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CLINICAL RESEARCH CASE STUDY Assessing FMD in overweight adults The efficacy of a product on flow mediated dilation (FMD) in healthy subjects with mild hypertension.
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Assessing FMD in overweight adults
Executive Summary This case study presents a human clinical study designed and conducted at our Cork Facility in Ireland. The sponsor needed a trusted research partner to recruit 80 healthy overweight volunteers and asse s s the efficacy of their investigational product versus placebo on FMD. About the Sponsor Endothelial function (EF) plays an important role in cardiovascular health. Impaired EF is a prominent health concern, as it typically contributes tocardiovasculardisease (CVD), i.e., hypertension, atherosclerosis, or myocardial infarction.
Atlantia was aware of the importance of the use of non-invasive techniques when assessing EF. It would be a critical factor when the study would be presented to the appropriated Ethics Committee following ICH GCP standards.
In an aging population, the high prevalence, increasing incidence, and alarming global number of deaths Year on Year due to CVD demonstrate the importance of counterbalancing CVD with the development of innovative preventive strategies integrated in everyday life. Furthermore, it is well known that clinical states of insulin resistance, including obesity, metabolic syndrome, and diabetes mellitus, are associated with impaired endothelium- dependent vasodilation. Based on this knowledge and considering the large intake of high-GI foods that characterizes today’s Western diet, low-GI foods might be effective in preventing ED. The sponsor, an ingredient producer company highly committed to nutrition research, has worked to develop a low-GI carbohydrate which can act as a sugar replacer Their investigational product, is a functional ingredient, which may contribute to improved cardiovascular health. Based on that hypothesis they understood that further clinical studies were needed in this field.
Challenges and Objectives
The main research objectives of this study were:
• To assess the effect of investigational product, relative to placebo, on change in postprandial flow mediated dilation (FMD). • To investigate the effect of investigational product, relative to placebo in healthy subjects with mild hypertension on changes in Blood glucose concentrations and Insulin concentrations. At this point, the Sponsor was struggling to get a trusted research partner to design and conduct a clinical study. Both techniques of assessment and access to the relevant population were critical for the success of this project.
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Assessing FMD in overweight adults
How Atlantia’s Solution Helped There are several techniques for assessing endothelial function. These techniques can be either invasive or non- invasive and assess different aspects of pathobiology. For the assessment of clinical pre-disease, the ideal technique for measuring endothelial function must be non-invasive, reliable, reproducible, cheap, and easy to perform . Atlantia was aware of the importance of the use of non- invasive techniques when assessing EF. It would be a critical factor when the study would be presented to the appropriated Ethics Committee following ICH GCP standards. EF can be assessed by brachial artery ultrasound imaging. With this completely non-invasive, subject-friendly technique, the shear stress-induced flow-mediated endothelium-dependent vasodilation (FMD) of the brachial artery can be measured. Brachial ultrasound FMD measurements are well reproducible and are considered a validated early marker of CVD risk. Atlantia’s expertise in cardiovascular human clinical studies (Figure 1) and their robust database of participants made the perfect fit for the Sponsor’s research needs.
DESIGN
ETHICS
RECRUITMENT
CONDUCT
ANALYSIS
REPORTING
About the Study The present exploratory study aimed to investigate the acute effects of the investigational product versus those of placebo on endothelium-dependent vasodilation, i.e., FMD, in overweight/obese subjects.
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Assessing FMD in overweight adults
About the Study Between August 2016 and March 2017, overweight and obese subjects with mild hypertension were recruited by Atlantia Food Clinical Trials in our Cork facility in Ireland. After screening, healthy persons aged 25–60 years were included if their body weight was stable and their physical activity level was low to moderate. Exclusion criteria were the use of medications influencing glucose metabolism or EF and chronic or acute diseases. Smokers, heavy coffee drinkers, and pregnant women were further excluded. Throughout the study, subjects were asked to follow their usual diet and exercise routine and to avoid the named medications that could interfere with the study outcomes. The study protocol was approved by the Clinical Research Ethics Committee of the Cork Teaching Hospitals. All participants gave their written informed consent before the study’s start according to the ICH Guidelines on Good Clinical Practice and the declaration of Helsinki. Subjects were recruited through the Atlantia Food Clinical Trials database and posting adverts in local Media. An initial phone screen was performed with 400 volunteers, where subjects were asked questions regarding their age and overall health. 143 eligible subjects were scheduled for a screening visit. The study involved 3 visits over a 3 to 12-week period. 80 subjectswere randomized into the study, with 40 to receive the investigational product / placebo and 40 to receive placebo / the investigational product. Beside the screening visit, in this double-blinded, controlled, cross-over trial, participants were tested on two different. intervention days, which were separated by a 2–6 week wash-out period. On the two intervention days, the participants attended the clinic after an overnight fast of at least 10 h. To minimize confounding variables, for premenopausal women, the intervention days were within the first seven days of their menstrual cycle. Moreover, the subjects were asked to avoid high-fat and high-flavonoid foods for 24 h and caffeine for 10 h and to abstain from exercise for 12 h before the intervention. The order of the assessments was the same on both intervention days. Prior to carbohydrate load (T0), a brachial ultrasound FMD scan was performed, with blood drawn shortly thereafter. All subjects were blinded to treatment and randomly assigned to consume either 50 g of the investigational product or 50 g of placebo in the form of instant citrus drinks.
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Assessing FMD in overweight adults
About the Study
Therefore, drink powders were dissolved in 500 mL of water shortly before consumption. The subjects were instructed to consume the citrus drinkwithin 10min after the T0 FMD. At 60 min (T1), 120 min (T2), and 180 min (T3) after the start of the citrus drink consumption, FMD scans and blood sample collections were performed. Ultrasound FMD scanning procedures were strictly standardized and quality controlled. In short, prior to the start of the study, two clinical trial assistants from Atlantia on site were trained and certified according to pre-set criteria of the FMD core lab (Imagelabonline & Cardiovascular, Erichem, The Netherlands). Validated
and FDA-approved image analysis software was used. All scans were performed with an Ultrasonix Sonix SP ultrasound instrument equipped with an L14-5MHz vascular transducer and fixed presets throughout the study. The examinations took place in a quiet room at temperatures between 20 °C and 26 °C and dimmed lighting. For each subject on both test days, initial and follow-up scans were performed by the same clinical trial assistant. Subjects comfortably reclined for 20 min prior to scans. A vein cannula was inserted into the subject’s left arm, and a blood sample (12 mL) was collected shortly after FMDmeasurement at T0, T1, T2, and T3 during both intervention days.
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CLINICAL RESEARCH CASE STUDY Assessing FMD in overweight adults The efficacy of a product on flow mediated dilation (FMD) in healthy subjects with mild hypertension.
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