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A Randomized Trial of Supplemental Parenteral Nutrition in Under and Over Weight Critically Ill Patients: The TOP UP Trial April 12 th 2012 Study Sponsor:

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Presentation on theme: "A Randomized Trial of Supplemental Parenteral Nutrition in Under and Over Weight Critically Ill Patients: The TOP UP Trial April 12 th 2012 Study Sponsor:"— Presentation transcript:

1 A Randomized Trial of Supplemental Parenteral Nutrition in Under and Over Weight Critically Ill Patients: The TOP UP Trial April 12 th 2012 Study Sponsor: Dr. Daren Heyland Project Leader: Rupinder Dhaliwal Project Assistant: Roger Leung Clinical Evaluation Research Unit

2 Protocol: Version April 11 th 2012

3 Background & Objectives

4 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 >72 hours

5 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

6

7 ICU patients are not all created equal…should we expect the impact of nutrition therapy to be the same across all patients?

8 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

9 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

10 ICU patients BMI <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: Site BMI Med vs Surg On EN

11 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.

12 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

13 Study Overview Imp Manual p 9

14 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 Nuns Hospital, Edmonton (Dan Stollery) University of Wisconsin (Ken Kudsk) Oregon Health Sciences University (Robert Martindale)

15 Pharmacist Checking allocation Dispensing Logs TOP UP Teamwork Dietitian Dosing Calculation Optimizing nutrition Monitoring Adequacy Study Coordinator Regulatory Screening/Randomization Pharmacy communication Data collection Study intervention monitoring Collaboration with SI SAE reporting Protocol Violation reporting Site Investigator Regulatory Inclusion/exclusion criteria ICU infection adjudication SAE reporting Nurse Adjust EN + PN hourly Product Reconstitution?

16 Role of Site Investigator Delegation of Authority Patient Eligibility ICU Infection adjudication SAE identification/assessment Investigator Confirmation

17 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

18 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 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

19 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

20 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 Childs 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

21 Eligibility confirmation Prompted at time of Pre randomization Refer to Consent Training Slides

22 Infection Adjudication Site Investigator to make determination of a newly acquired infection based on antibiotic and microbiology data

23 Infection Adjudication CRS/REDCAP manual p 21-27

24 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

25 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

26 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

27 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 for step by step process

28 SAE Identification and Reporting

29 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

30 SAE Reporting (to CERU) Imp Manual p X Must be done on electronic data capture system and faxed to CERU

31 Imp Manual p XX-XX

32

33 Imp Manual p XX

34 Imp Manual appendix J

35 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)

36 Investigator Confirmation CRS/REDCAP Manual p 30

37 Study Groups Name of Group Intervention Supplemental PNEN (enteral nutrition) plus Olimel EN only EN Imp Manual p X

38 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)

39 Protein and Calorie needs Minimum EnergyMinimum Protein BMI<2525 kcals/kg actual wt1.2 g/kg actual wt BMI 3520 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

40 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 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

41 Study Tools

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

43 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

44 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

45 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)

46 Baseline Nutrition CRFs p 12-13

47 CRFs p 20-21,23 Daily EN Monitoring

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

49 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

50 Supplemental PN group

51 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

52 Olimel N9E (with electrolytes) Product monograph

53 When to start Olimel? Start as soon as central line access Preferably within 2 hrs of randomization Imp Manual p X

54 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

55 Imp Manual appendix F

56 Sample MD orders (Supplemental Group) Imp Manual p X

57 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

58 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 first NO daily titration needed If in ICU & PN indicated, use Olimel If out of ICU & PN indicated, use standard PN Imp Manual p X

59 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 VIOLATION Report to CERU asap Imp Manual p X

60 EN only group

61 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

62 Imp Manual appendix C

63 Sample MD orders (EN only Group) Imp Manual p X

64 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

65 Both groups EN only & Supplemental PN group

66 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

67 Co-interventions Follow Canadian Nutrition Guidelines Glycemic Control Protocol Daily sedation vacations Sepsis management guidelines Daily trials of weaning from mechanical ventilation Imp Manual p X

68 Investigational Product Dispensing & Storage

69 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

70 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

71 Central Randomization System Upon randomization, Research Coordinator will be notified of the study group the patient has been randomized to EN only or EN + Supplemental PN CRS/REDCAP Manual p 12

72 Supplemental PN 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 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

73 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

74 Olimel in overpouch

75 Labels Study: The TOP-UP Study ID #: NCT 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) Imp Manual p X

76 Imp Manual appendix D

77 Imp Manual appendix E

78 Nursing Procedures Training Slides available on Reconstitution of Olimel nutrition.com Imp Manual p X

79 Reconstitution of Olimel done by Nurse and/or Research Coordinator

80 Olimel in overpouch

81 After removing pouch, check the Oxygen indicator Black Light yellow brown After overwrap has been removed, Olimel can be stored for 24 hours under refrigeration followed by 24 hours administration

82 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

83 1. Ensure that the product is at room temperature when breaking the non- permanent seals 2. After removing overpouch, manually roll bag from hanger side down

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

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

86

87 Mix well by inverting the bag 3 times

88 1.Solution will turn to a milky color & is ready to hang 2.Use immediately after reconstitution

89 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 Research Coordinator/Pharmacist dispenses product for patient Research Coordinator informs RN Patient started on intervention 72 hrs + 2 hrs from admission

90 Muscle Function Tests

91 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

92 Abdominal/Pelvic CT Scan Why? Assess muscle mass (at 3 rd 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, CRF p 34-35

93 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

94 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

95 Need to get from physio, RN flowsheet or RN (daily) CRF page 36,37 Rehab Practices

96 Research Coordinator Procedures Consent (Training Module) Training of nurses Data Collection Protocol Violations Imp Manual

97 Case Report Forms CRFs April 12 th 2012

98 Duration of Data Collection

99 · 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 :

100 Duration of Study Intervention

101 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 ICUAug 23:20 Study Day 2 = Patient randomized to TOP-UPAug 12:35 Study Day 8 = Patient discharged from ICUSept 18:04 Study Day 9 = Last day of Daily Data Collection (7 days post randomization*) Sep 23:59 Study Day 12 = Last day of Antibiotic and Microbiology collection (10 days post randomization**) Sep 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

102 CRS/REDCAP Manual April 11 th 2012

103 Resources online

104


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