The REDOXS © Study REducing Deaths from OXidative Stress Study Chair Dr. Daren Heyland, MD, FRCPC Project Leader Rupinder Dhaliwal, BASc, RD

Research Questions In critically ill patients with severe organ dysfunction, what is the effect of: 1) Glutamine supplementation compared to placebo on 28-day mortality? 2) Antioxidant supplementation compared to placebo on 28-day mortality?

Effect of Glutamine: A Systematic Review of the Literature Mortality

Effect of Glutamine: A Systematic Review of the Literature Infectious Complications

Effect of Combined Antioxidant Strategies in the Critically Ill Effect on Mortality

Inferences High dose appears safe High dose associated with –no worsening of SOFA Scores –greater resolution of oxidative stress –greater preservation of glutathione –Improved mitochondrial function Heyland JPEN Mar 2007 ParenterallyEnterally Glutamine/day0.35 gms/kg30 gms Antioxidants per day 500 mcg Selenium Vit C 1500 mg Vit E 500 mg B carotene 10 mg Zinc 20 mg Se 300 ug

1200 ICU patients Evidence of organ failure R glutamine placebo R R antioxidants placebo Factorial 2x2 design placebo antioxidants Design

Enteral Supplement Parenteral Supplement GLN +AOXGlutamine + AOXDipeptiven + Selenium AOXAOX onlyPlacebo + Selenium GLNGlutamine onlyDipeptiven + Placebo Placebo Placebo + Placebo Study Groups SC blindedPharmacist unblinded

Pharmacist Checking allocation Dispensing Logs REDOXS © Teamwork Study Coordinator Regulatory Screening/Randomization Pharmacy communication Data collection Supplement monitoring Collaboration with SI SAE reporting Protocol Violation reporting Dietitian Optimizing nutrition Monitoring Adequacy Site Investigator Regulatory Inclusion/exclusion criteria ICU infection adjudication SAE reporting

Optimizing Enteral Nutrition Canadian CPGs Feeding Protocol Elevate the Head of the Bed Motility Agents Small Bowel Feeding

Baseline Nutrition Dietitian to collect: Prescribed kcal and protein (baseline) Type of nutrition support Start and stop date and times Refer to Dietitian Manual

Dietitian Checklist

Study Supplement Compliance Volumes must be monitored DAILY in real time. If volumes < prescribed, need to report to CERU or provide explanation and take action to prevent recurrence. Protocol Violation Protocol Deviation

Administration of Study Supplements

Enteral Study Supplement EN REDOXS © Formula

Parenteral Study Supplements ( Dipeptiven and Selenium) +

Start of Supplements Start ASAP –within 24 hrs of admission to ICU –within 2 hrs of randomization Duration: 28 days or death or discharge –min of 5 days Parenteral supplements –as soon as patient resuscitated –10 ml/hr dedicated central port (eg. one of a triple lumen) –can run peripherally if needed (watch for phlebitis) –Do NOT infuse with medications; IV fluids, albumin, nutrition OK Enteral supplement –NG tube OK or feeding tube –20 ml/hr, can be given via Y connector –start regardless of whether docs want to start enteral nutrition

Maximize EN nutrient and nutrition delivery –use of feeding protocols –small bowel feeding Minimize interruptions, make up volume Other enteral formulas with supplmental glutamine, vitamins, minerals not allowed –No supplements with high amounts of Zinc Renal Dysfunction –Switch to lower protein formula –Restrict fluid –Refer to appendix If received volumes < Prescribed = Protocol Violation……….notify Methods Centre !! Pilot study: Interruptions due to high urea only in 2% patient days (9% patients)

Screening and Randomization

Web Login Page

Welcome Home Page (Site Status Page)

Patient Status Page

Inclusion/exclusion criteria Refer to inclusion/exclusion criteria cards

Inclusion Criteria

Exclusion Criteria CORRECTION: should be >24 hours from ICU admission to time of consent

Randomization Refer to Appendix 1 Randomization on Web

Screen New Subject “Only Subjects Who Meet Inclusion Criteria” Meets an Exclusion Screening Form Inclusion/Exclusion No End s  Consent Obtained  Subject’s Height in cm.  CLICK here to Randomize Patient button No Exclusion Eligible for Study Yes Explain why Pre Randomization Form Eligibility Must Be Confirmed By MD Do you obtain consent? Pharmacist Receives call from Study Coordinator Pharmacist Logs onto Web Pharmacist Receives  Treatment Assignment  Subject’s Initials  Date of Birth  Height Subject is now Randomized Enrollment Number Is____  Contact your Site Pharmacy and enter date and time of contact.  Provide Height/Subject Initials/ DOB/Enrollment Number After Randomization Study Coordinator Expected to Complete Baseline Form & APACHE Score and other Electronic CRFs End

Pre-Randomization  Consent

If Randomized Print the page and notify the study pharmacist of: Patient randomization number Height in cms Patient initials and DOB

 Consent

Enter Screening Data for ALL patients meeting inclusion criteria, including those meeting an exclusion criteria and those that refuse consent! END

Pharmacy

Pharmacy Log In

Pharmacy Treatment assignment Note: this is not the randomization list that will be used for the study.

Supply of Supplements Fresenius Kabi and Baxter (Calea) Before start: Supplies to be shipped to sites Need updated pharmacy contact and shipping address

Dispensing ICU pharmacist  dispensing pharmacist Sign signature log Enteral supplements –no mixing needed Parenteral supplements –Mixing required: Dipeptiven (Glutamine) + Selenium (AOX) + Normal Saline

Enteral Products Obtain appropriate enteral product Infuse at 20 ml/hour for all patients Generate pharmacy label (need 2 labels)

Remove company label and staple to Form B Attach pharmacy label to bottle (maintain blinding)

Enteral Dispensing Log

Mixing of Parenteral Supplements Dipeptiven (Glutamine) + Selenium (AOX) + Normal Saline Final volume = 250 mls, hourly rate = 10 ml/hr. 1. Determine dose of Glutamine according to Normal weight Normal Weight (kg) = height (cms) –100 cms Dose of Dipeptiven = Normal wt. X 2.5 mls (This equals to Normal wt. X 0.35 gms of Glutamine or Normal weight X 0.5 gms of L-alanyl-L-Glutamine). 2. Dose of Selenium = 12.5 ml (500 micrograms) = 1.25 vial 3. Combine the Glutamine + Selenium and remove this volume from 250 ml of normal saline. 4. Replace normal saline with this mixture. Final volume =250 mls.

Parenteral Worksheet: AOX Should be 10.8 ml/hr

Parenteral Worksheet: GLN Should be 10.8 ml/hr

Parenteral Worksheet: AOX+GLN Should be 10.8 ml/hr

Parenteral Worksheet: Placebo Should be 10.8 ml/hr

Expiration of Supplements Selenium once opened: 24 hrs if refrigerated Dipeptiven once opened: mix immediately Once mixed, parenteral solutions have an expiration of 96 hrs room temperature –Can make in batches to last 3 days!! Enteral Supplements once opened: 24 hrs

Parenteral Study Supplement Log

Parenteral Label

Dosages according to height (PN) If > 6 feet 5 inches (>196 cms) Final volume of parenteral solution will be between mls. Can still use 250 mls bag of saline If no normal saline to be used, use an empty sterile bag and add supplements to the bag (instead of removing all normal saline) Final rate of solution will exceed 10 ml/hr Central line needed but peripheral may be used (72 hrs max) Pilot Study: no one > 190 cms (6’3”)

Nutrient Accountability Logs One log for each product except for normal saline

Monthly Site Inventory Log Fax in to CERU monthly

Temperature Log Fax in to CERU monthly

Study Coordinator

General Rules for Data Collection CERU to assign passwords, site # Dates DD/MMM/YYYY, 00:00 Click on + to expand menu or taxonomy Site Status Page: shows all patients Patient Status Page : colour coding Input warnings : help with query process

Site Status Page

Patient Status Page

Duration of Data Collection For daily data from Study Day 1 until Day 30 unless ICU discharge (actual) or death occurs before day 30 EXCEPT the following: –Study Supplement Compliance: maximum of 28 days. –Microbiology: -7 days ICU admission to ICU discharge. –Antibiotics: -7 days ICU admission and stop dates may extend beyond ICU discharge. –Patients with ICU stay < 5 days and transferred to ward: collect all daily data from Study Day 1 and continue for 5 days in total (=120 hrs). Study Day 1 is from ICU admission to end of flowsheet. Study Day 2 and subsequent days are according to your 24 hr flowsheet

Baseline  Hypotension  Respiratory Failure OK to wait Must be completed Logical sequence

APACHE II May use existing APACHE score if available Lowest and highest values Score automatically generated

Study Supplement Timelines Duration of supplements: Minimum 5 days (120 hrs) Maximum 28 days Start and stop dates and times

Baseline Nutrition Dietitian to collect: Prescribed kcal and protein (baseline) Type of nutrition support Start and stop date and times Refer to Dietitian Manual

Daily Data Study Day 1 is from ICU admission to end of your 24 hr flowsheet. Study Day 2 and subsequent days are according to your 24 hr flowsheet. Dietitian may help by collecting the location of feeding tube

Daily Nutrition Dietitian to collect the data and give to SC Close to real time to ensure that patient is being fed adequately. Use checklist (see sample in Dietitian Manual)

Dietitian Checklist

Study Supplement Compliance Volumes must be monitored DAILY in real time. If volumes < prescribed, need to report to CERU or provide explanation and take action to prevent recurrence. Protocol Violation Protocol Deviation

Volume of study supplement actually received is less than the prescribed volume in 24hrs Enteral < 80% prescribed Parenteral <90% prescribed Complete Violation Form within 24 hours of discovery & Fax to CERU Attention: Project Leader (613) Volume of study supplement actually received is less than the prescribed volume in 24hrs Enteral ≥ 80% < 100% prescribed Parenteral ≥ 90% <100% prescribed Provide explanation on the worksheet/web based data entry (Study Supplement Compliance) Protocol Violation Protocol Deviation

Protocol Violation Form

Vasopressors/Inotropes Highest hourly dose received

Concomitant Medications

Input Warnings

Microbiology Collect all positive cultures starting 7 days prior to ICU admission. If culture date> 72 hrs ICU admission, 2 questions will be asked to help determine suspicion of ICU acquired infection.

Suspicion of ICU Infection Is this culture a manifestation of a previously diagnosed infection? Is this a routine surveillance swab? NEED TO ASK SITE INVESTIGATOR If NO to both………………..flag for adjudication (to be done after ICU outcomes).

Antibiotics Period of data collection starts 7 days prior to ICU admission and may extend beyond ICU discharge. If abx started > 72 hr ICU admission, 3 questions will be asked to help determine suspicion of ICU acquired infection.

Suspicion of ICU Infection Is this antibiotic prescribed for prophylaxis? Is this a dose adjustment for an antibiotic ordered for a previous infection? Is this a substitute for an antibiotic ordered for a previous infection? NEED TO ASK SITE INVESTIGATOR If NO to ALL………………..flag for adjudication (to be done after ICU outcomes).

ICU Outcomes All input warnings must be addressed before you can access this page. The input warnings will appear at the top of the Patient Status Page. This page MUST be completed before you can proceed to the next web pages

Infection Adjudication All input warnings must be resolved

Automatic listing of relevant clinical data (microbiology. antibiotics, daily data) that will enable the Site Investigator to adjudicate newly acquired ICU infections.

No Possible** NO END Was this culture or the prescription of this antibiotic for a NEW ICU acquired infection? (after 72 hours of admission from ICU admission)? Choose the appropriate Categories of Infection (1-12)* and if: Definite Yes or Probable Yes or Possible Yes Yes NO, because it is related to an infection previously diagnosed and adjudicated. NO, because it is NOT an infection END Probable* * NO Determination of ICU Infection *Categories of Infection: Appendix 8.2 **Definition of No: Appendix 8.3

Hospital Outcomes

3 and 6 month f/up

SF-36 at 3 and 6 months

Investigator’s Confirmation Only appears once the ICU and Hospital outcomes have been completed and all input warnings have been resolved (Patient Status Page).

SAE Reporting Serious and Unexpected events –regardless of relationships to supplements Initial report faxed within 48 hrs Final report at day 30, ICU d/c, death or 10 days from becoming aware of SAE Record the event, not the outcome (death)

SAE Initial Report

SAE Follow up Report

Daily Monitoring Enteral Study Supplement Volumes < 80 % prescribed: Protocol Violation Form >= 80 and < 100 %: Provide explanation Parenteral Study Supplement Volumes < 90% prescribed: Protocol Violation Form >=90 and < 100%: provide explanation SAEs: unexpected: report within 48 hrs, 10 days Start of antibiotics > 72 hrs ICU admit, ask SI Positive Cultures > 72 hrs ICU admit: ask SI

Threats to Success Poor enrollment, competing studies. Inadequate delivery of study supplements. Inadequate delivery of enteral nutrition. Additional training needs?

Questions?