Surgical RecoveryPhase 1/2NCT03123068
Cocoa Flavanols for Modulating Immune Response and Accelerating Recovery
A Phase 1/2 study testing CocoaVia® in people with Surgical Recovery, run by Stanford University at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 90 years
- Conditions the study is for
- Surgical Recovery
- What is being tested?
- CocoaVia®
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 74 participants
- Where
- 1 siteUnited States
- Study dates
- 17 Apr 2017to 14 Dec 2018
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 90 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 18 - 90 years of age
- Male or female
- Planning to undergo total hip or knee arthroplasty, either primary or revision
- Fluent in English
- Willing and able to sign an informed consent form and HIPAA authorization and to comply with study procedures
Who cannot join
- Infectious disease within the last month
- Immune-suppressant therapy within the last 2 months (e.g., azathioprine or cyclosporine)
- Chronic medication with potential immune-modulatory effects (e.g., daily oral morphine-equivalent intake > 30 mg)
- Major surgery within the last 3 months or minor surgery within the last month.
- History of substance abuse (e.g., alcoholism, drug dependency)
- Pregnancy
Show all 13Show fewer
- Autoimmune disease interfering with data interpretation (e.g. lupus)
- Renal, hepatic, cardiovascular, or respiratory diseases resulting in clinically relevant impaired function
- Active malignancy
- 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
- Other conditions compromising a participant's safety or the integrity of the study
- Allergy to active ingredient of CocoaVia®, the study intervention.
- Frequent consumption of dark chocolate and flavanol containing foods (e.g. black tea, red wine, apples)
Trial locations and contacts
1 site in 1 country.
United States1 site
Stanford University Hospital
Stanford, California, 94305
About this study
Official title: Cocoa Flavanols for Modulating the Surgical Immune Response and Accelerating Clinical Recovery
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.
Read the 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.
- Conditions
- Surgical Recovery
- Being tested
- CocoaVia®, Placebo
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CocoaVia®Drug
Also called Cocoa flavanol
CocoaVia® is manufactured by Mars, Inc. It is a dietary supplement of cocoa bean extract, containing 125 mg cocoa flavanols per capsule.
PlaceboOther
The placebo capsules will contain an inert ingredient packaged to be indistinguishable from the active treatment.
| Study group | Role | What they receive |
|---|---|---|
| Active treatment group - Group A | Active comparator | 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. Receives: Drug: CocoaVia® |
| Placebo treatment group - Group B | Placebo comparator | 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. Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 1 hour and 48 hours following surgery
Secondary outcomes (5)
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.
Measured: 1 hour and 48 hours following surgery.
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.
Measured: post-surgical observation period (6 weeks)
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
Measured: 5 days before surgery though 6 weeks post op.
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.
Measured: 5 days before surgery though 6 weeks post op.
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.
Measured: 5 days before surgery though 6 weeks post op.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Apr 2017
- Study start17 Apr 2017
- Primary completion14 Dec 2018
- Study completion14 Dec 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Surgical RecoveryStudies of the same condition, open and under way.
- More trials run by Stanford UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 74 participants (actual)
Sponsor and investigators
- Lead sponsor
- Stanford University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Martin Angst, Stanford University
- Investigators
- Martin S Angst, MD, Principal investigator, Stanford University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03123068
- Sponsor's protocol ID
- 39535
- Status last verified
- Sep 2022
- First submitted
- 18 Apr 2017
- Last updated
- 13 Oct 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 13 Oct 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Cocoa Flavanols for Modulating the Surgical Immune Response and Accelerating Clinical Recovery
- ClinicalTrials.gov ID
- NCT03123068
- Acronym / sponsor ID
- 39535
- Conditions
- Surgical Recovery
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 74 participants (actual)
- Lead sponsor
- Stanford UniversityUniversity, hospital or other
- Study start
- 17 Apr 2017 (actual)
- Primary completion
- 14 Dec 2018 (actual)
- Study completion
- 14 Dec 2018 (actual)
- First posted
- 21 Apr 2017 (actual)
- Results
- Posted 17 Nov 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Active treatment group - Group A | Active comparator | Drug: CocoaVia®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. |
| Placebo treatment group - Group B | Placebo comparator | Other: PlaceboParticipants 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. |
Who may qualify
- Ages
- 18 to 90 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 18 - 90 years of age
- Male or female
- Planning to undergo total hip or knee arthroplasty, either primary or revision
- Fluent in English
- Willing and able to sign an informed consent form and HIPAA authorization and to comply with study procedures
Key exclusion criteria (13 listed)
- Infectious disease within the last month
- Immune-suppressant therapy within the last 2 months (e.g., azathioprine or cyclosporine)
- Chronic medication with potential immune-modulatory effects (e.g., daily oral morphine-equivalent intake > 30 mg)
- Major surgery within the last 3 months or minor surgery within the last month.
- History of substance abuse (e.g., alcoholism, drug dependency)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| CocoaVia®Also: Cocoa flavanolCocoaVia® is manufactured by Mars, Inc. It is a dietary supplement of cocoa bean extract, containing 125 mg cocoa flavanols per capsule. | Drug | Active treatment group - Group A |
| PlaceboThe placebo capsules will contain an inert ingredient packaged to be indistinguishable from the active treatment. | Other | Placebo treatment group - Group B |
Primary outcome
NFkB Signaling in Innate Immune Cells
Time frame: 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).
5 secondary outcomes
HMGB1 Level in Blood Plasma
Time frame: 1 hour and 48 hours following surgery.
Step Count Per Minute as a Measure of Functional Recovery - Objective
Time frame: post-surgical observation period (6 weeks)
Days to Mild Impairment as a Measure of Functional Recovery - Subjective
Time frame: 5 days before surgery though 6 weeks post op.
Days to Mild Pain as Assessed by WOMAC Pain Scores
Time frame: 5 days before surgery though 6 weeks post op.
Days to Half Max Recovery From Fatigue
Time frame: 5 days before surgery though 6 weeks post op.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Oct 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Martin S Angst, MD principal investigator
Stanford University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing CocoaVia® in people with Surgical Recovery, run by Stanford University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 Oct 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 17 Nov 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
NFkB Signaling in Innate Immune Cells (time frame: 1 hour and 48 hours following surgery). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Oct 2022.