Nutraceutical composition for use in the treatment of post covid-19 chronic fatigue / fatigue

Abstract

The present invention relates to a composition, preferably a nutraceutical composition, for use in a method of treatment of post viral infection caused by the virus strain called SARS-CoV-2, or alternatively COVID- 19, chronic fatigue / fatigue.

Description

[0001] DESCRIPTION of the invention having title:

[0002] "Nutraceutical composition for use in the treatment of post Covid-19 chronic fatigue I fatigue

[0003] Field of invention

[0004] The present invention relates to a composition, preferably a nutraceutical composition, for use in a method of treatment of post viral infection caused by the virus strain called SARS-CoV-2, or alternatively COVID- 19, chronic fatigue / fatigue.

[0005] State of the art

[0006] The outbreak of the Coronavirus (SARS-CoV-2) pandemic in December 2019 has affected 123 million people worldwide to date and more than 3 million people in Italy. It has been found that once the acute phase of the viral disease is over, some individuals do not fully return to their initial state of health but continue to experience previous symptoms.

[0007] Several studies have verified that SARS-CoV-2 infection can leave medium- and long-term effects, collectively referred to as "post-Covid syndrome" or "long-Covid." In particular, the study by Dennis et al. (2020) showed persistent clinical consequences, involving one or more organs, in 70% of the population analyzed even after an average of 140 days after the end of the acute phase of infection. Among the symptoms most reported by patients the most prevalent was fatigue or chronic fatigue, followed by muscle weakness, dyspnea, and headache (1).

[0008] Chronic fatigue is a persistent symptom in both severely and mildly infected patients. Studies that have been conducted, both on patients discharged from the hospital and on patients managed at home, have shown that there was no association between the severity of Coronavirus disease (Covid-19) and the following chronic fatigue (2).

[0009] Specifically, a study conducted in the USA states that: (i) out of the population surveyed among individuals aged 18-34 years without chronic disease, one in five were unable to return to their initial health status after the end of the acute phase; (ii) this prolongation of disease had a major impact on their quality of life and also negative social implications (3). SARS-CoV-2 (COVID-19) is a new strain of coronavirus that has caused a severe epidemic this past year.

[0010] In Italy, as elsewhere in the world, there have been research groups addressing the problem of symptom persistence after SARS-CoV-2 infection. Carfi and coworkers (4) confirmed, on a group of 143 patients of the post-Covid outpatient clinic of the Gemelli Hospital in Rome, that the main symptom, found in 53.1% of patients, was chronic fatigue, and in 44.1% of the subjects a worsening of quality of life was reported. A further survey was conducted on 767 patients discharged from the hospital in Bergamo and the data showed that, 81 days after discharge, 51.4% still had symptoms, mainly chronic fatigue and dyspnea on exertion; 30.5% were still suffering from post-traumatic psychological consequences. An interesting and new finding from this survey is the higher incidence of post-Covid symptoms in women compared to men; in fact, women had about twice the incidence of chronic fatigue compared to men. In this study, 33.5% of the subjects still felt fatigued an average of 105 days after infection, falling within that segment of the population characterized by so-called "long-Covid" (5).

[0011] The most frequently found malaise is chronic fatigue, also called fatigue. This condition has been found both in individuals with severe infection and in those who have had a mild form of the infection, regardless of age.

[0012] The terms "chronic fatigue / fatigue" generally refer to a strong sense of fatigue and physical and / or mental exhaustion that persists over time, and which does not alleviate with rest. Chronic fatigue / fatigue can have different causes, which are not always identifiable, however it usually has an impact on normal daily activities, and can have even very serious consequences.

[0013] The term "Asthenia" in the present context refers to a global state of debilitation, characterized by a decrease in muscle strength and intellectual concentration capacity, which is a typical symptom of various chronic conditions or diseases.

[0014] In the present context, a particular type of chronic fatigue / fatigue has been studied, which is that caused by Covid-19 viral infection. Generally, this state of chronic fatigue / fatigue is a malaise that occurs as a result of infection, and which persists over time.

[0015] It is important to note that post Covid-19 chronic fatigue is different from "normal" fatigue. In addition to total exhaustion, people with post Covid-19 fatigue generally feel ill. Patients complain of symptoms such as persistent fatigue, especially mental fatigue, lack of concentration, inability to perform normal daily activities, symptoms that do not alleviate even with long rest. Added to this are unexplained muscle and joint pains, headaches, and not surprisingly, it can be extremely debilitating.

[0016] The persistence of these symptoms can seriously afflict the quality of life of individuals already hard- pressed by the viral infection, and may even result in problems such as isolation and / or depression.

[0017] To date, there are no remedies for this type of chronic fatigue, some times it is recommended to take painkillers to relieve muscle pain, but no good remedies have yet been found that can help effectively overcome the symptoms of post Covid-19 chronic fatigue.

[0018] The Applicant has engaged in research in order to provide a solution to the situation of suffering and distress affecting subjects after SARS-CoV-2 negativization with persistent fatigue.

[0019] The Applicant believed that nutrition could be the essential substrate on which to work to provide a useful immune response to overcome the post-Covid syndrome.

[0020] The Applicant, as a result of extensive research and development activity, has addressed and solved the problem related to the treatment of subjects after SARS-CoV-2 negativization with persistent fatigue (chronic fatigue / fatigue occurring following viral infection caused by the SARS-CoV-2 / COVID-19 viral strain) by developing oral compositions comprising selected mixtures of vitamins, minerals, amino acids, and plant extracts.

[0021] The compositions of the invention, formulated for oral use, preferably in solid form, are effective in the treatment of post Covid-19 chronic fatigue / fatigue and related symptoms or disorders. The compositions of the invention may be formulated, by the addition of specific excipients and additives, as solid compositions in a granular form dispersible in water, or in tablet form. Said solid form compositions are effective in the treatment of post Covid-19 chronic fatigue / fatigue and related symptoms or disorders.

[0022] The compositions of the invention, have no major side effects and can be administered to all categories of subjects in need, including the elderly, pregnant or lactating women, pediatric subjects (0-12 years), subjects with respiratory complications or diabetes. In addition, the compositions of the present invention, are particularly useful in the treatment of post Covid-19 chronic fatigue / fatigue in female subjects.

[0023] Moreover, the compositions of the invention are easy to prepare and cost-effective.

[0024] In addition, the compositions of the invention may be beneficial in that they are able to enhance the immune system response, and alleviate symptoms related to post Covid-19 chronic fatigue / fatigue in subjects in need, according to what is reported in this description and claims.

[0025] These purposes and others, which will be clear from the detailed description that follows, are achieved by the compositions and mixtures of the present invention through the technical features claimed in the united claims.

[0026] BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1. B: RTE trend for quality of life; D: RTE trend for health status; F: RTE trend for FACIT-Fatigue; H: RTE trend for mental fatigue. (*** p < 0.0001 for all pairs of questionnaires).

[0028] Figure 2: Percentage of improvement in chronic fatigue / fatigue of all subjects on at least 1, at least 5 or at least 10 units of the FACIT questionnaire.

[0029] Figure 3. B: RTE trend for quality of life; D: RTE trend for health status; F: RTE trend for FACIT-Fatigue; H: RTE trend for mental fatigue. [Significance between genders at each time: *** p < 0.0001. (dotted line represents female subset)].

[0030] Figure 4: Percentage of improvement in chronic fatigue / fatigue of all subjects, divided by female / male sex on at least 1 unit of the FACIT questionnaire.

[0031] Figure 5: Percentage of improvement in chronic fatigue / fatigue of all subjects, divided by age <60 years and >60 years, on at least 1 unit of the FACIT questionnaire.

[0032] Figure 6: Trends of FACIT-Fatigue and mental fatigue questionnaire scores in subject A with prolonged fatigue. Figure 7: ©FACIT-fatigue questionnaire. The TACIT and all related works are owned and copyrighted by David Celia, Ph.D, to whom the intellectual property of the same belongs.

[0033] Figure 8: Modified Chalder questionnaire.

[0034] DETAILED DESCRIPTION OF THE INVENTION

[0035] It is an object of the present invention a mixture for use in a method of treatment of post Covid-19 chronic fatigue / fatigue (in short, mixture M of the invention) comprising or, alternatively, consisting of:

[0036] (I) a vitamin selected from the group comprising or, alternatively, consisting of: vitamin C, vitamin E, B group vitamins, and mixtures thereof,

[0037] (ii) a compound comprising a mineral selected from the group comprising or, alternatively, consisting of zinc, iron, magnesium, and mixtures thereof,

[0038] (ill) an amino acid selected from the group comprising or, alternatively, consisting of carnitine, arginine and misture thereof, preferably selected from the group comprising or, alternatively, consisting of L-carnitine, L-arginine and misture thereof,

[0039] (iv) a plant extract selected from the group comprising or, alternatively, consisting of, ginseng or ginger extract, eleutherococcus extract, and mixtures thereof.

[0040] It is an object of the present invention also a composition comprising the mixture (M) and at least one pharmaceutical and / or food grade technological additive, wherein said composition is for use in a method for the treatment of post Covid-19 chronic fatigue / fatigue.

[0041] The viral infection causing chronic fatigue / fatigue treated by the composition of the invention is an infection caused by SARS-CoV-2 (or COVID-19 or 2019-nCoV) virus.

[0042] Symptoms or disorders arising from or related to said post Covid-19 chronic fatigue / fatigue, and treated / alleviated by the composition according to the present invention, may be: persistent physical and / or mental fatigue, shortness of breath, joint pain, respiratory pain, asthenia, exertional dyspnea, depressive states or negative mood states.

[0043] The mixture (M) of actives according to the present invention, comprises (I) a vitamin selected from the group comprising or, alternatively, consisting of vitamin C (or ascorbic acid or L-ascorbic acid, terms synonymous with vitamin C), vitamin E, B group vitamins, and mixtures thereof.

[0044] The vitamins used in this context are vitamins having a pharmaceutically acceptable purity grade. These may be selected from vitamins having a pharmaceutically acceptable purity grade that are commercially available.

[0045] Vitamin E is a group of eight fat-soluble compounds that includes four tocopherols and four tocotrienols. Both tocopherols and tocotrienols exist in the a (alpha), p (beta), y (gamma), and 5 (delta) forms, as determined by the number and position of methyl groups on the chromanol ring. Preferably, the vitamin E used in the present context is DL-o-tocopherol acetate.

[0046] The B group vitamin used in the present context preferably is a vitamin B1 and / or a vitamin B3. When both are present, these may be in a vitamin B1 :vitamin B3 weight ratio from 30:1 to 20:1, for example, in a weight ratio of 18:1.

[0047] Preferably, said vitamin (I) included in the mixture (M) is in an amount by weight from 1% to 5%, preferably from 2% to 4%, e.g., 1%, 2%, 3%, 4%, 5%, with respect to the total weight of the mixture.

[0048] In a preferred embodiment, (I) may be a mixture consisting of vitamin C, vitamin E, vitamin B1 and vitamin B3, preferably included in an amount by weight from 1% to 5%, preferably from 2% to 4%, e.g., 1%, 2%, 3%, 4%, 5%, with respect to the total weight of the mixture.

[0049] Mixture (M) also comprises (ii) a compound comprising a mineral selected from the group comprising or, alternatively, consisting of zinc, iron, magnesium, and mixtures thereof.

[0050] Preferably said compound (ii) comprising a mineral is a salt or complex or oxide of said mineral (iron, magnesium, or zinc), or a mixture of a salt or complex or oxide of said mineral.

[0051] Compound (ii) can then comprise a salt of a mineral, and / or an oxide of the same or a different mineral, and / or a complex of the same or a different mineral.

[0052] Preferably, said (ii) is present in an amount by weight from 7% to 15%, preferably from 8% to 10%, with respect to the total weight of the mixture.

[0053] Iron, as used in the present context, in the form of a salt or complex or iron oxide, may be a salt or complex comprising an iron (III) or iron (II) cation (iron salt or complex for short). The term "iron salt or complex" as used in the context of the present invention, refers to any iron salt, such as iron pyrophosphate or ferric diphosphate ferrous sulfate, ferrous gluconate, ferrous lactate and ammonium ferric citrate, as well as any iron salt that is slowly soluble in water but readily soluble in dilute acids, such as ferrous fumarate, ferrous succinate and ferric saccharate. Preferably, the iron used in the present context is iron pyrophosphate.

[0054] Zinc used in the present context, in the form of a salt or complex or zinc oxide, is preferably zinc oxide.

[0055] Magnesium used in the present context, in the form of a salt or complex or magnesium oxide, is preferably magnesium oxide.

[0056] In a preferred embodiment said (ii) is a mixture of iron pyrophosphate, zinc oxide, and magnesium oxide, included in an amount from 7% to 15%, preferably from 8% to 10%, with respect to the total weight of the mixture.

[0057] In a preferred embodiment, said compound comprising a mineral (ii) is a compound comprising (a) a salt or complex or oxide of said mineral (iron, zinc, or magnesium, each taken individually), (b) a phospholipid, preferably a lecithin, (c) a sucrestere, and optionally (d) pregelatinized rice starch. In the present context, it will be referred to briefly as a sucrosomal mineral. Examples of sucrosomal minerals, and methods of preparation thereof, are as disclosed in patent documents WO 2014 / 009806, WO 2015 / 033216, and WO 2019 / 239372. Commercial formulations of minerals such as Sideral®, Ferro Sucrosomiale ®, UltraMag®, UltraZin®, and Zinco Sucrosomiale ®, which are registered trademarks of patented products by Pharmanutra S.p.A., may also be used.

[0058] For example, (II) may be a compound comprising (a) an iron in the form of an iron salt or an iron complex or an iron oxide, preferably a iron pyrophosphate;

[0059] (b) at least one phospholipid;

[0060] (c) a sucrestere or sucrose esters, and optionally (d) pregelatinized rice starch (sucrosomal iron for short). Compound (ii) can also be a compound comprising (a) zinc oxide;

[0061] (b) at least one phospholipid;

[0062] (c) a sucrestere or sucrose esters, and optionally (d) pregelatinized rice starch (sucrosomal zinc for short). Compound (ii) can be a compound comprising (a) magnesium oxide;

[0063] (b) at least one phospholipid;

[0064] (c) a sucrestere or sucrose esters, and optionally (d) pregelatinized rice starch (sucrosomal magnesium for short).

[0065] In a preferred embodiment, compound (ii) is a mixture comprising or, alternatively, consisting of a sucrosomal iron, a sucrosomal zinc, and a sucrosomal magnesium, preferably in an amount by weight from 7% to 15%, preferably from 8% to 10%, with respect to the total weight of the mixture.

[0066] The mixture (M) also comprises (iii) an amino acid selected from the group comprising or, alternatively, consisting of arginine, carnitine and misture thereof.

[0067] Preferably, (iii) is present in an amount by weight from 20% to 80%, preferably from 40% to 75%, with respect to the total weight of the mixture.

[0068] Carnitine is a short-chain nonprotein amino acid, a zwitterion, found in animal tissues, and in modest amounts, in plants. Preferably, the carnitine used in the present context is an L-carnitine.

[0069] Arginine is a basic polar (with hydrophilic side chain) amino acid. The basicity of the amino acid is due to the guanidine group in its side chain, which is strongly basic. The L enantiomer is one of the 20 ordinary amino acids.

[0070] Carnitine and arginine used in this context have pharmaceutical and / or food grade purity and can be selected from commercially available products, preferably L-Carnitine-L-Tartrate is used.

[0071] Preferably, said amino acid (iii) is selected from the group comprising or, alternatively, consisting of L- carnitine, L-arginine and misture thereof.

[0072] Preferably (iii) is a mixture of L-carnitine and L-arginine in a weight ratio from 1:5 to 1 :1, such as 1 :2. Mixture (M) also comprises (iv) a plant extract selected from the group comprising or, alternatively, consisting of ginger extract, eleutherococcus extract, and mixtures thereof.

[0073] Preferably said extract (iv) is present in an amount by weight from 2% to 8%, preferably from 4% to 7%, with respect to the total weight of the mixture.

[0074] In this context, the term "ginger or ginseng extract" or " Panax extract" describes the extract obtained from the root of at least one of eleven different plant species belonging to the genus Panax, each typical of a different region of the world. The most common ginseng is derived from the root of Panax ginseng (C. Meyer). Ginseng root extract (or Panax root extract) or Panax ginseng comprises triterpene or pentacyclic, oleanoic acid-related, saponins (e.g., ginsenosides, panaxosides, chikusetsusaponins), polysaccharides (e.g., panaxans), sterols, and vitamin D. Preferably, an extract derived from ginger root, having a gingerol titer from 5% to 45% by weight with respect to the total weight of the extract, is used in the present context, e.g. titrated at (5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%).

[0075] Eleutherococcus (Eleuterococcus senticosus) is also known as Siberian ginseng, the plant extract has a rich composition comprising saponosides (such as eleuterosides A, B, E), phenylpropane compounds, caffeic acid derivatives, lignans, and coumarins. The extract preferably used in the present context is titrated from 0.2%-1% in eleuterosides B+E, and is obtained from the root / leaves.

[0076] In a preferred embodiment (iv) is a mixture of ginger or ginseng root extract and eleutherococcus root extract, preferably in a weight ratio from 1 :5 to 1 :1 .

[0077] The mixture (M) may further include at least one trace element, at least one antioxidant compound, at least one vitamin selected from the group consisting of vitamin E, H and misture thereof.

[0078] Preferably said trace element is a compound of iodine and / or selenium, and said antioxidant compound is Coenzyme Q10 and / or a lycopene.

[0079] Preferably, said at least one trace element, said at least one antioxidant compound, and said at least one vitamin are each included independently in sufficient amounts to meet at least or more than 100% of the Nutrient Reference Value (NRV).

[0080] An example of a mixture according to the present invention is shown in Table 1.a

[0081]

[0082] Table 1.a: *lron, zinc, and magnesium formulated as sucrosomal minerals. Amount is refferd to amount by weight of supplied mineral.

[0083] A second example of a mixture according to the present invention is shown in Table 1.b (e.g., product with trade name Apportal® ).

[0084]

[0085] Table 1.b: *lron, zinc, and magnesium formulated as sucrosomal minerals. Amount is refferd to amount by weight of supplied mineral.

[0086] Advantageously the mixture or composition comprising the mixture (M) are for use in a method for the treatment of post Covid-19 chronic fatigue / fatigue.

[0087] Preferably, said use is for the treatment of female subjects.

[0088] The mixture (M) or composition comprising the mixture (M) for use in a method for the treatment of post Covid-19 chronic fatigue / fatigue, is preferably administered orally, 1 time daily for at least 14 days, preferably for at least 28 days.

[0089] Preferably, said mixture is administered in a daily amount ranging from 600 mg to 2500 mg, preferably ranging from 1000 mg to 2100 mg, e.g., 2070 mg.

[0090] Advantageously, the authors of the present invention have found that the mixture (M), described in the present context, or the composition, comprising the mixture (M), is capable of treating / relieving symptoms or disorders arising from or related to said post Covid-19 chronic fatigue / fatigue. Specifically, it offers an advantage in the reduction of persistent physical and / or mental fatigue, asthenia, depressive states or negative mood states.

[0091] EXPERIMENTAL PART

[0092] Investigation of the benefit of taking the composition according to the present invention on chronic fatigue associated with the post Covid-19 infection course.

[0093] Primary Aim: To evaluate the benefit of the composition according to the present invention on chronic fatigue / fatigue associated with the post-covid course. Secondary Aim: To improve the quality of life of the patients involved and to evaluate tolerability and treatment compliance.

[0094] Study design: Patients who had Covid-19 infection who report symptoms of chronic fatigue are recruited after the end of the acute phase of infection (after at least 3 days without fever and without other symptoms except for ageusia and anosmia). Patients who had been admitted to the intensive care unit or had 3 or more chronic diseases were excluded. Subjects were advised to take the composition according to the present invention for 28 days. Each subject took one sachet per day of the supplement in the morning for 28 consecutive days and completed a questionnaire at the beginning (TO), after 14 days (T1), and after 28 days (T2). Specifically, the compositions tested in the present study are as shown in Table 2.

[0095] Table 2: Compositions of Examples tested in the present context. Comparable results are obtained for all tested compositions. For brevity, only the results obtained with the composition according to Example 1 will be reported.

[0096] The completed questionnaire consists of 3 parts:

[0097] - a first part on the assessment of quality of life and health status through the EuroQoL-5D (EQ- 50) questionnaire;

[0098] - a second part on chronic fatigue using the FACIT-Fatigue questionnaire;

[0099] - a third assessment of mental fatigue using the modified Chalder questionnaire.

[0100] The EQ-5D questionnaire (EQ-5D Section 1) is widely used as a screening tool on large populations and consists of two sections: the first asks for subjective ratings for five dimensions (mobility, self-care, activities of daily living, pain / discomfort, and anxiety / depression), with each item providing graded answers from 1 to 3. Level 1 represents no problem while level 3 represents extreme limitation.

[0101] The second section of the EQ-5D (EQ-5D Section 2) includes an assessment by visual analog (VAS) represented graphically by a graded scale ranging from 0 (the worst possible health status) to 100 (the best possible health status) in which the subject indicates his or her perceived level of health status. For simplicity, this scale was readjusted to whole numbers ranging from 0 to 10, and the score obtained in the first section was converted to the EQ-5D index, which is a score between 0 and 1, where 0 represents a very bad quality of life and 1 represents perfect health. From the first questionnaire (consisting of the first and second sections) two numerical indices are then derived representing the quality of life (EQ-5D index) (section 1 EQ-5D) and the subject's health status (section 2 EQ-5D).

[0102] The FACIT-Fatigue questionnaire consists of 13 items and was originally designed to understand the impact of asthenia on daily activities of patients with cancer, but it has also been validated for many other chronic diseases (e.g., rheumatoid arthritis, anemia). Each statement has 5 answer options depending on severity ranging from "not at all" to "very much." The total score, calculated according to official scoring, is on a numerical scale ranging from 0 to 52, where a higher score represents lower chronic fatigue / fatigue. The ©FACIT-Fatigue questionnaire is shown in Figure 7, Copyright by David Celia Ph.D. "The TACIT and all related works are owned and copyrighted by David Celia, Ph.D, to whom the intellectual property of the same belongs."

[0103] For the assessment of mental fatigue, we used the Chalder questionnaire, which has also been cited in other studies on patients with Covid-19, but using only the last 6 questions, which deal with mental symptoms, and readjusting them on a Likert scale from 0 to 4 similar to that provided for the FACIT questionnaire. Summing the scores of the individual answers yields a scale ranging from 0 to 24 where a higher score represents greater mental fatigue. The questionnaire used is shown in Figure 8.

[0104] Sample sizing

[0105] The main aim of the statistical analyses was the two-way analysis of variance for repeated measures (longitudinal study) on ordinal variables (Likert scale). In view of the complexity of the study and the need to use a nonparametric method based on ranks, the sample calculation was carried out considering the use of a parametric test, subsequently correcting the resulting sample size with Pitman's Asymptotic Relative Efficiency (ARE).

[0106] Referring to a two-way test of variance for repeated measures, considering an average effect size (0.25) in a study with 3 measures and 2 groups, with medium to high correlation of measures (0.7), a power of 95% and a type 1 error equal to 0.05 are assured from a sample of 170 subjects. Having calculated an ARE of 0.864, the sample needed for the nonparametric test increases to 197.

[0107] Statistical analysis

[0108] The collected variables are described as mean± standard deviation, median and interquartile range, or proportion, depending on their distribution. Longitudinal data are analyzed by a nonparametric rank-based method, calculating relative treatment effects (RTEs), and using the Wald statistic for comparisons on repeated measures and the groups into which the sample is divided. Given a group within a sample, the RTE relative to it is an estimate of the probability that the value observed in any one of the group's components will be greater than the value observed in any other component, randomly selected from the entire sample. Being a probability measure, RTE will have a value between 0 and 1. All statistical analyses were performed with the open source software R.

[0109] Results

[0110] 201 subjects were enrolled, each of whom signed the informed consent form regarding the survey. The survey was conducted in compliance with Good Clinical Practice and in accordance with the ethical principles of the Declaration of Helsinki. From the data obtained from the 3 questionnaires, 4 indices (Quality of Life (Section 1 EQ-5D), Health Status (Section 1 EQ-5D), FACIT-Fatigue, and Mental Fatigue) are derived, which take a snapshot of the trend of the parameters on the general population.

[0111] The RTE (relative treatment effect) was determined, which provides a better understanding of the progression of the analyzed parameter over time, as the result obtained is a relative value between 0 and 1.

[0112] The characteristics of the subjects analyzed are shown in Table 3.

[0113] The trend of RTE regarding (i) quality of life, (II) health status, (ill) FACIT-Fatigue, and (Illi) mental fatigue in the three questionnaires is statistically significant (Wald's Statistic, p <0.0001). In addition, the significances among the three pairs of possible values were tested and for all parameters were found to be highly significant (poi <0.0001, P02 <0.0001, P12 <0.0001). The results of the analyzed scores and RTE trend are shown in Figures 1 .

[0114] The increase in the absolute value and of RTE of the EQ-5D index, health status, and FACIT-Fatigue represent an improvement in the quality of life and less feeling of fatigue in the subjects. The decrease in the absolute value and of RTE of the mental fatigue index represents an improvement in this aspect in the subjects surveyed.

[0115] In addition, the results obtained from the FACIT-Fatigue questionnaire analysis showed an improving trend for the population analyzed.

[0116] The percentage of subjects who showed a reduction on the total score was evaluated. Considering as improvement the reduction of at least 1 unit in the questionnaire: in the step between TO and T1 154 subjects improve (76.62%); in the step between TO and T2 181 subjects improve (90.05%). Considering as improvement the reduction of at least 5 units in the questionnaire: in the step between TO and T1 115 subjects improve (57.21%); in the step between TO and T3 150 subjects improve (74.63%). Considering the reduction of at least 10 units in the questionnaire as improvement: in the step between TO and T1 65 subjects improve (32.34%); in the step between TO and T2 102 subjects improve (50.75%). The results are shown graphically in Figure 2. The percentage of improvement in chronic fatigue by female / male sex was also assessed.

[0117] Within the same gender, for both men and women, there are statistically significant differences between each pair of questionnaires for all 4 indexes analyzed.

[0118] Furthermore, analyzing the differences between genders (Women vs. Men) at the various times shows that the differences between genders are always statistically highly significant (p < 0.0001), except for the RTE of Health Status at TO. The results of the individual questionnaire scores and RTE trend are shown in Figure 3.

[0119] Specifically, on the men-women subgroup, the number of subjects improved in percentages was assessed by evaluating various steps of improvement on the total score of the FACIT questionnaire. Considering the reduction of at least 1 unit in the questionnaire: in the step between TO and T1, 98 women (80.33%) and 56 men (70.89) improved; in the step between TO and T2, 109 women (89.34%) and 72 men (91.13%) improved. These results are shown graphically in Figure 4.

[0120] In addition, improvement on the young / old subgroups was assessed. An analysis was then performed distinguishing 2 subgroups: subjects aged >60 years (28 subjects), for convenience referred to as "Seniors" and the others aged <60 years (173 subjects), herein referred to as "Youth."

[0121] Also on the youth-senior subgroup, the number of subjects improved in percentages was assessed by evaluating various steps of improvement on the total FACIT questionnaire score. Considering the reduction of at least 1 unit in the questionnaire: in the step between TO and T1, 24 elderly (85.71%) and 130 young people (75.14%) improved; in the step between TO and T2, 25 elderly (89.29%) and 156 young people (90.17%) improved. These results are shown graphically in Figure 5.

[0122] Finally, the effect of composition according to the present invention was evaluated in 2 subjects who had been reporting prolonged fatigue for much longer than the others. The subjects started the investigation approximately 265 days after the onset of SARS-CoV-2 infection. The characteristics of said subjects are shown in Table 4.

[0123] Table 4: Characteristics of subjects with prolonged fatigue.

[0124] Figure 6 shows the FACIT-Fatigue and Mental Fatigue questionnaire scores obtained for subject A. The increase in the FACIT-fatigue questionnaire score represents an improvement in the feeling of fatigue, the decrease in the mental fatigue index score represents an improvement in this aspect. Conclusions

[0125] Results on the whole population show a marked and significant improvement on chronic fatigue / fatigue both after 14 days and after 28 days of taking the composition according to the present invention.

[0126] The change in their condition already after the first 14 days shows that nutraceutical supplementation played a role in this change and thus that the positive effect is not solely attributable to the time elapsed since the end of the disease.

[0127] The effect of supplementation is further confirmed by the progressive improvement found also after 28 days.

[0128] The data on the percentage of improved patients further confirms the benefit from nutraceutical treatment, showing an improvement of at least 1 unit in 76.62% of subjects after 14 days and in 90.05% of subjects after 28 days. Even more interesting is the data of 10-unit improvement found in about one-third of the subjects after 14 days and in half of the subjects after 28 days.

[0129] Subgroup analysis shows that both women and those over 60 start from a higher degree of initial chronic fatigue, but steadily and progressively improve in the same way as men and young people, as evidenced by the relative effect trend of treatment (RTE).

[0130] The effects of nutraceutical composition according to the present invention were equally effective on all population groups. Women and those over 60 show greater absolute improvements and also greater percentage improvements than men and young people.

[0131] Mental symptoms have been evaluated and reported in many post-Covid studies and include, in more severe cases, severe headache, myalgia, depression, and disturbed sleep. In other subjects a feeling of cognitive decline, so-called "brain fog," is reported, consisting of difficulties in concentration, memory, and executive skills. The sample analyzed in this study is in the latter condition, judging from the answers to questions regarding the feeling of anxiety, ability to concentrate, ability to think clearly, and memory.

[0132] The emerging finding at the end of the supplementation period is an improvement in anxiety (QoL questionnaire) and mental fatigue, a sign that the correct nutritional set-up can also act on psychological well-being and not just physical well-being.

[0133] The objective improvement observed following nutraceutical treatment in subjects with chronic fatigue resulting from Covid-19 infection may be related to the synergistic activity of the nutrients contained in the nutraceutical composition according to the present invention.

[0134] In conclusion, the Applicant has shown that the combination of nutrients in the compositions according to the present invention has a positive synergistic effect on post-Covid 19 chronic fatigue / fatigue and its associated symptoms, thus leading to a significant improvement in quality of life. Thus, the present invention offers a solution to accelerate the recovery of individuals with post-Covid 19 chronic fatigue.

Claims

AMENDED CLAIMS received by the International Bureau on 23 FEBRUARY 2024 (23.02.24)1. A mixture for use in a method for the treatment of post Covid-19 chronic fatigue / fatigue comprising or, alternatively, consisting of:(i) a vitamin selected from the group comprising or, alternatively, consisting of: vitamin C, vitamin E, B group vitamins, and mixtures thereof,(ii) a compound comprising a mineral selected from the group comprising or, alternatively, consisting of zinc, iron, magnesium, and mixtures thereof,(iii) an amino acid selected from the group comprising or, alternatively, consisting of, carnitine, arginine and misture thereof, preferably selected from the group consisting of L-carnitine, L-arginine and misture thereof,(iv) a plant extract selected from the group including or alternately consisting of, ginger or ginseng extract, eleutherococcus extract, and mixtures thereof, wherein, with respect to the total weight of the mixture,- said (i) is present in an amount by weight from 1 % to 5%,- said (ii) is present in an amount by weight from 7% to 15%,- said (iii) is present in an amount by weight from 20% to 80%, and- said (iv) is present in an amount by weight from 2% to 8%.

2. The mixture for use according to claim 1 , wherein said (i) is present in an amount by weight from 2% to 4%, with respect to the total weight of the mixture.

3. The mixture for use according to any one of the preceding claims, wherein said group B vitamin is selected from the group comprising or, alternatively, consisting of vitamin B1 , vitamin B3, and mixtures thereof.

4. The mixture for use according to any one of the preceding claims, wherein said (ii) is present in an amount by weight from 8% to 10%, with respect to the total weight of the mixture, preferably in which said (ii) is a mineral in the form of a salt or complex or oxide of said mineral.

5. The mixture for use according to any one of the preceding claims, wherein said (iii) is present in an amount by weight from 40% to 75%, with respect to the total weight of the mixture.

6. The mixture for use according to any one of the preceding claims, wherein said (iv) is present in an amount by weight from 4% to 7%, with respect to the total weight of the mixture, preferably wherein said ginger or18AMENDED SHEET (ARTICLE 19)ginseng extract is ginger root extract having a gingerol titer from 5% to 45% by weight with respect to the total weight of the extract, and wherein said eleutherococcus extract is titrated in eleuterosides B+E from 0.2% to 1 %, by weight with respect to the total weight of the extract.

7. The mixture for use according to any one of the preceding claims, wherein said mixture further comprises at least one trace element, at least one antioxidant compound, at least one vitamin selected from the group consisting of vitamin E, vitamin H and mixtures thereof, preferably wherein said trace element is a compound of iodine and / or selenium, and wherein said antioxidant compound is Coenzyme Q10 and / or a lycopene, preferably wherein said at least one trace element, said at least one antioxidant compound, and said at least one vitamin are each independently included in sufficient quantities to meet at least or more than 100% of the Nutrient Reference Value (NRV).

8. The mixture for use according to any one of the preceding claims wherein said use is for the treatment of female subjects.

9. The mixture for use according to any one of the preceding claims wherein said mixture is administered orally, 1 time daily for at least 14 days, preferably for at least 28 days, preferably, wherein said mixture is administered in a daily amount ranging from 600 mg to 2500 mg, preferably ranging from 1000 mg to 2100 mg.

10. A composition comprising the mixture according to any one of the preceding claims and at least one pharmaceutical and / or food grade technology additive, wherein said composition is for use in a method for treating post Covid-19 chronic fatigue / fatigue.AMENDED SHEET (ARTICLE 19)

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