Clinical trial NCT04731987: Orange Juice, Hesperidin and Their Role in Vascular Health Benefit
Official title: Orange Juice, Hesperidin and Their Role in Vascular Health Benefit: a Human Double Blind, Randomized, Controlled, Cross Over Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Metabolic Syndrome
Vascular Compliance
Predisposition to Cardiovascular Disease
Keywords: Cardiovascular disease prevention
Endothelial dysfunction
Orange juice
Flavanone
Hesperidin
Nutrition Assessment
Nutritional Physiological Phenomena
Lead sponsor: University Hospital, Clermont-Ferrand
Sponsor class: OTHER
Collaborators: name: UMR 1019, Unité de Nutrition Humaine, INRAE, Auvergne-Rhône Alpes Center
name: Department of Beverage Research, Chair of analysis and technology of plant-based foods, Geisenheim University
name: European Fruit Juice Association (AIJN)
First posted: 2021-02-01
Enrollment: 50
Sex: ALL
Minimum age (years): 40
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: Although epidemiological studies have associated the consumption of sugary beverages with adverse health effects, experimental studies have demonstrated that the metabolic response of the human body to fruit juice as compared to artificial beverages is substantially different. Fruit juices do not just provide sugars and related calories, but they are rich sources of bioactive compounds especially of flavonoids. Flavanones constitute a class of flavonoids that are specifically and abundantly found in citrus fruits, with hesperidin being the major compound in orange. From prospective cohort studies, higher intakes of flavanones are associated with a lower incidence of mortality by cardiovascular disease (CVD). This relation is supported by results from a number of animal studies demonstrating a slowdown in atherosclerosis development and vascular protective effects in dietary interventions with flavanones. Randomized, controlled clinical trials to corroborate the suggested vasculo-protective effects of orange juice presumably mediated by the flavanones are scarce and available data do not allow to draw firm conclusions about their efficacy. To fill this gap, the "HESPER-HEALTH study" conducted in humans will assess the vascular protective effects of 100% orange juice consumption and evaluate the contribution of hesperidin in these effects.

Detailed description: This human dietary intervention study is a double blind, randomized, placebo controlled, cross over trial with 3 arms, carried out on subjects with predisposition to cardiovascular diseases (CVD) based on age and overweight. This study aims to demonstrate the vascular protective effects (with Flow Mediated Dilatation (FMD) as main criteria) of the consumption of a flavanone rich orange juice or of orange flavanones by comparison with a control sugary drink alone.

The 42 recruited participants will receive the 3 drinks in a random order. For each subject, the study is divided into 3 identical experimental periods of 45 days (period 1,2,3): including 3 days prior to the beginning of the product intake, during which specific dietary guidelines, samplings and measures will be asked to be performed at home followed by a 6 weeks period of consumption of each of the 3 beverages). A period of 4 to 6 weeks of wash-out is planned between each experimental period.

To summarize: Visit 1 (D-14) = inclusion, Visit 2 (D1: baseline) to 3 (D42) = period 1, Visit 3 (D42) to 4 (D70) = wash out 1, Visit 4 (D70) to 5 (D111) = period 2, Visit 5 (D111) to 6 (D139) = wash out 2, Visit 6 (D139) to 7 (D180) = period 3. The wash-out periods (minimum duration: 4 weeks) may be extended until 6 weeks for the convenience of participants.

The protocol includes a total of 7 visits to PIC/CIC Inserm 1405 of the Clermont-Fd University Hospital.

The total duration of the study will be between 28 and 34 weeks

Eligibility criteria: Inclusion Criteria:

* Man or post-menopausal woman ;
* 40-65 years old (inclusive) ;
* Body Mass Index (BMI)≤ 30 ;
* Waist circumference ≥80 cm for women, and ≥94 cm for men ;
* Weight \> 46 kg
* Normal biological balance sheet or considered normal by the investigator
* No aversion or intolerance to citrus foods ;
* Accept to limit their total intake of flavonoid rich beverages (tea, coffee, cocoa, wine, fruit juice) to 250 mL/day ;
* Ability to give informed consent to participate in research ;
* Willingness to accept randomization and undergo the testing and intervention procedures and deliver stool, blood and urine samples for testing ;
* Affiliation to Social Security.

Exclusion Criteria:

* Treated pre-diabetic or diabetic ;
* Treated for hypertension ;
* Use of statins or other medications for lowering cholesterol ;
* Treated with antibiotics, antifungals, probiotics or prebiotics in the 3 months before the enrolment ;
* Menopausal hormone replacement therapy ;
* Diagnosed gastrointestinal illness in the judgement of the investigator ;
* Any serious medical condition that precludes safe participation in the study, such as coronary artery disease, peripheral vascular disease, stroke, congestive heart failure, chronic obstructive pulmonary disease, insulin-dependent diabetes, psychiatric disease, renal disease, liver disease, active cancer and anemia ;
* History of eating disorders such as bulimia nervosa, anorexia nervosa and severe binge eating disorder in the last 5 years ;
* Digestive disorders with diarrhea during the 3 months preceding the beginning of the study ;
* Self-declared vegetarian, vegetalian, vegan ;
* History of substance abuse or alcohol abuse ;
* Involvement in a weight loss intervention program (including anti-obesity medication) within the past 3 months or who have had bariatric surgery ;
* Current smokers (within the last 30 days) ;
* Use of dietary supplements (vitamins, antioxidants) currently or in the past one month ;
* Strenuous exercise greater than 6 hours per week ;
* Anyone who in the opinion of the investigator is unlikely to be able to comply with the protocol ;
* Subjects involved in another clinical trial or being in the exclusion period of another study or having received a total compensation greater than 4,500 euros over the 12 months preceding the start of the trial ;
* Subject benefiting from a legal protection measure (curatorship, guardianship, safeguard of justice) ;
* Refusal to participate.

Primary outcomes:
measure: Brachial artery Flow Mediated Dilation (FMD)
timeFrame: Day 1
measure: Brachial artery Flow Mediated Dilation (FMD)
timeFrame: Day 42
measure: Brachial artery Flow Mediated Dilation (FMD)
timeFrame: Day 70
measure: Brachial artery Flow Mediated Dilation (FMD)
timeFrame: Day 111
measure: Brachial artery Flow Mediated Dilation (FMD)
timeFrame: Day 139
measure: Brachial artery Flow Mediated Dilation (FMD)
timeFrame: Day 180
Secondary outcomes:
measure: Sex
timeFrame: Day -14
measure: Age
timeFrame: Day 34
measure: Basal Systolic Blood Pressure
timeFrame: Day -14
measure: Basal Heart Rate
timeFrame: Day -14
measure: D-3 visit systolic Blood Pressure (BP)
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: D-3 visit diastolic BP
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: D-3 visit Heart Rate
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: FMD post prandial endothelial response 3h after a challenge meal
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: FMD post prandial endothelial response 6h after a challenge meal
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Arterial compliance assessment
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Rest flow by Flowmetry Laser Doppler (FLD) in fasted state
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Occlusion area by FLD in fasted state
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Hyperaemia area by FLD in fasted state
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Hyperaemia area / occlusion area ratio by FLD in fasted state
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Maximal flow by FLD in fasted state
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Hyperaemia half time by FLD in fasted state
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Rest flow by FLD 3h after a challenge meal
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Occlusion area by FLD 3h after a challenge meal
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Hyperaemia area by FLD 3h after a challenge meal
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Hyperaemia area / occlusion area ratio by FLD 3h after a challenge meal
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Maximal flow by FLD 3h after a challenge meal
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Hyperaemia half time by FLD 3h after a challenge meal
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Rest flow by FLD 6h after a challenge meal
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Occlusion area by FLD 6h after a challenge meal
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Hyperaemia area by FLD 6h after a challenge meal
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Hyperaemia area / occlusion area ratio by FLD 6h after a challenge meal
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Maximal flow by FLD 6h after a challenge meal
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Hyperaemia half time by FLD 6h after a challenge meal
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Hesperetin concentration in 24h urine
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Hesperetin concentration in plasma on fasted state
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Hesperetin catabolites concentration in plasma on fasted state
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Hesperetin concentration in plasma on 3h post prandial test
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Hesperetin catabolites concentration in plasma on 3h post prandial test
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Hesperetin concentration in plasma on 6h post prandial test
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Hesperetin catabolites concentration in plasma on 6h post prandial test
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Naringenin concentration in 24h urine
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Naringenin catabolites concentration in 24h urine
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Naringenin concentration in plasma on fasted state
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Naringenin catabolites concentration in plasma on fasted state
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Naringenin concentration in plasma on 3h post prandial test
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Naringenin catabolites concentration in plasma on 3h post prandial test
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Naringenin concentration in plasma on 6h post prandial test
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Naringenin catabolites concentration in plasma on 6h post prandial test
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Flavanone concentration in 24h urine
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Flavanone catabolites concentration in 24h urine
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Flavanone concentration in plasma on fasted state
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Flavanone catabolites concentration in plasma on fasted state
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Flavanone concentration in plasma on 3h post prandial test
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Flavanone catabolites concentration in plasma on 3h post prandial test
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Flavanone concentration in plasma on 6h post prandial test
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Flavanone catabolites concentration in plasma on 6h post prandial test
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Plasma nitrites dosage
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Plasma nitroso-thiols dosage
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Plasma Inter-Cellular Adhesion Molecules (ICAM) dosage on fasted state
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Plasma ICAM dosage on 6h post prandial state
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Plasma Vascular-CAM (VCAM) dosage on fasted state
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Plasma VCAM dosage on 6h post prandial state
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Plasma e-selectin dosage on fasted state
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Plasma e-selectin dosage on 6h post prandial state
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Plasma Extracellular Vesicles analyses (EVs) on fasted state
timeFrame: Day 42, Day 111, Day 180
measure: EVs analyses on 3h post prandial state
timeFrame: Day 42, Day 111, Day 180
measure: Plasma oxylipins identification on fasted state
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Plasma oxylipin concentration on fasted state
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Plasma oxylipins identification on 6h post prandial state
timeFrame: Day 42, Day 111, Day 180
measure: Plasma oxylipin concentration on 6h post prandial state
timeFrame: Day 42, Day 111, Day 180
measure: Plasma Interleukin 6 (IL-6) dosage
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Plasma Tumor Necrosis Factor α (TNFα) dosage
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Plasma high-sensitivity C-reactive protein (hs-CRP) dosage
timeFrame: Day -14, Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Plasma glucose dosage on fasted state
timeFrame: Day -14, Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Plasma glucose dosage on 3h post prandial state
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Plasma glucose dosage on 6h post prandial state
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: -Plasma Triacylglycerol (TAG) dosage on fasted state
timeFrame: Day -14, Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Plasma TAG dosage on 3h post prandial state
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Plasma TAG dosage on 6h post prandial state
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Plasma uric acid dosage on fasted state
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Plasma uric acid on 3h post prandial state
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Plasma uric acid on 6h post prandial state
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Plasma total cholesterol dosage
timeFrame: Day -14, Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Plasma High Density Lipoprotein cholesterol (HDL-chol) dosage
timeFrame: Day -14, Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Plasma High Density Lipoprotein cholesterol (LDL-chol) calculation
timeFrame: Day -14, Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Plasma Total Fatty Acids (FA) dosage
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Serum Insulin dosage
timeFrame: Day -14, Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Weight measure
timeFrame: Day -14, Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Height measure
timeFrame: Day -14
measure: Body Mass Index (BMI) calculation
timeFrame: Day -14, Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Waist circumference measure
timeFrame: Day -14, Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Fat mass ratio determination
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Lean mass ratio determination
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Water mass ratio determination
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: RNA profiling on fasted state
timeFrame: Day 42, Day 111, Day 180
measure: RNA profiling on 6h post prandial state
timeFrame: Day 42, Day 111, Day 180
measure: Gut microbiota profiling
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Plasma carotenoids dosage
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Plasma vitamine C dosage
timeFrame: Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
measure: Treatment compliance
timeFrame: Day 42, Day 111, Day 180
measure: Polyphenol intake
timeFrame: Day 1, Day 42, Day 111, Day 180
measure: Low-polyphenol diet compliance
timeFrame: Day 1, Day 42, Day 111, Day 180
measure: Calorie intake
timeFrame: Day 1, Day 42, Day 111, Day 180
measure: Protein intake
timeFrame: Day 1, Day 42, Day 111, Day 180
measure: Lipid intake
timeFrame: Day 1, Day 42, Day 111, Day 180
measure: Carbohydrate intake
timeFrame: Day 1, Day 42, Day 111, Day 180
measure: Diet division of protein/lipid/carbohydrate intakes
timeFrame: Day 1, Day 42, Day 111, Day 180
measure: Diet stability
timeFrame: Day 180
measure: Biobank for food metabolome
timeFrame: Day -14, Day 1, Day 42, Day 70, Day 111, Day 139, Day 180
Other outcomes:
Locations:
city: Clermont-Ferrand
country: France
facility: University Hospital, Clermont Ferrand
state: Aura
Study officials:
References:
citation: Verny MA, Milenkovic D, Macian N, Pereira B, Evrard R, Gilcher C, Steingass CB, Mosoni P, Gladine C, Monfoulet LE, Schweiggert R, Pickering G, Morand C. Evaluating the role of orange juice, HESPERidin in vascular HEALTH benefits (HESPER-HEALTH study): protocol for a randomised controlled trial. BMJ Open. 2021 Nov 30;11(11):e053321. doi: 10.1136/bmjopen-2021-053321.