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

• ClinicalTrials.gov Identifier: NCT02479568
• Recruitment Status: Unknown
• First Posted: June 24, 2015
• Last Update Posted: June 6, 2016
• Sponsor: Technological Centre of Nutrition and Health, Spain
• Collaborators: Florida Department of Citrus; Technological Centre of Nutrition and Health; Hospital Universitari Sant Joan de Reus; University Rovira i Virgili
• Information provided by (Responsible Party): Technological Centre of Nutrition and Health, Spain

Tracking Information

• First Submitted Date: June 17, 2015
• First Posted Date: June 24, 2015
• Last Update Posted Date: June 6, 2016
• Study Start Date: September 2015
• Estimated Primary Completion Date: May 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 19, 2015)

Systolic Blood Pressure [ Time Frame: 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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 19, 2015)

• Diastolic Blood Pressure [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: Every 4 weeks for a total of 12 weeks ]
  Multiplate analyzer, Roche
• Homocysteine [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: Every 4 weeks for a total of 12 weeks ]
  Mercodia Oxidized LDL ELISA kit will be used to measure the oxidized LDL (mU/L).

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: June 19, 2015)

• Transcriptomics [ Time Frame: 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 [ Time Frame: 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

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Beneficial Impact of Orange Juice Consumption on Risk Factors Associated With Cardiovascular Diseases
• 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
• 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.

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 Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Prevention
• Condition: Cardiovascular Risk Factors

Intervention

• Dietary Supplement: Control
  500 mL (250 mL; 2 times/day) of placebo drink for 12 weeks
• Dietary Supplement: 100% Florida OJ
  500 mL (250 mL; 2 times/day) of 100% Florida OJ for 12 weeks
• Dietary Supplement: 100% Florida OJ-enriched
  500 mL (250 mL; 2 times/day) of 100% Florida OJ-enriched for 12 weeks

Study Arms

• Active Comparator: Control
  Control drink (placebo)
  Intervention: Dietary Supplement: Control
• Experimental: Natural Florida orange juice
  100% Florida orange juice (OJ) (natural content of hesperidin)
  Intervention: Dietary Supplement: 100% Florida OJ
• Experimental: Enriched Florida orange juice
  100% Florida orange juice (OJ) (enriched hesperidin content)
  Intervention: Dietary Supplement: 100% Florida OJ-enriched

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Unknown status
• Estimated Enrollment (submitted: June 19, 2015): 252
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: January 2018
• Estimated Primary Completion Date: May 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Spain

Administrative Information

• NCT Number: NCT02479568
• Other Study ID Numbers: CITRUS 14-12
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Technological Centre of Nutrition and Health, Spain
• Study Sponsor: Technological Centre of Nutrition and Health, Spain

Collaborators

• Florida Department of Citrus
• Technological Centre of Nutrition and Health
• Hospital Universitari Sant Joan de Reus
• University Rovira i Virgili

Investigators

• Principal Investigator: Rosa Solà Alberich, Prof, MD; • University Rovira i Virgili / Hospital Universitari Sant Joan de Reus

• PRS Account: Technological Centre of Nutrition and Health, Spain
• Verification Date: June 2016