Surgical Recovery
Conditions
Brief 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.
Interventions
DRUGCocoaVia®
CocoaVia® is manufactured by Mars, Inc. It is a dietary supplement of cocoa bean extract, containing 125 mg cocoa flavanols per capsule.
OTHERPlacebo
The placebo capsules will contain an inert ingredient packaged to be indistinguishable from the active treatment.
Sponsors
Stanford University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Placebo and active treatments will be formulated in identical capsules, and bottled and labeled with coded study numbers that will allow for all parties to remain blinded throughout the data collection phase.
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
1. 18 - 90 years of age 2. Male or female 3. Planning to undergo total hip or knee arthroplasty, either primary or revision 4. Fluent in English 5. Willing and able to sign an informed consent form and HIPAA authorization and to comply with study procedures
Exclusion criteria
1. Infectious disease within the last month 2. Immune-suppressant therapy within the last 2 months (e.g., azathioprine or cyclosporine) 3. Chronic medication with potential immune-modulatory effects (e.g., daily oral morphine-equivalent intake \> 30 mg) 4. Major surgery within the last 3 months or minor surgery within the last month. 5. History of substance abuse (e.g., alcoholism, drug dependency) 6. Pregnancy 7. Autoimmune disease interfering with data interpretation (e.g. lupus) 8. Renal, hepatic, cardiovascular, or respiratory diseases resulting in clinically relevant impaired function 9. Active malignancy 10. Participation in another clinical trial of an investigational drug or device within the last month that, in the investigator's opinion, would create an increased risk to the participant or compromise the integrity of the study 11. Other conditions compromising a participant's safety or the integrity of the study 12. Allergy to active ingredient of CocoaVia®, the study intervention. 13. Frequent consumption of dark chocolate and flavanol containing foods (e.g. black tea, red wine, apples)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| NFkB Signaling in Innate Immune Cells | 1 hour and 48 hours following surgery | Blood samples will be collected to measure possible attenuation of surgery-evoked increase in NFkB signaling in innate immune cells shortly after surgery at specified time points. Phosphorylation of functional markers (activity) was expressed as the arcsinh-transformed value of the median value. Changes in activity over time were captured by building the arcsinh ratio between the arcsinh-value obtained in samples collected at a given time with the arcsinh-value obtained in samples collected at baseline, i.e., before starting the intervention with CocoaVia. Results are reported for NFkB (p65). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| HMGB1 Level in Blood Plasma | 1 hour and 48 hours following surgery. | Blood samples will be collected to measure possible attenuation of surgery-evoked increase of HMGB1 in blood plasma shortly after surgery at specified time points. |
| Step Count Per Minute as a Measure of Functional Recovery - Objective | post-surgical observation period (6 weeks) | Participants wear an Actigraph watch with measurements taken every 30 seconds. The watch objectively and continuously reports a participant's activity and sleep. |
| Days to Mild Impairment as a Measure of Functional Recovery - Subjective | 5 days before surgery though 6 weeks post op. | Participants will complete the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire (function subscale) before surgery, daily during hospitalization, and weekly through week 6 post op. Higher WOMAC scores equate to greater functional limitations. Range of possible scores is 0 - 68 |
| Days to Mild Pain as Assessed by WOMAC Pain Scores | 5 days before surgery though 6 weeks post op. | Participants will complete the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire (pain subscale) before surgery, daily during hospitalization, and weekly through week 6 post op. Higher WOMAC scores equate to greater pain. Range of possible scores is 0 - 20. |
| Days to Half Max Recovery From Fatigue | 5 days before surgery though 6 weeks post op. | Participants will complete the Surgery Recovery Scale (SRS) questionnaire before surgery, daily during hospitalization, and weekly through week 6 post op to evaluate post op fatigue. Higher SRS scores reflect less fatigue, lower scores reflect greater fatigue. Total SRS score range from 17.81 to 100. |
Countries
United States
Participant flow
Recruitment details
Recruitment took place in the pre-anesthesia and orthopedic clinics at Stanford Medical Center. Recruitment was conducted from 3/01/2017 with the final study intervention for the final patient on 12/14/2018.
Pre-assignment details
A total of 32 participants that were consented/enrolled were dropped prior to randomization for a variety of reasons. Participants changed their minds, exclusion criteria were identified after consent but before study participation began, and early non-compliance with the survey completion were all reasons for withdrawal after consent.
Participants by arm
| Arm | Count |
|---|---|
| Active Treatment Group - Group A Participants will receive a daily oral dose of 1,000 mg cocoa flavanol (CocoaVia®) for 5 days before surgery. The daily dose will consist of 8 capsules in divided doses throughout the day.
CocoaVia®: CocoaVia® is manufactured by Mars, Inc. It is a dietary supplement of cocoa bean extract, containing 125 mg cocoa flavanols per capsule. | 22 |
| Placebo Treatment Group - Group B Participants will receive a daily oral dose of a placebo for 5 days before surgery. The daily dose will consist of 8 capsules in divided doses throughout the day.
Placebo: The placebo capsules will contain an inert ingredient packaged to be indistinguishable from the active treatment. | 20 |
| Total | 42 |
Baseline characteristics
| Characteristic | Active Treatment Group - Group A | Placebo Treatment Group - Group B | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 14 Participants | 8 Participants | 22 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 12 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 3 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants | 16 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 5 Participants | 8 Participants |
| Race (NIH/OMB) White | 19 Participants | 13 Participants | 32 Participants |
| Sex: Female, Male Female | 14 Participants | 11 Participants | 25 Participants |
| Sex: Female, Male Male | 8 Participants | 9 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 22 | 0 / 20 |
| other Total, other adverse events | 8 / 22 | 7 / 20 |
| serious Total, serious adverse events | 1 / 22 | 0 / 20 |
Outcome results
Primary
NFkB Signaling in Innate Immune Cells
Blood samples will be collected to measure possible attenuation of surgery-evoked increase in NFkB signaling in innate immune cells shortly after surgery at specified time points. Phosphorylation of functional markers (activity) was expressed as the arcsinh-transformed value of the median value. Changes in activity over time were captured by building the arcsinh ratio between the arcsinh-value obtained in samples collected at a given time with the arcsinh-value obtained in samples collected at baseline, i.e., before starting the intervention with CocoaVia. Results are reported for NFkB (p65).
Time frame: 1 hour and 48 hours following surgery
Population: Participants with available data are included in the analysis.~Three patients were excluded from the molecular analysis because of incorrect intake of the study medication, difficulties obtaining blood draws, and a non-recognized immune disorder. Exclusion of patients from the analyses was determined before unblinding.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Active Treatment Group - Group A | NFkB Signaling in Innate Immune Cells | 1 hour following surgery | 0.68 NFkB (p65) arcsinh ratio |
| Active Treatment Group - Group A | NFkB Signaling in Innate Immune Cells | 48 hours following surgery | 0.71 NFkB (p65) arcsinh ratio |
| Placebo Treatment Group - Group B | NFkB Signaling in Innate Immune Cells | 1 hour following surgery | 0.69 NFkB (p65) arcsinh ratio |
| Placebo Treatment Group - Group B | NFkB Signaling in Innate Immune Cells | 48 hours following surgery | 0.71 NFkB (p65) arcsinh ratio |
Secondary
Days to Half Max Recovery From Fatigue
Participants will complete the Surgery Recovery Scale (SRS) questionnaire before surgery, daily during hospitalization, and weekly through week 6 post op to evaluate post op fatigue. Higher SRS scores reflect less fatigue, lower scores reflect greater fatigue. Total SRS score range from 17.81 to 100.
Time frame: 5 days before surgery though 6 weeks post op.
Population: Three patients were excluded from the molecular analysis because of incorrect intake of the study medication, difficulties obtaining blood draws, and a non-recognized immune disorder. Four additional patients were excluded from the analysis including clinical data because respective questionnaires were not answered reliably. Exclusion of patients from the analyses was determined before unblinding.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Active Treatment Group - Group A | Days to Half Max Recovery From Fatigue | 14 days |
| Placebo Treatment Group - Group B | Days to Half Max Recovery From Fatigue | 7 days |
Secondary
Days to Mild Impairment as a Measure of Functional Recovery - Subjective
Participants will complete the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire (function subscale) before surgery, daily during hospitalization, and weekly through week 6 post op. Higher WOMAC scores equate to greater functional limitations. Range of possible scores is 0 - 68
Time frame: 5 days before surgery though 6 weeks post op.
Population: Three patients were excluded from the molecular analysis because of incorrect intake of the study medication, difficulties obtaining blood draws, and a non-recognized immune disorder. Four additional patients were excluded from the analysis including clinical data because respective questionnaires were not answered reliably. Exclusion of patients from the analyses was determined before unblinding.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Active Treatment Group - Group A | Days to Mild Impairment as a Measure of Functional Recovery - Subjective | 35 days |
| Placebo Treatment Group - Group B | Days to Mild Impairment as a Measure of Functional Recovery - Subjective | 14 days |
Secondary
Days to Mild Pain as Assessed by WOMAC Pain Scores
Participants will complete the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire (pain subscale) before surgery, daily during hospitalization, and weekly through week 6 post op. Higher WOMAC scores equate to greater pain. Range of possible scores is 0 - 20.
Time frame: 5 days before surgery though 6 weeks post op.
Population: Three patients were excluded from the molecular analysis because of incorrect intake of the study medication, difficulties obtaining blood draws, and a non-recognized immune disorder. Four additional patients were excluded from the analysis including clinical data because respective questionnaires were not answered reliably. The total participants included in this analysis is 35. Exclusion of patients from the analyses was determined before unblinding.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Active Treatment Group - Group A | Days to Mild Pain as Assessed by WOMAC Pain Scores | 28 days |
| Placebo Treatment Group - Group B | Days to Mild Pain as Assessed by WOMAC Pain Scores | 25 days |
Secondary
HMGB1 Level in Blood Plasma
Blood samples will be collected to measure possible attenuation of surgery-evoked increase of HMGB1 in blood plasma shortly after surgery at specified time points.
Time frame: 1 hour and 48 hours following surgery.
Population: Three patients were excluded from the molecular analysis because of incorrect intake of the study medication, difficulties obtaining blood draws, and a non-recognized immune disorder. Four additional patients were excluded from the analysis including clinical data because respective questionnaires were not answered reliably. The total participants included in this analysis is 35. Exclusion of patients from the analyses was determined before unblinding.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Active Treatment Group - Group A | HMGB1 Level in Blood Plasma | 1 hour following surgery | NA ng/ml |
| Active Treatment Group - Group A | HMGB1 Level in Blood Plasma | 48 hours following surgery | NA ng/ml |
| Placebo Treatment Group - Group B | HMGB1 Level in Blood Plasma | 1 hour following surgery | NA ng/ml |
| Placebo Treatment Group - Group B | HMGB1 Level in Blood Plasma | 48 hours following surgery | NA ng/ml |
Secondary
Step Count Per Minute as a Measure of Functional Recovery - Objective
Participants wear an Actigraph watch with measurements taken every 30 seconds. The watch objectively and continuously reports a participant's activity and sleep.
Time frame: post-surgical observation period (6 weeks)
Population: Participants with available data are included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active Treatment Group - Group A | Step Count Per Minute as a Measure of Functional Recovery - Objective | 0.02 steps | Standard Deviation 0.05 |
| Placebo Treatment Group - Group B | Step Count Per Minute as a Measure of Functional Recovery - Objective | 0.04 steps | Standard Deviation 0.06 |
p-value: >0.05Mann Whitney U test