CITRUS: Beneficial Impact of Orange Juice Consumption on Risk Factors Associated With Cardiovascular Diseases

Sponsor

Technological Centre of Nutrition and Health, Spain (Other)

Overall Status

Completed

CT.gov ID

NCT02479568

Collaborator

Florida Department of Citrus (Other), Technological Centre of Nutrition and Health (Other), Hospital Universitari Sant Joan de Reus (Other), University Rovira i Virgili (Other)

159

Enrollment

Location

Arms

17.8

Duration (Months)

8.9

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary aim is to examine both the acute and chronic effects of hesperidin consumption from 100% Florida orange juice in various doses on functional and systemic markers associated with cardiovascular disease (CVD) risks.

Condition or Disease	Intervention/Treatment	Phase
Cardiovascular Risk Factors	Dietary Supplement: Control Dietary Supplement: 100% Florida OJ Dietary Supplement: 100% Florida OJ-enriched	Phase 3

Detailed Description

The aim of this study is to compare the effect of different doses of hesperidin in 100% Florida orange juice (OJ) when regularly or postprandially consumed on cardiovascular risk markers; in addition, the plausible role and mechanism of the hesperidin will be investigated.

The sample size was calculated using a previously available bibliography using systolic blood pressure (SBP) as the primary outcome measure. A total of 84 subjects per study product group were needed, assuming variance components of approximately 20.0, to detect differences between the three groups (control, orange juice and hesperidin-enriched orange juice (10 mm Hg)) with a bilateral significance level of α=0.05 and a power of 80 %.

The sample size was computed to be sufficient to detect differences between treatment groups regarding the evolution in time of SBP levels. Justification of chosen sample size is based on the clinically meaningful difference assigned to δ=10.0 mm Hg, which is equivalent to a difference of approximately 7.4 % in patients with baseline SBP levels of approximately 135 mm Hg. Thus, a sample of 252 participants can be used for the chronic three arm parallel trial design (84 subjects/arm) and will allow us to detect small but clinically relevant differences between the three groups with statistical robustness and direct interpretation in terms of the chronic treatment effect.

To the acute postprandial tests, the investigators have chosen n=20 subjects per arm according to the most studies that have addressed the metabolic effects of a postprandial intervention have been performed using a very similar number of subjects with statistically good quality results.

The statistical analysis will follow the principles specified in the guidelines of the ICHE9 and CPMP/EWP/908/99 ICHE9 Points to Consider on Multiplicity Issues in Clinical Trials.

The continuous efficacy variables will be analyzed by an ANCOVA (analysis of covariance) with the baseline value as a covariate.

The efficacy outcomes will be determined using the absolute values and absolute differences from the baseline. The efficacy analysis will be performed using the Available Data Only approach. In addition, the analysis of the primary efficacy variable will be performed with the Baseline Observation Carried Forward approach.

A suitable hypothesis test will be applied to the rest of the variables according to the nature of each variable, such as the Fisher exact test for categorical variables, Student's T-test for continuous variables and Mann-Whitney U test for ordinal scale variables.

The statistical tests will be applied with an α=0.05 two-sided significance level. Post-hoc analyses and comparisons between pairs of groups will be done as for exploratory purposes.

In addition, the statistical plan will be transferred to the application form of the electronic data collection report (e-CDR), which allows the improvement of data management, diminishes human errors (according threshold values of each outcome) and, overall, guarantees the maximum exploitation of human data in the context of statistical analysis.

Study Design

Study Type:

Interventional

Actual Enrollment :

159 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Prevention

Official Title:

Randomized, Parallel and Double Blind Placebo-controlled Study for the Evaluation of Both Acute and Chronic Role of Hesperidin Consumption in 100% Orange Juice

Study Start Date :

Jan 12, 2016

Actual Primary Completion Date :

Jul 6, 2017

Actual Study Completion Date :

Jul 6, 2017

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Control Control drink (placebo)	Dietary Supplement: Control 500 mL (250 mL; 2 times/day) of placebo drink for 12 weeks
Experimental: Natural Florida orange juice 100% Florida orange juice (OJ) (natural content of hesperidin)	Dietary Supplement: 100% Florida OJ 500 mL (250 mL; 2 times/day) of 100% Florida OJ for 12 weeks
Experimental: Enriched Florida orange juice 100% Florida orange juice (OJ) (enriched hesperidin content)	Dietary Supplement: 100% Florida OJ-enriched 500 mL (250 mL; 2 times/day) of 100% Florida OJ-enriched for 12 weeks

Arm

Intervention/Treatment

Active Comparator: Control

Control drink (placebo)

Dietary Supplement: Control

500 mL (250 mL; 2 times/day) of placebo drink for 12 weeks

Experimental: Natural Florida orange juice

100% Florida orange juice (OJ) (natural content of hesperidin)

Dietary Supplement: 100% Florida OJ

500 mL (250 mL; 2 times/day) of 100% Florida OJ for 12 weeks

Experimental: Enriched Florida orange juice

100% Florida orange juice (OJ) (enriched hesperidin content)

Dietary Supplement: 100% Florida OJ-enriched

500 mL (250 mL; 2 times/day) of 100% Florida OJ-enriched for 12 weeks

Outcome Measures

Primary Outcome Measures

Systolic Blood Pressure [Every 2 weeks for a total of 12 weeks.]
During each visit, SBP will be measured after 5 min in a seated position in a comfortable room by the physician. The measurement will be taken in duplicate at 1-min intervals using an automatic sphygmomanometer (OMRON HEM-907; Peroxfarma, Barcelona, Spain), and the average of the two measurements will be calculated.

Secondary Outcome Measures

Diastolic Blood Pressure [Every 2 weeks for a total of 12 weeks.]
During each visit, diastolic BP will be measured after 5 min in a seated position in a comfortable room by the physician. The measurement will be taken in duplicate at 1-min intervals using an automatic sphygmomanometer (OMRON HEM-907; Peroxfarma, Barcelona, Spain), and the average of the two measurements will be calculated.
Ischemic reactive hyperemia (IRH) [Every 4 weeks for a total of 12 weeks]
The endothelial-dependent vasomotor functions will be measured as IRH by a Laser-Doppler linear Periflux 5000 flowmeter (Perimed AB, Järfälla, Stockholm, Sweden)
Platelet aggregation [Every 4 weeks for a total of 12 weeks]
Multiplate analyzer, Roche
Homocysteine [Every 4 weeks for a total of 12 weeks]
Homocysteine concentrations will be measured by liquid chromatography-mass spectrometry (LC-MS/MS)
C-reactive protein (inflammatory marker) [Every 4 weeks for a total of 12 weeks]
High sensitivity C-reactive protein (hsCRP) by standardized methods in a Cobas Mira Plus autoanalyzer (Roche Diagnostics Systems, Madrid, Spain)
oxidized LDL (as oxidative stress biomarker) [Every 4 weeks for a total of 12 weeks]
Mercodia Oxidized LDL ELISA kit will be used to measure the oxidized LDL (mU/L).

Other Outcome Measures

Transcriptomics [At week 0 (V1) and 12 week (V7).]
Plasma collected at 0 h (V1 and V7) of 20 samples each arm (volunteers in the postprandial study). These cells will be used to perform transcriptomics analysis to detect whole gene expression changes due to the chronic consumption of two doses of hesperidin in 100% Florida orange juice.
Non-targeted Metabolomics [At week 0 (V1) and 12 week (V7).]
Plasma collected at 0 h (V1 and V7) of 20 samples each arm (volunteers in the postprandial study) will be used to perform non-targeted metabolomics by Nuclear Magnetic Response Spectroscopy (NMR) to detect metabolomic profile changes due to the chronic consumption of two doses of hesperidin in 100% Florida orange juice

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion criteria

Men or women 18-65 years old
No evidence of chronic disease
No familial CVD history
Written informed consent provided before the initial screening visit.
Blood pressure (with no drug intervention) >120 mm Hg systolic blood pressure ≤ 159 mmHg

Exclusion criteria

Body mass index (BMI) ≥ 35 kg/m2
Glucose >125 mg/dl
Systolic blood pressure ≥ 160 mm Hg and diastolic blood pressure >100 mm Hg or taking antihypertensive medications
Total cholesterol >240 mg/dl
LDL-cholesterol >160 md/dl
TAG >350
Smoking
Pregnant or intending to become pregnant
Use of medications, antioxidants, or vitamin supplements
Chronic alcoholism
Intense physical activity (5h/week)
Intestinal disorders
Following of a vegetarian diet
Anemia (hemoglobin ≤13 g/dL in men and ≤12 g/dL in women)
Current or past participation in a clinical trial or consumption of a research product in the 30 days prior to inclusion in the study
Failure to follow the study guidelines.