A Comparison Chocolate With and Without High Cocoa Solids in Patients With Type 2 Diabetes in a Randomised Clinical Trial

• Sponsor: Nestlé (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01617603
• Collaborator: (none)
• Enrollment: 62
• Location: 1
• Arms: 3
• Duration (Months): 25
• Patients Per Site Per Month: 2.5

Study Details

Study Description

Brief Summary

Type 2 diabetes is being acknowledged as a potential public health time bomb, whose incidence is predicted to double over the next 10 years in the UK, associated with the rise in obesity and increasing sedentary lifestyles. Increased insulin resistance has been shown to be an important feature of type 2 diabetes (especially in those presenting with obesity and in particular visceral or abdominal obesity). Insulin resistance is implicated as a risk factor of cardiovascular disease and may lead to pancreatic dysfunction through increased β-cell stress in the pancreas. A combination of insulin resistance and pancreatic beta cell failure then leads to type 2 diabetes. The main cause of morbidity and mortality in type 2 diabetes is cardiovascular disease as the condition is associated with impaired vascular functioning and increased levels of oxidation markers.

Epidemiological studies suggest dietary flavonoids decrease the risk of death from coronary heart disease, cancer, and stroke. Flavonoid-rich foods include fruits and vegetables as well as tea, red wine, and chocolate. In a cohort of elderly men, cocoa intake was inversely associated with blood pressure and 15-year cardiovascular and all-cause mortality. It has been reported that in healthy humans, consumption of flavanol-rich dark chocolate decreased daytime and night time blood pressure, reduced insulin resistance, and improved nitric oxide dependent vaso-relaxation. Another trial found that cocoa powder increased postprandial insulinaemia in lean young adults. These research papers have led to the hypothesis that chocolate containing high cocoa liquor may help to reduce the risk of developing type 2 diabetes.

This study is design as a double-blind, controlled, single center, randomized, parallel design clinical trial. The primary outcome measure is to compare parameters of insulin resistance and glycaemic control in volunteers with type 2 diabetes after consumption of 3 different chocolates (one dark and two milk chocolates) with a secondary outcome of endothelial function, cholesterol profile and oxidative stress. Subjects will undergo medical screening, anthropometry, physical activity and dietary assessments before randomization.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Type 2	Other: Cocoa Polyphenols	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 62 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Prevention
• Study Start Date: Apr 1, 2009
• Actual Primary Completion Date: Apr 1, 2011
• Actual Study Completion Date: May 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: High polyphenol milk chocolate High polyphenol milk chocolate containing approximately 1 mg/g of epicatechin	Other: Cocoa Polyphenols; 20g/d of product, two active products provide 20 mg/d epicatechin, on visiting occasions, an acute dose of 40g product to be given
Active Comparator: Nestle Noir 70 % chocolate Nestle Noir 70 % chocolate containing approximately 1 mg/g of epicatechin	Other: Cocoa Polyphenols; 20g/d of product, two active products provide 20 mg/d epicatechin, on visiting occasions, an acute dose of 40g product to be given
Placebo Comparator: Low polyphenol milk Low polyphenol milk control (matched to product 1 as closely as possible for milk content, carbohydrate, fat and calories, made from cocoa butter, sugar, milk powder and small amount of cocoa liquor to improve taste, giving approximately 0.05mg/g epicatechin.	Other: Cocoa Polyphenols; 20g/d of product, two active products provide 20 mg/d epicatechin, on visiting occasions, an acute dose of 40g product to be given

Outcome Measures

Primary Outcome Measures

1. Difference in Insulin Resistance (HOMA) Between Treatments After 12 Weeks of Product Intake [84th day of product intake]

   HbA1c with measurement of plasma glucose and insulin (to determine HOMA index) at the 84th day after product intake minus value at baseline (1st day of product intake. Insulin resistance is defined by a HOMA index > 2.4

Secondary Outcome Measures

1. Endothelial Function After 12 Weeks of Product Intake [84th day of product intake]

   Endothelial function is assessed from arterial stiffness measurements at the 84th day minus the value at baseline (1st day of product intake)

2. Cholesterol Profile After 12 Weeks of Product Intake [84th day of product intake]

   Cholesterol profile is assessed from plasma HDL, LDL and total cholesterol measurements at the 84th day of product intake

3. Oxidative Stress After 12 Weeks of Product Intake [84th day of product intake]

   Oxidative stress is assessed from measurements of plasma markers (High sensitivity CRP, IL-1, IL-6, and alpha-TNF) at the 84th day of product intake

Eligibility Criteria

Criteria

• Ages Eligible for Study: 45 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

• The diagnosis of type 2 diabetes will be based on the WHO guidelines. These are 2 fasting plasma glucose readings of greater than 7.0mmoll-1 or 2 random plasma glucose readings >11mmoll-1 in the absence of symptoms or concurrent illness or medication which might lead to hyperglycaemia (e.g. thiazide diuretics). Or one reading meeting the diagnostic level with the presence of symptoms of polyuria, polydipsia, nocturia, fatigue or blurring of vision. The final diagnostic method of diagnosis type 2 diabetes is a positive oral glucose tolerance test (OGTT) using a 75g glucose load. If doubt exists on the diagnosis of diabetes an OGTT will be performed.

• Diabetes managed by diet alone or diet and metformin. If metformin is used the dose should have been stable for a minimum of 3 months prior to the start of the study.

• Hba1c up to and including 9.9%

• Age 45-75

• If female, should be post-menopausal

• BMI 25-39kgm-2

• Patients will have attended a structured group patient education programme (and be on stable medication for hypertension, lipids and gout (if appropriate) for 3 months prior to entry into the study. Subjects will be encouraged to incorporate the chocolate into their diet as advised during the education programme

• Having obtained his/her or his/her legal representative's informed consent.

Exclusion Criteria:

• Patients with concurrent illness or any changes in medication in the last 3 months.

• Patients whose diabetes is managed with TZDs, DPP-IV inhibitors, GLP-1 analogues, insulin or sulphonylureas or prandial regulators

• Patients not wishing to allow disclosure to their GPs.

• Pregnancy

• Hba1c at recruiting stage of >10.0%

• Patient who cannot be expected to comply with treatment

• Currently participating or having participated in another clinical trial during the last 3 months prior to the beginning of this study

• Patients who consuming more than 20g/d of chocolate or having a very high polyphenol content of their diet, who are not willing to change their diet

• Patients taking high dose antioxidant supplements including single and multivitamin preparations including A,C,E.

• Women on HRT treatment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Endocrinology, Diabetes & Metabolism, Hull York Medical School, Michael White Diabetes Centre, 220-236, Anlaby Road	Hull		United Kingdom	HU3 2RW

Sponsors and Collaborators

• Nestlé

Investigators

• Principal Investigator: Stephen L Atkin, MD, Prof, Head of Academic Endocrinology, Diabetes & Metabolism; Hull York Medical School; Michael White Diabetes Centre, Hull, UK

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Nestlé
• ClinicalTrials.gov Identifier: NCT01617603
• Other Study ID Numbers: 07.52.NRC
• First Posted: Jun 12, 2012
• Last Update Posted: Jul 19, 2013
• Last Verified: Jul 1, 2013

• Keywords provided by Nestlé: diabetes type 2; insulin resistance; glycaemic control; Endothelial function; Cocoa Polyphenols
• Additional relevant MeSH terms: Diabetes Mellitus, Type 2

Study Results

Participant Flow

Recruitment Details	62 subjects were recruited. The intention-to-treat (ITT) set comprised of all the subjects who completed V4. One subject joined another trial after recruitment while two other subjects dropped out in course of the trial. These three subjects were not included in the full analysis population. Finally, PP dataset comprised of n = 48.
Pre-assignment Detail	Two subjects withdrew their consent quickly after giving it and were replaced so that the total number of recruited subjects was 62. Patients were randomly assigned to one of the three groups using age and gender as the stratification factors. The randomization was performed using the software TRIALSYS (developed internally at Nestlé).

Arm/Group Title	High Polyphenol Milk Chocolate	Low Polyphenol Milk	Nestle Noir 70 % Chocolate
Arm/Group Description	High polyphenol milk chocolate containing approximately 1 mg/g of epicatechin Cocoa Polyphenols : 20g/d of product, two active products provide 20 mg/d epicatechin, on visiting occasions, an acute dose of 40g product to be given	Low polyphenol milk control (matched to product 1 as closely as possible for milk content, carbohydrate, fat and calories, made from cocoa butter, sugar, milk powder and small amount of cocoa liquor to improve taste, giving approximately 0.05mg/g epicatechin. Cocoa Polyphenols : 20g/d of product, two active products provide 20 mg/d epicatechin, on visiting occasions, an acute dose of 40g product to be given	Nestle Noir 70 % chocolate containing approximately 1 mg/g of epicatechin Cocoa Polyphenols : 20g/d of product, two active products provide 20 mg/d epicatechin, on visiting occasions, an acute dose of 40g product to be given
Period Title: Overall Study
STARTED	20	21	21
COMPLETED	17	19	20
NOT COMPLETED	3	2	1

Baseline Characteristics

Arm/Group Title	High Polyphenol Milk Chocolate	Low Polyphenol Milk	Nestle Noir 70 % Chocolate	Total
Arm/Group Description	High polyphenol milk chocolate containing approximately 1 mg/g of epicatechin Cocoa Polyphenols : 20g/d of product, two active products provide 20 mg/d epicatechin, on visiting occasions, an acute dose of 40g product to be given	Low polyphenol milk control (matched to product 1 as closely as possible for milk content, carbohydrate, fat and calories, made from cocoa butter, sugar, milk powder and small amount of cocoa liquor to improve taste, giving approximately 0.05mg/g epicatechin. Cocoa Polyphenols : 20g/d of product, two active products provide 20 mg/d epicatechin, on visiting occasions, an acute dose of 40g product to be given	Nestle Noir 70 % chocolate containing approximately 1 mg/g of epicatechin Cocoa Polyphenols : 20g/d of product, two active products provide 20 mg/d epicatechin, on visiting occasions, an acute dose of 40g product to be given	Total of all reporting groups
Overall Participants	20	21	21	62
Age, Customized (participants) [Number]
<= 45 years	0 0%	0 0%	0 0%	0 0%
Between 45 and 75 years	20 100%	21 100%	21 100%	62 100%
>=75 years	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	10 50%	11 52.4%	10 47.6%	31 50%
Male	10 50%	10 47.6%	11 52.4%	31 50%
Region of Enrollment (participants) [Number]
United Kingdom	20 100%	21 100%	21 100%	62 100%
HOMA at the begining of product intake (HOMA index) [Mean (Inter-Quartile Range) ]
Mean (Inter-Quartile Range) [HOMA index]	6.50	4.63	4.45	5.19

Outcome Measures

1. Primary Outcome

Title	Difference in Insulin Resistance (HOMA) Between Treatments After 12 Weeks of Product Intake
Description	HbA1c with measurement of plasma glucose and insulin (to determine HOMA index) at the 84th day after product intake minus value at baseline (1st day of product intake. Insulin resistance is defined by a HOMA index > 2.4
Time Frame	84th day of product intake

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	High Polyphenol Milk Chocolate	Low Polyphenol Milk	Nestle Noir 70 % Chocolate
Arm/Group Description	High polyphenol milk chocolate containing approximately 1 mg/g of epicatechin Cocoa Polyphenols : 20g/d of product, two active products provide 20 mg/d epicatechin, on visiting occasions, an acute dose of 40g product to be given	Low polyphenol milk control (matched to product 1 as closely as possible for milk content, carbohydrate, fat and calories, made from cocoa butter, sugar, milk powder and small amount of cocoa liquor to improve taste, giving approximately 0.05mg/g epicatechin. Cocoa Polyphenols : 20g/d of product, two active products provide 20 mg/d epicatechin, on visiting occasions, an acute dose of 40g product to be given	Nestle Noir 70 % chocolate containing approximately 1 mg/g of epicatechin Cocoa Polyphenols : 20g/d of product, two active products provide 20 mg/d epicatechin, on visiting occasions, an acute dose of 40g product to be given
Measure Participants	17	19	20
Mean (Inter-Quartile Range) [HOMA index]	2.82	2.21	2.75

2. Secondary Outcome

Title	Endothelial Function After 12 Weeks of Product Intake
Description	Endothelial function is assessed from arterial stiffness measurements at the 84th day minus the value at baseline (1st day of product intake)
Time Frame	84th day of product intake

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Cholesterol Profile After 12 Weeks of Product Intake
Description	Cholesterol profile is assessed from plasma HDL, LDL and total cholesterol measurements at the 84th day of product intake
Time Frame	84th day of product intake

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Oxidative Stress After 12 Weeks of Product Intake
Description	Oxidative stress is assessed from measurements of plasma markers (High sensitivity CRP, IL-1, IL-6, and alpha-TNF) at the 84th day of product intake
Time Frame	84th day of product intake

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Arm/Group Title	High Polyphenol Milk Chocolate		Low Polyphenol Milk		Nestle Noir 70 % Chocolate
Arm/Group Description	High polyphenol milk chocolate containing approximately 1 mg/g of epicatechin Cocoa Polyphenols : 20g/d of product, two active products provide 20 mg/d epicatechin, on visiting occasions, an acute dose of 40g product to be given		Low polyphenol milk control (matched to product 1 as closely as possible for milk content, carbohydrate, fat and calories, made from cocoa butter, sugar, milk powder and small amount of cocoa liquor to improve taste, giving approximately 0.05mg/g epicatechin. Cocoa Polyphenols : 20g/d of product, two active products provide 20 mg/d epicatechin, on visiting occasions, an acute dose of 40g product to be given		Nestle Noir 70 % chocolate containing approximately 1 mg/g of epicatechin Cocoa Polyphenols : 20g/d of product, two active products provide 20 mg/d epicatechin, on visiting occasions, an acute dose of 40g product to be given
All Cause Mortality
	High Polyphenol Milk Chocolate		Low Polyphenol Milk		Nestle Noir 70 % Chocolate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	High Polyphenol Milk Chocolate		Low Polyphenol Milk		Nestle Noir 70 % Chocolate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/20 (5%)		1/21 (4.8%)		0/21 (0%)
Cardiac disorders
Pacemaker installation	0/20 (0%)	0	1/21 (4.8%)	1	0/21 (0%)	0
Renal and urinary disorders
Cyst resection	1/20 (5%)	1	0/21 (0%)	0	0/21 (0%)	0
Other (Not Including Serious) Adverse Events
	High Polyphenol Milk Chocolate		Low Polyphenol Milk		Nestle Noir 70 % Chocolate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/21 (0%)		0/21 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.