Trial Outcomes & Findings for Cocoa Flavanols for Modulating Immune Response and Accelerating Recovery (NCT NCT03123068)

Last Updated: 2022-10-13

Results Overview

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).

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

74 participants

Primary outcome timeframe

1 hour and 48 hours following surgery

Results posted on

2022-10-13

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	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.	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.
Overall Study STARTED	22	20
Overall Study COMPLETED	22	20
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Cocoa Flavanols for Modulating Immune Response and Accelerating Recovery

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Active Treatment Group - Group A n=22 Participants 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.	Placebo Treatment Group - Group B n=20 Participants 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.	Total n=42 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	8 Participants n=5 Participants	12 Participants n=7 Participants	20 Participants n=5 Participants
Age, Categorical >=65 years	14 Participants n=5 Participants	8 Participants n=7 Participants	22 Participants n=5 Participants
Sex: Female, Male Female	14 Participants n=5 Participants	11 Participants n=7 Participants	25 Participants n=5 Participants
Sex: Female, Male Male	8 Participants n=5 Participants	9 Participants n=7 Participants	17 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	18 Participants n=5 Participants	16 Participants n=7 Participants	34 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	19 Participants n=5 Participants	13 Participants n=7 Participants	32 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	3 Participants n=5 Participants	5 Participants n=7 Participants	8 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Active Treatment Group - Group A n=20 Participants 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.	Placebo Treatment Group - Group B n=19 Participants 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.
NFkB Signaling in Innate Immune Cells 1 hour following surgery	0.68 NFkB (p65) arcsinh ratio Interval 0.41 to 0.8	0.69 NFkB (p65) arcsinh ratio Interval 0.53 to 0.79
NFkB Signaling in Innate Immune Cells 48 hours following surgery	0.71 NFkB (p65) arcsinh ratio Interval 0.44 to 0.81	0.71 NFkB (p65) arcsinh ratio Interval 0.59 to 0.85

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Active Treatment Group - Group A n=17 Participants 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.	Placebo Treatment Group - Group B n=18 Participants 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.
HMGB1 Level in Blood Plasma 1 hour following surgery	NA ng/ml Value below level of sensitivity for this assay.	NA ng/ml Value below level of sensitivity for this assay.
HMGB1 Level in Blood Plasma 48 hours following surgery	NA ng/ml Value below level of sensitivity for this assay.	NA ng/ml Value below level of sensitivity for this assay.

SECONDARY outcome

Timeframe: post-surgical observation period (6 weeks)

Population: Participants with available data are included in the analysis.

Participants wear an Actigraph watch with measurements taken every 30 seconds. The watch objectively and continuously reports a participant's activity and sleep.

Outcome measures

Outcome measures
Measure	Active Treatment Group - Group A n=18 Participants 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.	Placebo Treatment Group - Group B n=18 Participants 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.
Step Count Per Minute as a Measure of Functional Recovery - Objective	0.02 steps Standard Deviation 0.05	0.04 steps Standard Deviation 0.06

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Outcome measures
Measure	Active Treatment Group - Group A n=17 Participants 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.	Placebo Treatment Group - Group B n=18 Participants 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.
Days to Mild Impairment as a Measure of Functional Recovery - Subjective	35 days Interval 14.0 to 42.0	14 days Interval 7.0 to 35.0

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Active Treatment Group - Group A n=17 Participants 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.	Placebo Treatment Group - Group B n=18 Participants 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.
Days to Mild Pain as Assessed by WOMAC Pain Scores	28 days Interval 14.0 to 37.0	25 days Interval 3.0 to 28.0

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Outcome measures
Measure	Active Treatment Group - Group A n=17 Participants 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.	Placebo Treatment Group - Group B n=18 Participants 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.
Days to Half Max Recovery From Fatigue	14 days Interval 7.0 to 21.0	7 days Interval 3.0 to 14.0

Adverse Events

Active Treatment Group - Group A

Serious events: 1 serious events

Other events: 8 other events

Deaths: 0 deaths

Placebo Treatment Group - Group B

Serious events: 0 serious events

Other events: 7 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Active Treatment Group - Group A n=22 participants at risk 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.	Placebo Treatment Group - Group B n=20 participants at risk 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.
General disorders Pain	4.5% 1/22 • Number of events 1 • 8 weeks	0.00% 0/20 • 8 weeks

Other adverse events

Other adverse events
Measure	Active Treatment Group - Group A n=22 participants at risk 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.	Placebo Treatment Group - Group B n=20 participants at risk 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.
Renal and urinary disorders bladder pain	0.00% 0/22 • 8 weeks	5.0% 1/20 • 8 weeks
Skin and subcutaneous tissue disorders blisters at wound site	4.5% 1/22 • 8 weeks	10.0% 2/20 • 8 weeks
Infections and infestations bursitis	0.00% 0/22 • 8 weeks	10.0% 2/20 • 8 weeks
Nervous system disorders dizziness	0.00% 0/22 • 8 weeks	5.0% 1/20 • 8 weeks
Vascular disorders elevated BP	0.00% 0/22 • 8 weeks	5.0% 1/20 • 8 weeks
Vascular disorders labile BP	0.00% 0/22 • 8 weeks	5.0% 1/20 • 8 weeks
Metabolism and nutrition disorders loss of appitite	9.1% 2/22 • 8 weeks	0.00% 0/20 • 8 weeks
Vascular disorders lower extremity swelling	22.7% 5/22 • 8 weeks	5.0% 1/20 • 8 weeks
Gastrointestinal disorders nausea	9.1% 2/22 • 8 weeks	5.0% 1/20 • 8 weeks
General disorders pain	0.00% 0/22 • 8 weeks	10.0% 2/20 • 8 weeks
Cardiac disorders tachycardia	4.5% 1/22 • 8 weeks	5.0% 1/20 • 8 weeks
Renal and urinary disorders urinary frequency	0.00% 0/22 • 8 weeks	5.0% 1/20 • 8 weeks

Additional Information

Professor of Anesthesia

Stanford University

Phone: 650-723-6412

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place