Cocoa Flavanols for Modulating Immune Response and Accelerating Recovery
Condition: Surgical Recovery
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      This double-blind, placebo-controlled proof-of-concept clinical trial is intended to
      demonstrate that preemptive oral administration of cocoa flavanol for five days before
      surgery will attenuate the surgery-evoked increase of HMGB1 in blood plasma and NFkB
      signaling in innate immune cells shortly after surgery. A secondary aim is to capture
      preliminary patient-centered outcomes data and relate these outcomes to the intake of oral
      cocoa flavanol and surgery-evoked activation of the HMGB1-NFkB signaling axis. Participants
      will be randomized to receive either an over the counter supplement containing cocoa
      flavanols, or placebo, for 5 days before surgery.
    

Detailed description: 
      During the last two decades significant effort has been made to enhance recovery after
      surgery. Despite the implementation of pragmatic and standardized clinical protocols to
      enhance recovery and shorten hospital length of stay, the utility of these protocols for
      improving patient-centered recovery cost-effectively remains uncertain. Critical elements of
      recovery that greatly matter to patients and health care providers include the resolution of
      pain, daily functioning, and loss of postoperative fatigue. A patient-centered and
      cost-effective focus on postoperative recovery pays tribute to three goals of health care:
      Improving patients' experience, improving health, and constraining per capita cost. As such,
      novel and cost-effective strategies are greatly needed to accelerate patient-recovery after
      surgery.

      Preliminary data by Dr. Angst and his collaborators indicate that administration of a cocoa
      flavanol extract that is equivalent in dose to the amount of cocoa flavanol contained in
      about 50 grams of dark chocolate decreases plasma levels of HMGB1. HMGB1 is an archetypical
      alarmin, i.e., an endogenous mediator that is released upon cellular stress and injury. HMGB1
      triggers a pro-inflammatory cascade by binding to toll-like receptors (TLRs) on innate immune
      and other cells, which results in activation of pro-inflammatory transcription factors (e.g.
      NFkB) and the subsequent release of major pro-inflammatory cytokines (e.g. TNFα). The
      prominent role of the HMGB1-TLR axis in inflammatory disease states including surgery,
      trauma, stroke, and myocardial infarction has recently been highlighted.16-19 Importantly,
      dampening activity along this pathway in preclinical injury models has been shown to improve
      outcomes.

      The potential of HMGB1 as a therapeutic target in acute inflammatory disease states has
      recently been emphasized. A major challenge is the identification of effective and non-toxic
      clinical strategies that can safely modulate HMGB1 in humans. This research study will
      evaluate a safe, highly scalable, and relatively cheap pre-surgical nutritional intervention
      that has significant potential to do just that, safely modulate HMGB1 and improve clinical
      recovery after surgery. As such, this proposed research could change clinical practice within
      years. While studied intervention targets a specific pro-inflammatory pathway implicated in
      aggravated tissue damage and delayed healing/recovery, the use of broader and less specific
      anti-inflammatory interventions in the perioperative period including non-steroidal
      anti-inflammatory drugs and corticosteroids is common clinical practice.
    

Intervention name(s): CocoaVia®; Placebo
Intervention type(s): Drug; Other
Intervention description(s): CocoaVia® is manufactured by Mars, Inc. It is a dietary supplement of cocoa bean extract, containing 125 mg cocoa flavanols per capsule.; The placebo capsules will contain an inert ingredient packaged to be indistinguishable from the active treatment.
Other intervention name(s): Cocoa flavanol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment