Study on the Effectiveness and Safety of Two Olive Extract- Based (Olea Europea L. Folium) Supplements, Alone or Combined With a Mullein Extract (Verbascum Thapsus L. Herba Cum Floribus), for the Maintenance of Cognitive Function.

Background and study aims:

Dementia is defined as a condition in which memory, attention (concentration), mental clarity (alertness), learning, intelligence, language and problem-solving skills are compromised to such an extent that they interfere with the normal course of daily life activities in those affected. In the early stages, it is a form of mild cognitive impairment (MCI) which is defined as a condition characterized by a mild involvement of one or more cognitive domains, with preservation of the person's independence in functional abilities. Importantly, the condition of MCI does not necessarily progress to dementia. Therefore, it is particularly important to act early with treatments aimed at reducing risk factors at least to avoid or slow the progression to dementia, helping to improve and/or maintain cognitive function and allow the person to continue to perform their activities and cope with behavioral symptoms. This study assumes that the intake of two food supplements, the first based on an olive leaf extract (Olea europea L. folium) and the second on the combination of the latter with an extract of mullein (Verbascum thapsus L. herba cum floribus), can play a positive role in improving cognitive function in subjects with MCI. Therefore, the aim of the present efficacy study is to demonstrate that the two food supplements are useful in maintaining cognitive lucidity, i.e. reducing its loss, maintaining or reducing the loss of selective concentration, prolonged concentration, or both, and maintaining or reducing the loss of one or more cognitive processes related to memory.

Who can participate? Subjects of both sexes, between the ages of 60 and 85, who have mild cognitive impairment (MCI) diagnosed through the questionnaire score of the Montreal Cognitive Assessment (MoCA) between 20 and 25 will be included in the study.

What does the study involve?

A single-center, randomized, placebo-controlled, three-arm, double-blind, clinical trial will be conducted with a treatment period of 24 weeks (approximately 6 months) with the study products (two dietary supplements or placebo). Participants will be divided into the following experimental groups:

• GROUP 1 (22 subjects): subjects who will have to take 2 capsules a day - possibly between meals, to be swallowed with a small amount of water - of the food supplement based on olive leaf extract (containing a total of 600 mg of dry extract of Olea europea - 72 mg of oleuropein).
• GROUP 2 (22 subjects): subjects who will have to take 2 capsules a day (containing a total of 600 mg of dry extract of Olea europea - 72 mg of oleuropein, and 400 mg of dry extract of Verbascum thapsus - 12 mg of verbascoside) possibly between meals, to be swallowed with a small amount of water.
• GROUP 3 (22 subjects): subjects who will have to take 2 capsules a day of placebo. The placebo consists of inert excipients and is the same in shape, color, odor, taste, weight and packaging to the active treatment, in order to ensure blinding.

Each subject of the three experimental groups before, during and after the administration of the dietary supplements or placebo, will undergo the evaluation of the primary and secondary endpoints. The primary outcome of the study is to evaluate the effect of supplementation with the two active treatments based on plant extracts on cognitive functions, measured using the Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE) questionnaires at baseline (t0), after 3 months (t1) and after 6 months of treatment (t2). The design of the proposed study assumes as a secondary outcome the evaluation of the efficacy of the two food supplements in improving the perception of general quality of life (physical and mental component), measured using the Short Form-12 (SF-12), a measure that assesses the impact of overall health on an individual's daily life, at baseline (t0) and after 6 months of treatment (t2).

What are the possible benefits and risks of participating? The food supplements, notified to the Italian Ministry of Health, are marketed on the Italian market where no reports of adverse events have been recorded. In particular, the use of the components of the food supplements under study is currently governed by the Ministerial Decree of 10 August 2018 on the regulation of the use of herbal substances and preparations in food supplements as updated by Decree of 9 January 2019, which does not provide for any limitation relating to pregnancy among the prescriptions to be reported on the label, in the case of a partner of childbearing age of a subject recruited in the study. Therefore, being food ingredients allowed in supplements as they have a significant history of consumption in the European Union, they are safe products for which no adverse event related to the intake of the food supplement is expected, including damage to the fetus such as congenital damage or malformations in pregnant women, partners of recruited subjects. Although no adverse event related to the intake of the food supplement is expected, the subjects will be continuously monitored and, in the event of suspected adverse reactions, these will be reported through the VigiErbe (www.vigierbe.it) online phytovigilance system, as provided by the Italian Istituto Superiore di Sanità. On the other hand, an improvement in the clinical picture is hypothesized. However, it is possible that no benefit is achieved.

Participants of both sexes who meet the following characteristics will be included in the study:

• aged between 60 and 85 years;
• able to understand and sign the informed consent form;
• able to understand and comply with the protocol requirements;
• negative HIV test;
• score between 20 and 25 on the Montreal Cognitive Assessment (MoCA) questionnaire (Nasreddine et al., 2005).
• total Instrumental Activities of Daily Living (IADL) + Activities of Daily Living (ADL) score of 14;
• Geriatric Depression Scale (GDS) score between 0 and 5;
• Generalized Anxiety Disorder (GAD-7) score between 0 and 4;
• not currently taking or taking any medications, including antidiabetics, drugs that affect the nervous system such as antidepressants, anxiolytics, or opioids;
• who are not taking antibiotics or have not taken antibiotics in the last four weeks, or in the last 6 months, based on the intensity and duration of antibiotic treatment.

Subjects with the following characteristics will be excluded from the study:

• aged < 60 and > 85 years;
• individuals with a MoCA questionnaire score < 20 and > 26;
• Geriatric Depression Scale (GDS) score > 5;
• Generalized Anxiety Disorder (GAD-7) score > 4;
• who show no willingness to cooperate;
• who have difficulty traveling to the referral facility on time;
• who are deemed unsuitable by the investigator due to the presence of other conditions deemed incompatible with enrollment and which require pharmacological treatments (e.g., active systemic diseases, diabetes, neurological and psychiatric conditions, including cognitive disorders that prevent completion of the questionnaires);
• affected by HIV-acquired immunodeficiency;
• individuals with severe visual and hearing impairments;
• with known allergies to ingredients of the investigational products (active or placebo);
• who abuse alcohol, drugs, nicotine, caffeine, or theine;
• who take medications.