The HepatoPancreaticoBiliary Resection Arginine Immunomodulation (PRIMe) Trial

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

Detailed Description
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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.

Official Title
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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

Conditions
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Hepatopancreaticobiliary (HPB) Malignancy, Surgery

Intervention / Treatment
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* Dietary Supplement: Active A
* Dietary Supplement: Active B
* Dietary Supplement: Lipid bolus
* Dietary Supplement: Placebo oil


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>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<br>* Powdered formula containing whey protein and arginine<br>Dietary Supplement: Lipid bolus<br>* Omega-3 fatty acids<br>|
| Active Comparator: Group B<br>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<br>* Powdered formula containing whey protein and arginine<br>Dietary Supplement: Placebo oil<br>* Control placebo oil that does not contain omega-3 fatty acids<br>|
| Placebo Comparator: Comparator<br>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: Active B<br>* Powdered formula containing whey protein<br>Dietary Supplement: Placebo oil<br>* Control placebo oil that does not contain omega-3 fatty acids<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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immunomodulation, omega-3 fatty acids, arginine