Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12607000239460
Ethics application status
Approved
Date submitted
1/05/2007
Date registered
7/05/2007
Date last updated
18/12/2018
Date data sharing statement initially provided
30/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
The effect of long term intervention with cocoa flavanols on metabolic control and cardiovascular parameters in subjects with and without type 2 diabetes.
Scientific title
The effect of long term intervention with cocoa flavanols on metabolic control and cardiovascular parameters in subjects with and without type 2 diabetes
Secondary ID [1] 296747 0
nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
People with hypertension, with and without type 2 diabetes 1775 0
Condition category
Condition code
Metabolic and Endocrine 1861 1861 0 0
Diabetes
Cardiovascular 1862 1862 0 0
Hypertension

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a randomised double-blind, controlled study conducted within a clinical setting with a parallel arm design. Participants randomised to the intervention group will receive a high flavanol content drink (494 mg) consumed twice a day (2 x 494 mg/day, i.e. total of 988 mg/day) for 24 weeks.
Intervention code [1] 1733 0
Other interventions
Comparator / control treatment
Particants randomised to the comparator group will consume very low flavanol drinks(29 mg) twice a day (2 x 29 mg.day i.e. 58 mg/day) for 24 weeks.
Control group
Dose comparison

Outcomes
Primary outcome [1] 2640 0
Systolic and Diastolic blood pressure (BP)
Timepoint [1] 2640 0
At 12 weeks compared to baseline
Secondary outcome [1] 4487 0
Lipids
Total cholesterol, HDL, LDL and triglycerides
Timepoint [1] 4487 0
Baseline, 12 and 24 weeks.
Secondary outcome [2] 4488 0
Urinary albumin: creatinine ratio (ACR)
Timepoint [2] 4488 0
Baseline, 12 and 24 weeks.
Secondary outcome [3] 4489 0
Retinal vessel diameters.
Timepoint [3] 4489 0
Baseline and 12 weeks.
Secondary outcome [4] 4490 0
Ankle brachial pressure index (ABPI)
Timepoint [4] 4490 0
Baseline, 12 and 24 weeks.
Secondary outcome [5] 4491 0
Blood pressure at 24 weeks
Timepoint [5] 4491 0
Baseline and 24 weeks
Secondary outcome [6] 4492 0
Marker of fibrosis: procollagen type 1 C peptide; Diastolic function (assessed by trans thoracic echocardiograph
Timepoint [6] 4492 0
Baseline and 24 weeks
Secondary outcome [7] 4493 0
Mechanistic measurements Flavanol level achieved by supplementation. Plasma circulating flavanol levels, 24 hour urinary flavanol excretion ; Urine transforming growth factor-beta (TGF beta); Nitric oxide system: Plasma arginine; Circulating asymmetric dimethylarginine (ADMA)
Timepoint [7] 4493 0
At 12 weeks compared to baseline (and 24 hour urinary flavanol also at 24 weeks)
Secondary outcome [8] 4494 0
Inflammation: high-sensitivity C-reactive protein (hs-CRP), interleukin-1, interleukin-6, tumour necrosis factor-alpha (TNF-a). All of these are measured in blood samples.
Timepoint [8] 4494 0
At baseline and 12 weeks for all (and 24 weeks for hs CRP)
Secondary outcome [9] 4495 0
Gene expression profile
Timepoint [9] 4495 0
Baseline, 12 weeks, 24 weeks
Secondary outcome [10] 4496 0
Other
• Renin
• Aldosterone
•Endothelin – 1
• Catecholamines
Timepoint [10] 4496 0
Baseline and 12 weeks
Secondary outcome [11] 6654 0
Endothelial function: Biochemical measurements of circulating Von Willebrand's Factor (vWF), soluble E-selectin, soluble intercellular adhesion molecule-1 (ICAM-1), soluble vascular cellular adhesion molecule-1 (VCAM-1), thrombomodulin
Timepoint [11] 6654 0
Baseline and 12 weeks
Secondary outcome [12] 6655 0
Endothelial function: Brachial artery Flow mediated dilatation (FMD); Endo-PAT (commercial name for a non-invasive fingertip test, marketed by Itamar Medical Ltd; peripheral arterial tonometry [PAT])
Timepoint [12] 6655 0
Baseline, 12 weeks, 24 weeks
Secondary outcome [13] 6656 0
Coagulation: Tissue-plasminogen activator (tPA), Plasminogen activator inhibitor-1 (PAI-1)
Timepoint [13] 6656 0
Baseline and 12 weeks
Secondary outcome [14] 6657 0
Insulin Sensitivity: HbA1c, fasting plasma glucose (FPG) and fasting plasma insulin.
Timepoint [14] 6657 0
Baseline, 12 weeks, 24 weeks for all. FPG also at 4,8,16, and 20 weeks
Secondary outcome [15] 6658 0
Blood glucose level for 7-point (24hr) blood glucose profile obtained by Self-monitored blood glucose (SMBG) - in diabetics only.
Timepoint [15] 6658 0
Baseline, 12 weeks, 24 weeks

Eligibility
Key inclusion criteria
Only patients who fulfil all of the following criteria will be eligible for inclusion in the study: type 2 diabetes for diabetes arm; Blood pressure (BP) as defined by the following (BP in Non-diabetic subjects: stable treated hypertension: 140 mm Hg less than or equal to SBP less than or equal to 179 mmHg and DBP less than or equal to 95 mm Hg, OR 90 mm Hgless than or equal to DBP less than or equal to 105mmHg and SBP less than or equal to 179 mm Hg. Diabetic subjects: stable treated hypertension: 130mm Hg less than or equal to SBP less than or equal to 179 mm Hg and DBP less than or equal to 95 mmHg, OR 80 mm Hgless than or equal to DBP less than or equal to 100 mm Hg and SBP less than or equal to 179 mm Hg.); For subjects with type 2 diabetes: 6.5% less than or equal to HbA1c less than or equal to 8.5%, and stable diabetes for 2 months preceding entry, and during the trial there will be no change in diabetes management unless fasting plasma glucose (FPG) > 12mM or hypoglycaemic events occur, and already on angiotensin converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) (for subjects with diabetes).
Minimum age
35 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients will be excluded from the study if any of the following apply1. Pregnancy2. Women of childbearing age who are contemplating pregnancy within the study period or who will not be using an adequate method of contraception3. Proliferative retinopathy4. Macro albuminuria5. Baseline urinary albumin: creatinine ratio less than assay detection limit6. Poorly controlled diabetes (HbA1c > 8.5%)7. On insulin8. Body mass index <18.0 or >40.09. Significant co-morbidity, including a history of cerebral infarction, cerebral haemorrhage or acute myocardial infarction10. On renal dialysis11. Life expectancy less than 6 months12. High baseline oral flavanol intake+Dietary entry exclusion criteria• vegetarians• habitual consumers of dietary of herbal supplements, including multivitamin supplements• habitual consumers of chocolate (daily consumption of any amount)• habitual consumers of cocoa drinks (daily consumption of any amount)• habitual consumers of > 2 cups of tea/day• habitual consumers of > 1 apple /day• habitual consumers of > glass of red wine per daySubjects will be asked to maintain a consistent flavanol intake for the duration of the study, and this will be assessed by food diaries.13. Current smokers, current tobacco users or current nicotine replacement users, defined as consumers of cigarettes, cigars, snuff, tobacco, nicotine replacement chewing gum or nicotine replacement transdermal patches within the preceding 90 days14. Habitual consumption of alcohol >2 standard (10g) drinks/day in men and women15. Allergies to cocoa or chocolate16. Allergies to nuts, especially peanuts17. Allergies to methylxanthines, i.e. caffeine and theobromineDiscontinuation of subjects from treatmentWithdrawal of subjects from this study may occur because of:• Withdrawal of informed consent• Development of exclusion criteria• Incorrect enrolment• Occurrence of an adverse event severe enough to warrant withdrawal• Deterioration in subject’s condition severe enough to warrant withdrawal.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Randomisation among groups with and without diabetes; 1:1 randomisation (high flavanol supplement:low flavanol supplement) . An independent person at the International Diabetes Institute will hold all the envelopes for each possible subject type with a list of randomly generated treatment allocations. After each subjects' eligibility for the study has been determined the independant person with the envelopes will be contacted by the study co-ordinator and the next available envelope with the allocation will be opened. The allocation of each subjects will be recorded by the independent person and the study co-ordinator simultaneously.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer-generated random numbers using Microsoft Excel. Stratify by gender in groups; stratify by Body mass index (BMI) in groups - (a) 18.0</= BMI </=30.0, (b) 30.0 < BMI </=40.0;stratify by statin use in groups; stratify by Angiotensin converting enzyme inhibitor/ angiotensin II receptor blocker (ACEI/ARB) use in non diabetic groups
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
This study is a double blind study. The people who are blinded are the subjects receiving the treatment and the therapist administering the treatment.
Phase
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
15/03/2008
Actual
7/05/2008
Date of last participant enrolment
Anticipated
Actual
7/04/2011
Date of last data collection
Anticipated
Actual
18/08/2011
Sample size
Target
120
Accrual to date
Final
133
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment postcode(s) [1] 24978 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 2010 0
Commercial sector/Industry
Name [1] 2010 0
Mars Symbioscience, a division of Mars Incorporated,
Country [1] 2010 0
United States of America
Primary sponsor type
Other
Name
Baker IDI Heart and Diabetes Institute
Address
250 Kooyong Road CAULFIELD VIC 3162
Country
Australia
Secondary sponsor category [1] 1821 0
Hospital
Name [1] 1821 0
Alfred Hospital
Address [1] 1821 0
Commercial Road PRAHRAN VIC 3191
Country [1] 1821 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 3738 0
International Diabetes Institute
Ethics committee address [1] 3738 0
Ethics committee country [1] 3738 0
Australia
Date submitted for ethics approval [1] 3738 0
Approval date [1] 3738 0
28/03/2007
Ethics approval number [1] 3738 0
10/2006

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 27836 0
Prof Paul Zimmet
Address 27836 0
Prof Paul Zimmet: Department of Diabetes, Monash University, Level 6, Alfred Centre, 99 Commercial Road, Melbourne VIC 3004
Country 27836 0
Australia
Phone 27836 0
+61 3 9903 0254
Fax 27836 0
Email 27836 0
[email protected]
Contact person for public queries
Name 10922 0
Jonathan Shaw
Address 10922 0
Baker Heart and Diabetes Institute, Level; 4, 99 Commercial Road, Melbourne VIC 3004
Country 10922 0
Australia
Phone 10922 0
+61 3 8532 1821
Fax 10922 0
61 3 8532 1100
Email 10922 0
[email protected]
Contact person for scientific queries
Name 1850 0
Jonathan Shaw
Address 1850 0
Baker Heart and Diabetes Institute, Level; 4, 99 Commercial Road, Melbourne VIC 3004
Country 1850 0
Australia
Phone 1850 0
+61 3 8532 1821
Fax 1850 0
+61 3 8532 1100
Email 1850 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Confidential information.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.