Oleuropein and Muscle Energy Metabolism

Study Overview
=================
Brief Summary
-----------------
Preclinical studies performed at Nestlé Research (NR) identified oleuropein as a novel activator of mitochondrial calcium import. This potentiated mitochondrial calcium uptake resulted in decreased phosphorylation of the enzyme pyruvate dehydrogenase (PDH), which is linked to its activation as a rate limiting enzyme for mitochondrial oxidation, as well as increasing mitochondrial oxygen consumption, resulting ultimately in decreases in muscle fatigue. In addition, NR demonstrated that during aging, mitochondrial calcium and oxygen consumption rates are decreased in isolated skeletal muscle fibers. The next step in the evidence development is to demonstrate efficacy of oleuropein for improved muscle energy and decreased physical fatigue in a healthy aging population.

Official Title
-----------------
A Randomized, Double-blind, Placebo Controlled Study to Investigate the Efficacy of Oleuropein on Skeletal Muscle Energy Metabolism and Fatigue in Humans

Conditions
-----------------
Muscular Fatigue

Intervention / Treatment
-----------------
* Other: Olive leaf extract
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male 50 to 70 years old BMI 18.5-29.9 kg/m2 Healthy as per medical history and investigator's/ physician's judgement Having given informed consent Exclusion Criteria: Allergy/intolerance to the study product >5% body mass change in the previous 3 months HbA1c ≥ 6.5% Blood pressure >140/90 mmHg Participating in a structured (progressive) exercise program Smoking Diagnosed acute or chronic medical conditions that, in the opinion of the investigator, could impact study outcomes Diagnosed musculoskeletal disorders Chronic use of gastric acid suppressing medication Unauthorized concomitant medications such as calcium antagonists (e.g. valproate), oral corticosteroids, anything that will prevent subjects from safely completing the study according to the investigator or medications / drugs known interfering with the expected mechanism of action of IP or to affect the outcome parameters Alcohol (intake higher than 3 servings per day. One serving is 0.4 dl of alcohol, 1 dl of wine, or 3 dl of beer) or drug abuse Overly imbalanced or restrictive diet (e.g. hyperproteic, vegan, ketogenic, etc.) Subjects not willing and/or not able to comply with scheduled visits and the requirements of the study protocol Any implants that would be a contra-indication for performing an MRI scan. Participation in another study at the same time Blood donation in the past 2 months

Ages Eligible for Study
-----------------
Minimum Age: 50 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a single-centre, double-blind, placebo controlled, randomised 2-arms parallel group study.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Investigational product<br>The investigational product is a capsule containing 100mg of the active ingredient oleuropein and will be provided once daily in the form of a 250mg olive leaf extract (i.e. 100mg of oleuropein per day) product for the duration of the intervention period (36 days). | Other: Olive leaf extract<br>* The investigational product is a capsule containing 100mg of the active ingredient oleuropein and will be provided once daily in the form of a 250mg olive leaf extract (i.e. 100mg of oleuropein per day) product for the duration of the intervention period (36 days).<br>|
| Placebo Comparator: Control arm<br>The control will be a placebo capsule containing 336 mg of cellulose microcrystalline, matching the investigational product appearance. | Other: Placebo<br>* The control will be a placebo capsule containing 336 mg of cellulose microcrystalline, matching the investigational product appearance.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Exploratory outcomes - Evaluate the changes in Pyruvate dehydrogenase activation between oleuropein and placebo groups following 1 single dose | measured by western blotting | Chronic effect after 36 days of intake | 
| Exploratory outcomes - Evaluate the changes in Pyruvate dehydrogenase activation between oleuropein and placebo groups following 1 single dose | measured by biochemical assay analysis | Acute effect after first product intake + chronic effect after 36 days of intake | 
| Exploratory outcomes - to evaluate the changes Mitocondrial respiration between oleuropein and placebo groups following 1 single dose | measured the rates of oxygen consumption (respiration or JO2) using Oroboros Oxygraph 2K systems with physiological ADP concentrations using permeabilized muscle fibres. | Acute effect after first product intake + chronic effect after 36 days of intake | 
| Exploratory outcomes- to evaluate the changes of fatigue between oleuropein and placebo groups following 1 single dose | measured using Biodex dynamometer | After 4 weeks of supplementation | 
| Exploratory outcomes - to evaluate the changes of fatigue between oleuropein and placebo groups | measured using Biodex dynamometer | Chronic effect (after 29 days of supplementation) | 
| Exploratory outcomes - to evaluate the changes of Pyruvate dehydrogenase activation between oleuropein and placebo groups | measured by western blotting | Chronic effect (after 36 days of supplementation) | 
| Exploratory outcomes - to evaluate the changes of Pyruvate dehydrogenase activation between oleuropein and placebo groups | measured by biochemical assay analysis | Chronic effect (after 36 days of supplementation) | 
| Exploratory outcomes - To evaluate the changes of Mitochondrial respiration between oleuropein and placebo groups | measured the rates of oxygen consumption (respiration or JO2) using Oroboros Oxygraph 2K systems with physiological ADP concentrations using permeabilized muscle fibres. | Chronic effect (after 36 days of supplementation) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Exploratory outcomes - to evaluate the changes of whole body respiratory exchange ratio (RER) between oleuropein and placebo groups following 1 single dose | measured the oxygen and carbon dioxide volume using indirect calorimetry with ventilated hood | Acute effect after first product intake+ chronic effect after 36 days of intake | 
| Exploratory outcomes - to evaluate the changes of oleuropein metabolites between oleuropein and placebo groups following 1 single dose | measured by the analyze of oleuropein metabolites in blood | Acute effect after first product intake + chronic effect after 36 days of intake | 
| Exploratory outcomes - to evaluate the changes of glucose concentration between oleuropein and placebo groups following 1 single dose | measured by the analyze glucose in blood | Acute effect after first product intake + chronic effect after 36 days of intake | 
| Exploratory outcomes - to evaluate the changes Blood glucose, insulin, free fatty acid concentrations -between oleuropein and placebo groups following 1 single dose | measured by the analyze of Insulin in blood | Acute effect after first product intake + chronic effect after 36 days of intake | 
| Exploratory outcomes - to evaluate the changes of free fatty acid concentration between oleuropein and placebo groups following 1 single dose | measured by the analyze of free fatty acid concentration (FFA, TG) in blood | Acute effect after first product intake + chronic effect after 36 days of intake | 
| Exploratory outcomes - to evaluate the changes of blood pressure between oleuropein and placebo groups following 1 single dose | measured using automated inflatable cuff | Acute effect after first product intake + chronic effect after 36 days of intake | 
| Exploratory outcomes - to evaluate the changes of anti-inflammatory markers between oleuropein and placebo groups | measured by the analyze of anti-inflammatory markers in blood | Chronic effect (after 29 days of supplementation) | 
| Exploratory outcomes - to evaluate the changes of Antioxidant markers between oleuropein and placebo groups | measured by the analyze of antioxidant markers in blood | Chronic effect (after 29 days of supplementation) | 
| Exploratory outcomes - to evaluate the changes in glucose concentration between oleuropein and placebo groups | measured by the analyze glucose in blood | Chronic effect (after 29 days of supplementation) | 
| Exploratory outcomes - to evaluate the changes of insulin concentration between oleuropein and placebo groups | measured by the analyze of insulin in blood | Chronic effect (after 29 days of supplementation) | 
| Exploratory outcomes - to evaluate the changes of free fatty acid concentration between oleuropein and placebo groups | measured by the analyze of free fatty acid concentration (FFA, TG) in blood | Chronic effect (after 29 days of supplementation) | 
| Exploratory outcomes - to evaluate the changes in Mood state and quality of life between oleuropein and placebo groups | measured with the World Health Organisation quality of life questionnaire (WHOQOL-BREF) (rating 0 for 'not at all' and 5 for 'an extreme amount') | Chronic effect (after 29 days of supplementation) | 
| Exploratory outcomes - to evaluate the changes in Mood state and quality of life between oleuropein and placebo groups | measured with the Profile of Mood States - short-form (POMS-SF) - scale (rating 0 for 'not at all' and 4 for 'extremely') | Chronic effect (after 29 days of supplementation) | 
| Exploratory outcomes - to evaluate the changes in Mood state and quality of life between oleuropein and placebo groups | measured with the Quality of Life (QoL) questionnaires | Chronic effect (after 29 days of supplementation) | 
| Exploratory outcomes - to evaluate the changes in the fatigue perception and mood state pre/post Biodex measurement between oleuropein and placebo groups | measured with the current mood questionnaire (rating 0 for 'not at all' - 4 for 'extremely') | Chronic effect (after 29 days of supplementation) | 
| Exploratory outcomes - to evaluate the changes in the fatigue perception and mood state pre/post Biodex measurement between oleuropein and placebo groups | RPE visual analog scale Questionnaire - BORG scale (6 for 'no exertion - 20 for 'maximal exertion' | Chronic effect (after 29 days of supplementation) | 
| Exploratory outcomes to evaluate the changes in body composition between oleuropein and placebo groups | measure the whole body muscle and fat content using Magnetic resonance imaging (MRI) | Chronic effect (after 29 days of supplementation) | 
| Exploratory outcomes - Whole body respiratory exchange ratio - To evaluate the changes of Whole body respiratory exchange ratio (RER) between oleuropein and placebo groups | measure the oxygen and dioxygen volume using Indirect calorimetry with ventilation hood | Chronic effect (after 36 days of supplementation) | 
| Exploratory outcomes - To evaluate the changes of oleuropein metabolites between oleuropein and placebo groups | measure by analyzing Oleuropein metabolites in blood | Chronic effect (after 36 days of supplementation) | 
| Exploratory outcomes - to evaluate the changes of molecular signalling, and protein and mRNA levels of regulators of muscle metabolism between oleuropein and placebo groups | measured by analyzing RNAseq and MS-based proteomics | Chronic effect (after 36 days of supplementation) | 
| Exploratory outcomes - to evaluate the changes of molecular signalling, and protein and mRNA levels of regulators oleuropein and placebo groups | measured using Western Blot | Chronic effect (after 36 days of supplementation) | 
| Exploratory outcomes - to evaluate the changes of molecular signalling, and protein and mRNA levels of regulators oleuropein and placebo groups | measured by analyzing polymerase chain reaction | Chronic effect (after 36 days of supplementation) | 
| Exploratory outcomes - to evaluate the changes in Strength between oleuropein and placebo groups | measured using biodex dynanometer | After 4 weeks of supplementation | 
| Exploratory outcomes to evaluate the changes of strenght between oleuropein | measured using biodex dynanometer | Chronic effect (after 29 days of supplementation) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Skeletal muscle energy and fatigue