Cocoa Flavanols for Peripheral Arterial Disease

(COCOA-PAD II Trial)

Recruiting at 2 trial locations

Overseen By Mary McDermott, MD

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Northwestern University

Disqualifiers: Amputation, Critical limb ischemia, Wheelchair, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

190 Participants Needed

Trial Summary

What is the purpose of this trial?

Among people with peripheral artery disease (PAD) age 55 and older, the investigators will test the hypothesis that PAD participants randomized to cocoa flavanols will have greater improvement or less decline in six-minute walk distance at six-month follow-up, compared to those randomized to placebo. The study will randomize 190 participants with PAD age 55 and older to one of two groups for six months: cocoa flavanols vs placebo. Our primary outcome is change in six-minute walk distance at six-month follow-up. Secondary outcomes are Actigraph-measured physical activity, brachial artery flow-mediated dilation (FMD), gastrocnemius muscle biopsy measures of endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS, gastrocnemius muscle perfusion (measured by magnetic resonance imaging (MRI)) and gastrocnemius muscle characteristics (measured by muscle biopsy). To achieve the specific aims, the study will randomize 190 participants age 55 and older with PAD to one of two groups: cocoa flavanols vs placebo. Participants will be followed for six months.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, it does mention that participants should not have taken cocoa supplements in the past three months and should avoid taking cocoa flavanol supplements during the study.

What data supports the effectiveness of the treatment Cocoa Flavanols for Peripheral Arterial Disease?

Research suggests that cocoa and its component epicatechin may help improve blood flow and muscle activity in people with peripheral artery disease (PAD). Additionally, a study on Annurca apple polyphenols, which are similar to cocoa flavanols, showed improved walking ability in PAD patients, indicating potential benefits of flavanol-rich treatments. ^{1 2 3 4 5}

Is cocoa flavanol supplementation safe for humans?

Research on cocoa flavanols, often found in chocolate, suggests they are generally safe for human consumption, with studies showing no significant adverse effects on vascular function in people with coronary artery disease or diabetes. ^{5 6 7 8 9}

How is the treatment of cocoa flavanols unique for peripheral arterial disease?

Cocoa flavanols are unique because they are derived from cocoa and may improve blood flow and muscle function in the legs, which is different from standard treatments that typically focus on medications or surgical interventions. This treatment leverages the natural compounds in cocoa to potentially enhance vascular health and walking performance. ^{1 5 6 9 10}

Research Team

Mary McDermott, MD

Principal Investigator

Northwestern University

Eligibility Criteria

The COCOA-PAD II Trial is for individuals aged 55 or older with peripheral artery disease (PAD), defined by specific diagnostic criteria. Excluded are those with severe cognitive impairment, current foot ulcers, recent major surgeries or cardiovascular events, certain allergies, and other serious health conditions that limit walking or life expectancy.

Inclusion Criteria

I am 55 years old or older.

I have been diagnosed with peripheral artery disease.

Exclusion Criteria

I haven't taken cocoa supplements or eaten dark chocolate regularly in the last 3 months.

I can walk less than 500 feet or more than 1600 feet in six minutes.

You have been in a monitored treadmill exercise program in the last three months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are randomized to receive either cocoa flavanols or placebo for six months

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of six-minute walk distance and other secondary outcomes

6 months

Post-intervention Follow-up

Assessment of persistent effects on six-minute walk distance at two and four weeks after the study intervention is completed

4 weeks

Treatment Details

Interventions

• Cocoa Flavanols
• Placebo

Trial Overview This trial investigates whether cocoa flavanols can improve walking distance over six months in PAD patients compared to a placebo. The study will enroll 190 participants who will be randomly assigned to receive either the cocoa flavanols or a placebo.

Participant Groups

Group I: cocoa flavanols Active Control 1 Intervention

Group II: placebo Placebo Group 1 Intervention

Who Is Running the Clinical Trial?

Northwestern University

Lead Sponsor

Trials

1,674

Recruited

989,000+

National Institute on Aging (NIA)

Collaborator

Trials

1,841

Recruited

28,150,000+

University of Minnesota

Collaborator

Trials

1,459

Recruited

1,623,000+

University of Chicago

Collaborator

Trials

1,086

Recruited

844,000+

Findings from Research

In a phase II clinical trial involving 44 participants with peripheral artery disease (PAD), a cocoa beverage containing epicatechin significantly improved walking distance by 42.6 meters after 6 months compared to a placebo, indicating potential therapeutic benefits for PAD patients.

Cocoa consumption also enhanced calf muscle mitochondrial activity and capillary density, suggesting that its mechanism of action may involve improved muscle perfusion and energy production, although further studies are needed to confirm these effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cocoa to Improve Walking Performance in Older People With Peripheral Artery Disease: The COCOA-PAD Pilot Randomized Clinical Trial. McDermott, MM., Criqui, MH., Domanchuk, K., et al.[2021]

In a study involving 21 patients with symptomatic peripheral artery disease (PAD), consuming 50 g of flavonoid-rich dark chocolate did not improve endothelial function as measured by flow-mediated dilatation (FMD) or microvascular function after 2 hours.

Both dark chocolate and a cocoa-free control (white chocolate) showed no significant changes in vascular function, indicating that a single intake of dark chocolate does not benefit patients with PAD in terms of vascular health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dark chocolate and vascular function in patients with peripheral artery disease: a randomized, controlled cross-over trial. Hammer, A., Koppensteiner, R., Steiner, S., et al.[2015]

In a study involving 20 healthy men, dark chocolate significantly improved vascular function, as shown by increased flow-mediated dilation (FMD) and decreased augmentation index (AIx), while pure epicatechin did not show significant improvements compared to placebo.

Both pure epicatechin and dark chocolate had similar bioavailability of epicatechin, indicating that the vascular benefits of dark chocolate may be attributed to its overall composition rather than just the epicatechin content.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does epicatechin contribute to the acute vascular function effects of dark chocolate? A randomized, crossover study. Dower, JI., Geleijnse, JM., Kroon, PA., et al.[2018]

In a randomized, placebo-controlled trial with 180 patients suffering from peripheral arterial disease (PAD), those treated with Annurca apple polyphenolic extract (AMS) showed a significant 69% improvement in walking autonomy after 24 weeks, indicating its potential efficacy in managing PAD symptoms.

The AMS treatment also resulted in notable improvements in ankle-brachial index and acceleration time, while the placebo group showed no significant changes, suggesting that AMS could be a safe and effective natural option for PAD treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Annurca Apple Polyphenols on Intermittent Claudication in Patients With Peripheral Artery Disease. Tenore, GC., D'Avino, M., Caruso, D., et al.[2019]

In a large study involving 21,442 older adults, cocoa extract supplementation did not significantly reduce total cardiovascular events, but it was associated with a 27% reduction in cardiovascular death, suggesting potential benefits for heart health.

The study found no safety concerns with cocoa extract, and per-protocol analyses indicated a lower risk of total cardiovascular events, highlighting the need for further research to explore its effects on clinical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of cocoa flavanol supplementation for the prevention of cardiovascular disease events: the COcoa Supplement and Multivitamin Outcomes Study (COSMOS) randomized clinical trial. Sesso, HD., Manson, JE., Aragaki, AK., et al.[2023]

Regular consumption of flavanol-rich cocoa products can significantly lower systolic blood pressure, with a study showing a mean reduction of 5.8 mmHg in a population with mild hypercholesterolemia.

Human dietary intervention trials indicate that flavanol-containing foods, like cocoa, improve endothelial and platelet function, supporting their potential cardiovascular benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of cocoa flavanols on risk factors for cardiovascular disease. Erdman, JW., Carson, L., Kwik-Uribe, C., et al.[2008]

In a 6-week study involving 40 individuals with coronary artery disease, consuming flavanol-rich cocoa did not lead to any significant changes in vascular function, as measured by flow-mediated dilation and systemic arterial compliance.

Despite the known cardiovascular benefits of flavonoid-rich diets, this study found that daily intake of flavanol-rich cocoa (444 mg/day) did not improve vascular responses compared to a placebo, indicating that it may not be effective for modifying vascular function in patients with established coronary artery disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute and chronic effects of flavanol-rich cocoa on vascular function in subjects with coronary artery disease: a randomized double-blind placebo-controlled study. Farouque, HM., Leung, M., Hope, SA., et al.[2015]

Cacao flavonoids have been shown to potentially reduce risk factors for chronic diseases like cardiovascular and neurodegenerative diseases through various mechanisms, supported by 20 years of research including in vitro, animal, and clinical studies.

Recent advancements in understanding the synthesis of flavonoids have led to targeted research on cocoa flavanols, with systematic reviews indicating their potential role in lowering cardiovascular disease risk and upcoming clinical trials planned to explore their effects on disease outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The science of cocoa flavanols: bioavailability, emerging evidence, and proposed mechanisms. Blumberg, JB., Ding, EL., Dixon, R., et al.[2023]

This study aims to investigate the acute effects of cocoa flavanols (790 mg) on blood pressure and vascular reactivity in patients with type 2 diabetes, including those with and without hypertension, through a randomized, double-blinded, placebo-controlled cross-over trial.

Participants will be assessed for macrovascular endothelial function and blood flow before and after consuming the cocoa extract or placebo, providing insights into the potential vascular benefits of cocoa flavanols in a diabetic population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute Effects of Cocoa Flavanols on Blood Pressure and Peripheral Vascular Reactivity in Type 2 Diabetes Mellitus and Essential Hypertension: A Protocol for an Acute, Randomized, Double-Blinded, Placebo-Controlled Cross-Over Trial. Tanghe, A., Celie, B., Shadid, S., et al.[2021]

A 30-day dietary intervention with flavanol-rich cocoa significantly improved vascular function in 41 medicated diabetic patients, increasing flow-mediated dilation (FMD) by 30%, indicating its potential as a therapeutic option for cardiovascular health.

The study demonstrated that acute ingestion of cocoa led to significant increases in circulating flavanols and FMD, with no adverse effects reported, suggesting that flavanol-rich diets are safe and effective for improving vascular function in diabetic patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sustained benefits in vascular function through flavanol-containing cocoa in medicated diabetic patients a double-masked, randomized, controlled trial. Balzer, J., Rassaf, T., Heiss, C., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Cocoa to Improve Walking Performance in Older People With Peripheral Artery Disease: The COCOA-PAD Pilot Randomized Clinical Trial. [2021]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Dark chocolate and vascular function in patients with peripheral artery disease: a randomized, controlled cross-over trial. [2015]

3. Germany pubmed.ncbi.nlm.nih.gov

Does epicatechin contribute to the acute vascular function effects of dark chocolate? A randomized, crossover study. [2018]

4. United States pubmed.ncbi.nlm.nih.gov

Effect of Annurca Apple Polyphenols on Intermittent Claudication in Patients With Peripheral Artery Disease. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Effect of cocoa flavanol supplementation for the prevention of cardiovascular disease events: the COcoa Supplement and Multivitamin Outcomes Study (COSMOS) randomized clinical trial. [2023]

6. China pubmed.ncbi.nlm.nih.gov

Effects of cocoa flavanols on risk factors for cardiovascular disease. [2008]

7. England pubmed.ncbi.nlm.nih.gov

Acute and chronic effects of flavanol-rich cocoa on vascular function in subjects with coronary artery disease: a randomized double-blind placebo-controlled study. [2015]

8. United States pubmed.ncbi.nlm.nih.gov

The science of cocoa flavanols: bioavailability, emerging evidence, and proposed mechanisms. [2023]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Acute Effects of Cocoa Flavanols on Blood Pressure and Peripheral Vascular Reactivity in Type 2 Diabetes Mellitus and Essential Hypertension: A Protocol for an Acute, Randomized, Double-Blinded, Placebo-Controlled Cross-Over Trial. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

Sustained benefits in vascular function through flavanol-containing cocoa in medicated diabetic patients a double-masked, randomized, controlled trial. [2022]