This article presents a case study of a human clinical study designed and conducted at Atlantia Clinical Trials’ Cork Facility in Ireland. The Sponsor required a trusted research partner to recruit 80 healthy overweight volunteers and assess the efficacy of their investigational product versus placebo on FMD.
About the Sponsor
An important role in cardiovascular health is played by endothelial function (EF). Impaired EF typically contributes to cardiovascular diseases (CVD) like myocardial infarction, atherosclerosis or hypertension, making it a prominent health concern.
The importance of counterbalancing CVD with the development of innovative preventive strategies integrated into everyday life is demonstrated by the high prevalence, increasing incidence and the alarming number of deaths occurring globally year on year due to CVD in an aging population.
It is also well known that clinical states of insulin resistance, including diabetes mellitus, metabolic syndrome and obesity, are associated with impaired endotheliumdependent vasodilation.
Low-GI foods might be effective in preventing ED, considering the large intake of high-GI foods that characterizes today’s Western diet.
The Sponsor was an ingredient producer company highly committed to nutrition research and has worked to develop a low-GI carbohydrate that can act as a sugar replacer.
The product they wished to investigate is a functional ingredient that may contribute to improved cardiovascular health. They understood that further clinical studies were needed in this field based on their hypothesis.
Challenges and objectives
Atlantia knew how important it was to use non-invasive techniques to assess EF as it would be a crucial factor when the study was presented to the appropriate Ethics Committee following ICH GCP standards. The central research objectives of this study were:
- To investigate the effect of the investigational product on changes in Insulin concentrations and blood glucose concentrations in healthy subjects with mild hypertension relative to placebo.
- To assess the effect of the investigational product on change in postprandial flow mediated dilation (FMD) relative to placebo.
The Sponsor was struggling to find a trusted research partner at this point who could design and conduct an appropriate clinical study. For the success of this project, both techniques of assessment and access to the relevant population were critical.
How Atlantia’s solution helped
For assessing endothelial function, there are several techniques. These techniques assess different aspects of pathobiology and can be either non-invasive or invasive. The ideal technique for measuring endothelial function for the assessment of clinical pre-disease must be easy to perform, cheap, reproducible, reliable and non-invasive.
Atlantia was aware of the importance of assessing EF using non-invasive techniques. Using non-invasive techniques would be a critical factor when the study was be presented to the appropriate Ethics Committee following ICH GCP standards.
Brachial artery ultrasound imaging can be used to assess EF. The brachial artery's shear stress-induced flow-mediated endothelium-dependent vasodilation (FMD) can be measured using this completely non-invasive, subject-friendly technique.
Brachial ultrasound FMD measurements are considered a validated early marker of CVD risk and are easily reproducible. Figure 1 shows how Atlantia’s robust database of participants and expertise in cardiovascular human clinical studies made them the perfect fit for the Sponsor’s research needs.
About the Study
The aim of the present exploratory study was to investigate the acute effects of the investigational product on endothelium-dependent vasodilation, i.e., FMD, in overweight/obese subjects versus the effects of placebo.
Image Credit: Atlantia Clinical Trials
Atlantia Food Clinical Trials recruited overweight and obese subjects with mild hypertension between August 2016 and March 2017 in their Cork facility in Ireland. Following a screening, healthy persons aged 25–60 years were included if their physical activity level was low to moderate and their body weight was stable.
The criteria for exclusion were EF and chronic or acute diseases or the use of medications influencing glucose metabolism. Pregnant women, heavy coffee drinkers and smokers were also excluded.
Subjects were asked to follow their usual diet and exercise routine throughout the study and to avoid the named medications that could interfere with the study outcomes. Clinical Research Ethics Committee of the Cork Teaching Hospitals approved the study protocol.
Before the study started, each participant gave written informed consent in accordance with the ICH Guidelines on Good Clinical Practice and the declaration of Helsinki.
Recruitment of subjects was done by posting adverts in local media and through the Atlantia Food Clinical Trials database. Four hundred volunteers underwent an initial phone screen in which they were asked questions regarding their overall health and age.
Of these, screening visits were scheduled for 143 eligible subjects. There were three visits over a 3 to 12-week period for the study. There were 80 subjects randomized into the study, with 40 to receive placebo / the investigational product and 40 to receive the investigational product / placebo.
Participants were tested on two different intervention days in this double-blinded, controlled, cross-over trial (besides the screening visit), which were separated by a 2–6 week wash-out period. After an overnight fast of at least 10 hours, the participants attended the clinic on the two intervention days.
The intervention days were within the first seven days of the menstrual cycle for premenopausal women to minimize confounding variables. Additionally, subjects were instructed to abstain from exercise for 12 hours, to avoid high-fat and high-flavonoid foods for 24 hours and caffeine for 10 hours before the intervention.
Both intervention days had the same order of assessments. A brachial ultrasound FMD scan was performed prior to carbohydrate load (T0), and blood was drawn shortly thereafter.
Subjects were all blinded to treatment and randomly assigned to consume either 50 g of placebo or 50 g of the investigational product in the form of instant citrus drinks.
Shortly before consumption, drink powders were dissolved in 500 mL of water. The subjects were instructed that after the T0 FMD that they were to consume the citrus drink within 10 minutes.
FMD scans and blood sample collections were performed at 60 minutes (T1), 120 minutes (T2) and 180 minutes (T3) after the start of the citrus drink consumption. There were strict standardizing procedures and quality controls for the ultrasound FMD scanning procedures.
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) prior to the start of the study. Validated and FDA-approved image analysis software was then used.
An Ultrasonix Sonix SP ultrasound instrument equipped with an L14-5MHz vascular transducer was used for all scans, using fixed presets throughout the study. A quiet room was used for examinations, with dimmed lighting and at temperatures between 20 °C and 26 °C.
Initial and follow-up scans were performed by the same clinical trial assistant for each subject on both test days. For 20 minutes prior to scans, subjects comfortably reclined. During both intervention days, a vein cannula was inserted into the subject’s left arm, and a blood sample (12 mL) was collected shortly after FMD measurement at T0, T1, T2 and T3.
About Atlantia Clinical Trials
Atlantia Clinical Trials Ltd is a CRO that specializes in conducting studies in foods, beverages and supplements for companies world-wide that want to scientifically validate their functional ingredients to support an: EFSA (European Food Safety Authority) Health Claim; FDA (Food & Drug Administration) Structure Function Claim; or General Product Marketing Claim.
Atlantia works with world leading scientists (among the top cited 1% internationally, in the areas of digestive health and functional foods) at the: APC Microbiome Institute in University College Cork, Ireland; Teagasc, Moorepark, Ireland and recognized centers of excellence globally.
Atlantia runs and operates its own clinic sites and conducts all studies to ICH-GCP standard (International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use - Good Clinical Practice). Its team includes physician experts in digestive health, mental health (psychological stress and cognition), cardiovascular health, sports performance, metabolic disease, bone health, immune health and healthy ageing. The clinical team also includes project managers, research nurses, nutritionists, certified sports trainers and lab researchers.
Atlantia manages all elements from protocol design, placebo manufacture, recruitment, and study execution, to sample and data analysis, statistics and report/dossier preparation to provide a service which is technically, scientifically and clinically superior.
The clinical studies cover a broad spectrum of functional food and beverage categories, such as dairy, cereal, probiotic, different protein forms, infant-specific foods, vitamins/minerals, plant or marine extracts and medical foods.
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