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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if cocoa flavanols can help individuals with peripheral artery disease (PAD) walk farther after six months compared to a placebo. Peripheral artery disease reduces blood flow to the legs, making walking difficult. The study seeks participants aged 55 and older who have PAD and experience walking difficulties. By comparing two groups—one taking cocoa flavanols and the other a placebo—researchers aim to discover if cocoa can enhance walking ability and overall leg health. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants an opportunity to contribute to potentially groundbreaking treatment advancements.

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.

Is there any evidence suggesting that cocoa flavanols are likely to be safe for humans?

Research has shown that cocoa flavanols are generally safe for consumption. One study found that people with peripheral artery disease (PAD) who took cocoa flavanols for six months experienced no major side effects compared to those on a placebo. Cocoa flavanols, natural compounds in cocoa, may improve blood flow and lower blood pressure. While the evidence is supportive but not conclusive, it suggests that cocoa flavanols might be safe for most people. However, individuals should consider their own health conditions and consult a doctor before starting any new treatment. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about cocoa flavanols as a treatment for peripheral arterial disease (PAD) because they offer a new approach that could complement or even enhance current treatments like medications, lifestyle changes, and surgical interventions. Cocoa flavanols, naturally occurring compounds found in cocoa, are thought to improve blood flow by enhancing the function of the blood vessels' lining, which is different from how most current treatments work. This potential to improve circulation and reduce symptoms in a natural way is what makes cocoa flavanols stand out and why there's a lot of interest in their potential benefits for people with PAD.

What evidence suggests that cocoa flavanols might be an effective treatment for peripheral artery disease?

This trial will compare cocoa flavanols with a placebo to assess their effects on peripheral artery disease (PAD). Research has shown that cocoa flavanols might help people with PAD walk better. In one study, patients who consumed cocoa walked almost 43 meters farther in a six-minute walking test than those who took a placebo. Cocoa flavanols may improve blood flow and muscle function, benefiting people with PAD. Another study found that taking cocoa flavanols reduced deaths from heart disease by 27% in older adults. While cocoa flavanols don't greatly reduce all heart-related problems, they seem promising for easing PAD symptoms. ^{1 6 7 8 9}

Who Is on the Research Team?

Mary McDermott, MD

Principal Investigator

Northwestern University

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7141749/

The Cocoa-Pad Pilot Randomized Clinical Trial - PMC In a phase II randomized clinical trial, to assess whether six months of cocoa improved walking performance in people with PAD, compared to placebo.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04794530

Study Details | NCT04794530 | The COCOA-PAD II Trial 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 ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8762806/

Cocoa may improve walking in people with peripheral ... Researchers found that the patients who consumed cocoa showed significant improvement, walking an average of almost 43 m further in the six-minute walking test ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S0002916522002751

Effect of cocoa flavanol supplementation for the prevention ... Cocoa extract supplementation did not significantly reduce total cardiovascular events among older adults but reduced CVD death by 27%.

5. withpower.com withpower.com/trial/phase-3-peripheral-arterial-disease-3-2021-b6d89

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).

6. fda.gov fda.gov/media/165090/download

Petition for a Qualified Health Claim – for Cocoa Flavanols ... “Supportive but inconclusive scientific evidence suggests that consuming at least 200 mg of cocoa flavanols daily, such as provided by high ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S027869152100154X

Impact of cocoa flavanols on human health A meta-analysis of seven observational studies (114,009 participants) showed that greater chocolate consumption was linked with a 37% lower risk of CVD and a 29 ...

8. examine.com examine.com/supplements/cocoa-extract/research/?srsltid=AfmBOorgfeexyJJiq70NQZIDx6z12_ocyDyjUvGHnWhxEZvbAQr_boSO

Research Breakdown on Cocoa Extract Cocoa products can have effects like lowering blood pressure and inflammation and have resulted in small improvements to some outcomes in ...

9. ajcn.nutrition.org ajcn.nutrition.org/article/S0002-9165(23)02817-4/fulltext

Epicatechin ingested via cocoa products reduces blood ... INTRODUCTION. Epidemiologic studies suggest that regular cocoa consumption may contribute to a reduced risk of development of hypertension, a well-known risk ...