

*ABW=adjusted body weights. Weights in obese patients to be calculated according to the following formula:Obesity-adjusted body weight= IBW +[actual weight-IBW] X 0.25 where IBW is ideal body weight based on BMI of 25

Minimum Protein1.2 g/kg actual weight

1.2 g/kg Obesity– ABW*

Minimum energy

20kcals/kg ABW*

25 kcals/kg actual weight

Study Tools

Other considerations…Propofol

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

Enteral Nutrition (both groups)• 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

Imp Manual p X

Trace Elements and Multivitamins

• DO NOT add to the PN solution• If patient does not receive EN and is dependant on PN for >48 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

Imp Manual p X

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)

Baseline NutritionCRFs p 12-13

CRFs p 20-21,23

Daily EN Monitoring

Daily PN Monitoring (non study PN) CRFs p 22, 24

CRFs p 3

Data MUST be collected according to calendar day as described below

Do NOT collect data according to your flow sheet unless it runs from 00:00 to 23:59 (midnight to midnight)

Study Days and Data Collection

Supplemental PN group

Olimel N9E (5.7%) Amino acids

Dextrose

Spike insertion site

Lipid emulsion

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

Imp Manual p XX, XX

Olimel N9E (with electrolytes)Product monograph

When to start Olimel?

Start as soon as central line access

Preferably within 2 hrs of randomization

Imp Manual p X

Paired Feeding

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

Imp Manual p XX-XX

Imp Manual appendix F

Sample MD orders (Supplemental Group)

Imp Manual p X

Duration of Study Intervention

ICU admission

7 days post randomization (means day of randomization PLUS 7 full days)

Study Intervention

Randomization

Consent to be obtained within 72 hrs from

ICU admit

Imp Manual p X

Before or at 7 days: Supplemental Group

Duration of intervention = ICU admission to 7 days post randomization (=day of randomization PLUS 7 full days)

ICU admit 7 days post randomization

If d/c from ICU to ward prior to 7 days

Continue study PN until: • 50 % goal rate until day 7 OR• until patient tolerating adequate po intake, whatever happens firstNO daily titration needed

If in ICU & PN indicated, use Olimel

If out of ICU & PN indicated, use standard PN

Imp Manual p X

Use of Non Study Parenteral Nutrition

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 VIOLATIONReport to CERU asap

Imp Manual p X

EN only group

Enteral Nutrition• 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

Imp Manual p X

Imp Manual appendix C

Sample MD orders (EN only Group)

Imp Manual p X

Before or at 7 days: EN only group

Duration of intervention = ICU admission to 7 days post randomization (= day of randomization PLUS 7 full days)

ICU admit 7 days post randomization

If within 7 days, PN is clinically indicated and still in ICU, Use Olimel

If Olimel or any PN is received before 7 days, this is considered a Protocol

Violation and must be reported to CERU!

If after 7 days,

PN is clinically indicated and still in ICU use Olimel

If out of ICU & PN indicated, use standard PN

Imp Manual p X

Both groups

EN only &

Supplemental PN group

Trace Elements and Multivitamins

• DO NOT add to the PN solution• If patient does not receive EN and is dependant on PN for >48 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

Imp Manual p X

Co-interventions

Follow Canadian Nutrition GuidelinesGlycemic Control Protocol

Daily sedation vacations

Sepsis management guidelines

Daily trials of weaning from mechanical ventilation

Imp Manual p X

Investigational Product

Dispensing & Storage

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

Olimel N9E

Will be supplied to all sites before enrollment starts

At time of delivery, if pre-activation occurs (solution has turned milky) do not

use and report to CERU Project Leader

Unmixed product: store between 15 to 30 degrees C. Do not freeze.

Imp Manual p X

Dedicated Central line needed, piggybacking with other lines not recommended unless standard practice for PN at your site

Central Randomization System Upon randomization, Research Coordinator will be notified of the study group

the patient has been randomized to

EN only orEN + Supplemental PN

CRS/REDCAP Manual p 12

Supplemental PNFor 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

 

• Pharmacy to prepare the parenteral solution according to group

• Add dextrose to meet minimum calorie and protein needs• Add trace elements, vitamins as per protocol

• Send to ICU within 4 hrs of randomization• Attach a blinded label on packages • Complete dispensing logs (pending)

Imp Manual p X

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

 

Olimel in overpouch

Labels

Study: The TOP-UP StudyID #: NCT01206166Olimel 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 temperatureExpiration: 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)

Imp Manual p X

Imp Manual appendix D

Imp Manual appendix E

Nursing Procedures

Training Slides available on Reconstitution of Olimel

www.criticalcare nutrition.com

Imp Manual p X

Reconstitution of Olimel

done by Nurse and/or Research Coordinator

Olimel in overpouch

After removing pouch, check the Oxygen indicator 

Black Light yellow brown

After overwrap has been removed, Olimel can be stored for 24 hours underrefrigeration followed by 24 hours administration

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

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

Continue rolling the bag until all non permanent seals are broken ½ way

Solution turns milky showing that the seals are broken (1/2 way)

Mix well by inverting the bag 3 times

1. Solution will turn to a milky color & is ready to hang2. Use immediately after reconstitution

Overview of steps and timelinesScreen 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 chartFacilitates Medical Orders in chart

Research Coordinator/Pharmacist dispenses product for patient

Research Coordinator informs RNPatient started on intervention

72 hrs + 2 hrs from

admission

Muscle Function Tests

Weekly U/Sounds

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 in Imp Manual

Imp Manual p X, CRFs 32-33

Abdominal/Pelvic CT Scan

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.

CRF p 34-35

Hand Grip Strength

Why?To assess the physical strength

When?ICU and hospital 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)

Imp Manual p X

6 Minute Walk Test

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

Imp Manual p X

Need to get from physio, RN flowsheet or RN (daily)

CRF page 36,37

Rehab Practices

Research Coordinator Procedures

Consent (Training Module)

Training of nurses

Data Collection

Protocol Violations

Imp Manual

Case Report FormsCRFs April 12th 2012

Duration of Data Collection

· Collected once: Baseline Barthel ADL Index, Baseline SF-36, Nutritional Assessment, Baseline,

Nutrition Timing, Ventilation/Dialysis, Outcomes Barthel ADL Index, Muscle Function Testing (6-min Walk Test & Hand Grip Strength Test only), Hospitalization Overview, 3-month SF-36 Follow-up and 6-month SF-36 Follow-up

· Daily from Study Day 1 until ICU discharge or death for a maximum of 28 days from ICU admission:

Daily Nutrition Monitoring, Daily Organ Dysfunction, Daily Laboratory and Intra Abdominal Pressure, Rehabilitation Practices and Concomitant Medications

· Daily from Study Day 1 until 3 days after ICU discharge or death for a maximum of 28 days:

Antibiotic/Antiviral/Antifungal and Microbiology

· Weekly/Other specified intervals: Muscle Function Testing (Weekly study Femoral Ultrasounds) and Abdominal/Pelvis CT Scans/Femoral Ultrasounds 

 

The duration of daily data collection and frequency will vary depending upon each data element/form and is as follows:

Duration of Study Intervention

Exceptions: If the patient is discharged from the ICU to your hospital ward before 7 days:• Supplemental PN Group: Continue PN intervention until day 7 post randomization* or until

the patient is tolerating adequate amounts of oral nutrition (i.e. > 50% caloric goal orally)• Both groups: Collect daily data from Study Day 1 until 7 days post randomization* • Both groups: Collect antibiotic and microbiology data from Study Day 1 until 10 days post

randomization** 

Study Day 1 = Patient admitted to ICU Aug 30 @ 23:20

Study Day 2 = Patient randomized to TOP-UP Aug 31 @ 12:35

Study Day 8 = Patient discharged from ICU Sept 6 @ 18:04

Study Day 9 = Last day of Daily Data Collection (7 days post randomization*)

Sep 7 @ 23:59

Study Day 12 = Last day of Antibiotic and Microbiology collection (10 days post randomization**)

Sep 10 @ 23:59

EXAMPLE:

*7 Days post randomization = Day of randomization Plus 7 full days**10 Days post randomization = Day of randomization Plus 10 full days

The duration of the study intervention is:

7 days post randomization* or until death whichever comes first

CRS/REDCAP Manual April 11th 2012

Resources online

www.criticalcarenutrition.com