The HepatoPancreaticoBiliary Resection Arginine Immunomodulation (PRIMe) Trial (PRIMe)

The HepatoPancreaticoBiliary Resection Arginine Immunomodulation (PRIMe) Trial: A Randomized Phase II Trial of the Impact of Perioperative Immunomodulation on Immune Function Following Resection for HepatoPancreaticoBiliary Malignancy

This is a randomized controlled blinded superiority trial to evaluate the impact of perioperative immunosupplementation on immune function following resection for hepatopancreaticobiliary (HPB) malignancy.

Study Overview

• Status: Completed
• Conditions: Surgery; Hepatopancreaticobiliary (HPB) Malignancy
• Intervention / Treatment: Dietary supplement: Active A; Dietary supplement: Lipid bolus; Dietary supplement: Placebo oil; Dietary supplement: Active B

Detailed Description

This is a 1:1:1 randomized controlled blinded superiority trial to evaluate the impact of perioperative immunosupplementation on immune function following resection for hepatopancreaticobiliary (HPB) malignancy. Two variations of immunosupplementation will be compared to control nutritional supplement containing whey protein with an additional teaspoon (tsp) of placebo oil. These variations will be 1) a powdered formula containing whey protein and arginine (Active A) with an additional tsp of lipid bolus containing omega-3 fatty acids, and 2) a powdered formula containing whey protein and arginine (Active A) with an additional tsp of placebo oil which does not contain omega-3 fatty acids. The control nutritional supplement will be a powdered formula containing whey protein with an additional tsp of placebo oil.

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • The Ottawa Hospital - General Campus
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Sciences Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients age 18 and over at time of diagnosis
• Resectable presumed liver, pancreas, or bile duct malignancy (i.e., liver metastases, HCC, cholangiocarcinoma, pancreatic or periampullary adenocarcinoma, NETs)as determined by surgeon in clinic
• Anticipated hospital stay at least three days post-surgery
• Ability to tolerate oral intake and comply with protocol requirements

Exclusion Criteria:

• Documented significant immunodeficiency due to underlying illness (e.g. HIV/AIDS) and/or medication (e.g. systemic corticosteroids, azathioprine, cyclosporin A). Subjects may be on physiologic doses of replacement prednisone or equivalent doses of corticosteroid (<7.5 mg daily)
• Subjects with resting hypotension (BP <90/50 at rest)
• History of autoimmune disease, such as but not restricted to, inflammatory bowel disease, systemic lupus erythematosus, ankylosing spondylitis, scleroderma, or multiple sclerosis
• Serious, active, intercurrent chronic or acute illness, or other active illness considered by the investigator as an unwarranted high risk for an investigational product
• Active infection of any site and/or active herpes requiring ongoing treatment
• Known pregnancy or nursing mothers
• Subjects with an allergy to the nutritional supplement or comparator including milk, fish and/or shellfish allergies
• Subjects with religious or other objections to consuming fish or shellfish
• Subjects with severe asthma defined as asthma not controlled with inhaled corticosteroids and additional controllers or by oral corticosteroid treatment (arginine can cause allergic response or make swelling in airways worse)
• Subjects with a known inherited guanidinoacetate methyltransferase deficiency (due to an inability to convert arginine to creatine)
• Subject with known current liver cirrhosis
• Subjects with documented myocardial infarction or life-threatening arrhythmia
• Subjects with known current cardiac failure or coronary artery disease causing unstable angina

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A; Powdered formula containing whey protein and arginine (Active A) and lipid bolus containing omega 3 fatty acids. Participants will mix the powder (Active A) with 250 mL of water and drink the formula 3 times per day for 5 days. Each drink will be followed by consuming 1 tsp of the lipid bolus. This will be done for 5 days prior to the operation and for 5 days after the operation.	Dietary supplement: Active A; Powdered formula containing whey protein and arginine; Dietary supplement: Lipid bolus; Omega-3 fatty acids
Active Comparator: Group B; Powdered formula containing whey protein and arginine (Active A) and placebo oil. Participants will mix the powder (Active A) with 250 mL of water and drink the formula 3 times per day for 5 days. Each drink will be followed by consuming 1 tsp of the lipid bolus. This will be done for 5 days prior to the operation and for 5 days after the operation.	Dietary supplement: Active A; Powdered formula containing whey protein and arginine; Dietary supplement: Placebo oil; Control placebo oil that does not contain omega-3 fatty acids
Placebo Comparator: Comparator; Powdered formula containing whey protein (Active B) and placebo oil. Participants will mix the powder (Active B) with 250 mL of water and drink the formula 3 times per day for 5 days. Each drink will be followed by consuming 1 tsp of the lipid bolus. This will be done for 5 days prior to the operation and for 5 days after the operation.	Dietary supplement: Placebo oil; Control placebo oil that does not contain omega-3 fatty acids; Dietary supplement: Active B; Powdered formula containing whey protein

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Natural killer (NK) cell killing	Reduction in NK cell killing as measured on post-operative day one (POD1) as compared to baseline (pre-operative) between the control and experimental cohorts. Nutritional supplementation will be considered effective at reducing postoperative NK cell dysfunction if there is a 50% or greater improvement in postoperative suppression of NK cell cytotoxicity (reduction of 27% from baseline).	Post-operative day 1 (Day 1) as compared to baseline (pre-operative)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Secondary immune function outcomes: Immune cell subsets	Flow cytometric analysis of different immune cell subsets to compare their proportions at all time points.	Day of surgery to 30-days after surgery
Secondary immune function outcomes: NK cell activating and inhibitory receptors	Flow cytometric characterization of NK cell activating and inhibitory receptors to assess whether they are affected by immunosupplementation.	Day of surgery to 30-days after surgery
Secondary immune function outcomes: amino acid levels	Systemic blood levels of amino acids will be measured via liquid chromatography-mass spectrometry protein card analysis.	Day of surgery to 30-days after surgery
Incidence of pancreatic fistula	Pancreatic fistula of International Study Group on Pancreatic Fistula (ISGPF) Grade B & C (i.e. clinically significant) will be diagnosed clinically.	Day of surgery to 90-days after surgery
Postoperative wound complication and surgical site infection	Wound complications including dehiscence and infection will be diagnosed clinically.	Day of surgery to 90-days after surgery
Length of stay	Length of stay will be measured as number of days from admission to discharge.	Day of surgery to day of discharge after surgery, assessed until day of discharge after surgery occurs
90-day postoperative complications (Clavien-Dindo 3-5)	Postoperative complications with Clavien-Dindo Grades 3-5 (i.e. requiring procedural intervention or ICU admission, or causing death) will be recorded.	Day of surgery to 90-days after surgery
90-day postoperative mortality	The incidence of readmission within 90 days of surgery will be recorded as the number of days associated with each re-admission. Death within 90 days of surgery will be considered complications of the surgery.	Day of surgery to 90-days after surgery
Incidence of liver insufficiency	Posthepatectomy liver failure of International Study Group of Liver Surgery (ISGLS) Grade B & C (i.e. clinically significant) will be diagnosed clinically	Day of surgery to 90-days after surgery

Collaborators and Investigators

• Sponsor: Sunnybrook Health Sciences Centre
• Collaborators: Enhanced Medical Nutrition; Sunnybrook Health Sciences Centre Clinical Research Grant Competition; Sunnybrook Health Sciences Centre AFP Innovation Fund
• Investigators: Principal Investigator: Paul Karanicolas, MD, PhD, Sunnybrook Health Sciences Centre

Study record dates

Study Major Dates

• Study Start (Actual): June 16, 2021
• Primary Completion (Actual): February 12, 2024
• Study Completion (Actual): February 12, 2024

Study Registration Dates

• First Submitted: August 14, 2020
• First Submitted That Met QC Criteria: September 14, 2020
• First Posted (Actual): September 16, 2020

Study Record Updates

• Last Update Posted (Actual): April 3, 2024
• Last Update Submitted That Met QC Criteria: April 2, 2024
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: immunomodulation; arginine; omega-3 fatty acids
• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: 076-2017

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No