The Effects of Microbiological Spectrum Changes to Improve Cognitive Health in Aging Population

Study Overview
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Brief Summary
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The goal of this project is to develop probiotic dietary supplements intended for the elderly, which can modify the composition of the intestinal microbiota typically occurring in the aging population. According to currently held scientific knowledge, it is postulated that the probiotics-induced normalization of the physiological axis in the brain-intestinal microbiota affects the activity of the nervous system. Thus, normalization of this axis should lead to observable improvements in cognitive functions and quality of life.

Detailed Description
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With an increasing age of the population, the incidence of age-related problems, such as memory deficits or negative changes in mood, is on the rise. On this account, an increased emphasis has been placed on identifying natural ways to reduce the occurrence of such problems. One of the proposed methods to achieve this is to modify the composition of gut bacteria and their by-products, which has shown a surprising, yet highly promising potential to benefit the brain function and blood composition. In the recent years, gut bacteria have been of great interest to many medical professionals from various disciplines. It is postulated that they might exert some influence on memory and emotions, but there is a lack of evidence to confirm these hypotheses. Our study would like to address this issue and examine the beneficial effects of probiotics into more depth. Probiotics are dietary supplements in the form of bacteria, which are often artificially added e.g. into some dairy products. This is done to promote gut health and to improve the quality of gut microflora. The subject selection and assessment are summarised as follows: Participants will be pre-selected electronically and given an electronic memory test. Further selection of eligible subjects based on their preliminary results will be followed by the first personal appointment, where each participant will undergo memory and mood-focused psychological testing and testing for gut bacteria composition. One week after the initial appointment, participants will be asked to bring in a stool and urine sample, their blood will be collected and their fitness and dietary habits assessed. Each participant will also be given an electronic watch, which will monitor their physical activity, and supplements in the pill form, which either contain specially cultivated human gut bacteria (i.e. probiotics) or placebo. Identical tests and blood, urine and stool collection will be repeated three months after administering the first pill. The participants will receive another set of pills, which will contain the probiotics if the participant has initially received placebo and vice versa. After three more months, participants will be subjected to the same tests as in the previous two instants. To test for lasting effects of treatment, participants will be tested again after 3 more months and the project will reach its termination. Using the above-mentioned methods, the aim of this project is to provide sufficient evidence of the beneficial effects of the new probiotics on memory, mood and the biochemical components contained in the blood, stool and urine in elderly population.

Official Title
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Biotechnology Research Into Microbiological Spectrum Changes to Improve Cognitive Functions, Depression and Other Neuropsychiatric Disorders in Aging Population

Conditions
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Memory Deficits, Mood Change, Gut Health, Aging Problems, Aging, Cognitive Decline

Intervention / Treatment
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* Dietary Supplement: Probiotics C2P


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: is 55-80 years of age His/her native language is Czech Is willing to visit the testing centre four times within half a year Is willing to provide blood, urine and stool samples three times within half a year Is willing to self-administer the probiotic/placebo pill once every day for half a year is self-sufficient (handling finances, travelling without a chaperone, administration of medication, correct phone usage, filling forms, meal preparation) Has good vision; Can read and write, glasses are acceptable Has good hearing to hear and understand all instructions during examination Can walk well (walking aids are acceptable) to attend all the examinations Exclusion Criteria: Suffers with disorder(s) of digestive system, primarily gastrointestinal disorders (celiac disease, ulcerative colitis, Crohn's disease, frequent diarrhoea) Had severe neurological difficulties (epilepsy, stroke, severe head trauma, meningitis in the past 10 years, brain surgery, brain tumour, prolonged period(s) in an unconscious state - excluding general anaesthesia) Had been treated/Is currently being treated for the following psychiatric disorders: alcohol/medication/drug of abuse dependance, schizophrenia, psychotic disorder, bipolar disorder Is taking medication for depression or low mood Suffers from internal organ failure (heart, liver or kidney failure etc.) Suffered from an oncological problem (cancer) in the past 5 years Underwent radiotherapy or chemotherapy in the past Underwent a surgery/procedure under general anaesthesia in the past three years or has a planned procedure/surgery under general anaesthesia in the next 6 months over the course of this trial Suffered from hepatitis (hepatitis B, C), HIV or syphilis in the past Had taken any probiotics in the past three months

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: First 3 months: group A on probiotics; group B on placebo Next 3 months: group A on placebo; group B on probiotics. Next 3 months: no intervention in either group
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Probiotics C2P/Placebo<br>Crossover design does not confine one group of patients strictly either to an intervention in question or a placebo. Each group will receive both placebo and probiotics in tandem, but in a reversed order. | Dietary Supplement: Probiotics C2P<br>* Probiotics will supplement normal diet. Unlike other products available on the market, which are usually of bovine origin, our probiotic has been manufactured using human-stemmed lines. The supplements are composed of a mixture of naturally occurring human gut bacteria.<br>|
| Experimental: Placebo/Probiotics C2P<br>Crossover design does not confine one group of patients strictly either to an intervention in question or a placebo. Each group will receive both placebo and probiotics in tandem, but in a reversed order. | Dietary Supplement: Probiotics C2P<br>* Probiotics will supplement normal diet. Unlike other products available on the market, which are usually of bovine origin, our probiotic has been manufactured using human-stemmed lines. The supplements are composed of a mixture of naturally occurring human gut bacteria.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline cognitive function in the Amnesia Light and Brief Assessment (ALBA) at 3 months | ALBA is a validated measure assessing memory. The scale spans 0-12 points with higher number of points signifying better outcome | baseline to 3 months | 
| Change from baseline cognitive function in the Amnesia Light and Brief Assessment (ALBA) at 6 months | ALBA is a validated measure assessing memory. The scale spans 0-12 points with higher number of points signifying better outcome | baseline to 6 months | 
| Change from 3 months cognitive function in the Amnesia Light and Brief Assessment (ALBA) at 6 months | ALBA is a validated measure assessing memory. The scale spans 0-12 points with higher number of points signifying better outcome | 3 months to 6 months | 
| Change from 6 months cognitive function in the Amnesia Light and Brief Assessment (ALBA) at 9 months | ALBA is a validated measure assessing memory. The scale spans 0-12 points with higher number of points signifying better outcome | 6 months to 9 months | 
| Difference in cognitive function in the Amnesia Light and Brief Assessment (ALBA) at 3 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | ALBA is a validated measure assessing memory. The scale spans 0-12 points with higher number of points signifying better outcome | 3 months | 
| Difference in cognitive function in the Amnesia Light and Brief Assessment (ALBA) at 6 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | ALBA is a validated measure assessing memory. The scale spans 0-12 points with higher number of points signifying better outcome | 6 months | 
| Change from baseline cognitive function in the Assessment Battery of Cognition (ABACO) at 3 months | ABACO is a measure of cognitive function, results are in points and range from 0-35, higher point attainment signals better outcome | baseline to 3 months | 
| Change from baseline cognitive function in the Assessment Battery of Cognition (ABACO) at 6 months | ABACO is a measure of cognitive function, results are in points and range from 0-35, higher point attainment signals better outcome | baseline to 6 months | 
| Change from 3 months cognitive function in the Assessment Battery of Cognition (ABACO) at 6 months | ABACO is a measure of cognitive function, results are in points and range from 0-35, higher point attainment signals better outcome | 3 months to 6 months | 
| Change from 6 months cognitive function in the Assessment Battery of Cognition (ABACO) at 9 months | ABACO is a measure of cognitive function, results are in points and range from 0-35, higher point attainment signals better outcome | 6 months to 9 months | 
| Difference in cognitive function in the Assessment Battery of Cognition (ABACO) at 3 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | ABACO is a measure of cognitive function, results are in points and range from 0-35, higher point attainment signals better outcome | 3 months | 
| Difference in cognitive function in the Assessment Battery of Cognition (ABACO) at 6 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | ABACO is a measure of cognitive function, results are in points and range from 0-35, higher point attainment signals better outcome | 6 months | 
| Change from baseline cognitive function in Semantic word recollection (category: animals, 1 min) at 3 months | Semantic word recollection is a measure of cognitive function, results range from 0-cca 40, more points signify better outcome | baseline to 3 months | 
| Change from baseline cognitive function in Semantic word recollection (category: animals, 1 min) at 6 months | Semantic word recollection is a measure of cognitive function, results range from 0-cca 40, more points signify better outcome | baseline to 6 months | 
| Change from 3 months cognitive function in Semantic word recollection (category: animals, 1 min) at 6 months | Semantic word recollection is a measure of cognitive function, results range from 0-cca 40, more points signify better outcome | 3 months to 6 months | 
| Change from 6 months cognitive function in Semantic word recollection (category: animals, 1 min) at 9 months | Semantic word recollection is a measure of cognitive function, results range from 0-cca 40, more points signify better outcome | 6 months to 9 months | 
| Difference in cognitive function in Semantic word recollection (category: animals, 1 min) at 3 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | Semantic word recollection is a measure of cognitive function, results range from 0-cca 40, more points signify better outcome | 3 months | 
| Difference in cognitive function in Semantic word recollection (category: animals, 1 min) at 6 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | Semantic word recollection is a measure of cognitive function, results range from 0-cca 40, more points signify better outcome | 6 months | 
| Change from baseline cognitive function in Rey Auditory Verbal Learning Test (RAVLT) at 3 months | RAVLT is a validated measure of cognitive function, it has 8 subscales, each of them ranging from 0-15, measured in raw scores which are connected to age-dependent population norm | baseline to 3 months | 
| Change from baseline cognitive function in Rey Auditory Verbal Learning Test (RAVLT) at 6 months | RAVLT is a validated measure of cognitive function, it has 8 subscales, each of them ranging from 0-15, measured in raw scores which are connected to age-dependent population norm | baseline to 6 months | 
| Change from 3 months cognitive function in Rey Auditory Verbal Learning Test (RAVLT) at 6 months | RAVLT is a validated measure of cognitive function, it has 8 subscales, each of them ranging from 0-15, measured in raw scores which are connected to age-dependent population norm | 3 months to 6 months | 
| Change from 6 months cognitive function in Rey Auditory Verbal Learning Test (RAVLT) at 9 months | RAVLT is a validated measure of cognitive function, it has 8 subscales, each of them ranging from 0-15, measured in raw scores which are connected to age-dependent population norm | 6 months to 9 months | 
| Difference in cognitive function in Rey Auditory Verbal Learning Test (RAVLT) at 3 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | RAVLT is a validated measure of cognitive function, it has 8 subscales, each of them ranging from 0-15, measured in raw scores which are connected to age-dependent population norm | 3 months | 
| Difference in cognitive function in Rey Auditory Verbal Learning Test (RAVLT) at 6 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | RAVLT is a validated measure of cognitive function, it has 8 subscales, each of them ranging from 0-15, measured in raw scores which are connected to age-dependent population norm | 6 months | 
| Change in baseline cognitive function in Wechsler Adult Intelligence Scale, Third edition (WAIS III) - Symbols subtest at 3 months | The WAIS III, subtest Symbols is a validated measure of cognitive function, the point scale ranges from 0-133 with larger point attainment signalling better outcome | baseline to 3 months | 
| Change in baseline cognitive function in Wechsler Adult Intelligence Scale, Third edition (WAIS III) - Symbols subtest at 6 months | The WAIS III, subtest Symbols is a validated measure of cognitive function, the point scale ranges from 0-133 with larger point attainment signalling better outcome | baseline to 6 months | 
| Change in 3 month cognitive function in Wechsler Adult Intelligence Scale, Third edition (WAIS III) - Symbols subtest at 6 months | The WAIS III, subtest Symbols is a validated measure of cognitive function, the point scale ranges from 0-133 with larger point attainment signalling better outcome | 3 months to 6 months | 
| Change in 6 month cognitive function in Wechsler Adult Intelligence Scale, Third edition (WAIS III) - Symbols subtest at 9 months | The WAIS III, subtest Symbols is a validated measure of cognitive function, the point scale ranges from 0-133 with larger point attainment signalling better outcome | 6 months to 9 months | 
| Difference in cognitive function in Wechsler Adult Intelligence Scale, Third edition (WAIS III) - Symbols subtest at 3 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | The WAIS III, subtest Symbols is a validated measure of cognitive function, the point scale ranges from 0-133 with larger point attainment signalling better outcome | 3 months | 
| Difference in cognitive function in Wechsler Adult Intelligence Scale, Third edition (WAIS III) - Symbols subtest at 6 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | The WAIS III, subtest Symbols is a validated measure of cognitive function, the point scale ranges from 0-133 with larger point attainment signalling better outcome | 6 months | 
| Change in baseline cognitive function in Trail Making Test (TMT), Parts A & B at 3 months | The TMT is a validated measure of cognitive function, the time upon completion is measured | baseline to 3 months | 
| Change in baseline cognitive function in Trail Making Test (TMT), Parts A & B at 6 months | The TMT is a validated measure of cognitive function, the time upon completion is measured | baseline to 6 months | 
| Change in 3 month cognitive function in Trail Making Test (TMT), Parts A & B at 6 months | The TMT is a validated measure of cognitive function, the time upon completion is measured | 3 months to 6 months | 
| Change in 6 month cognitive function in Trail Making Test (TMT), Parts A & B at 9 months | The TMT is a validated measure of cognitive function, the time upon completion is measured | 6 months to 9 months | 
| Difference cognitive function in Trail Making Test (TMT), Parts A & B at 3 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | The TMT is a validated measure of cognitive function, the time upon completion is measured | 3 months | 
| Difference cognitive function in Trail Making Test (TMT), Parts A & B at 6 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | The TMT is a validated measure of cognitive function, the time upon completion is measured | 6 months | 
| Change in baseline mood in Geriatric Depression Scale at 3 months. | A self-report measure of mood, measured on 0-15 point scale, higher point attainment signifies worse outcome | baseline to 3 months | 
| Change in baseline mood in Geriatric Depression Scale at 6 months. | A self-report measure of mood, measured on 0-15 point scale, higher point attainment signifies worse outcome | baseline to 6 months | 
| Change in 3 month mood in Geriatric Depression Scale at 6 months. | A self-report measure of mood, measured on 0-15 point scale, higher point attainment signifies worse outcome | 3 months to 6 months | 
| Change in 6 month mood in Geriatric Depression Scale at 9 months. | A self-report measure of mood, measured on 0-15 point scale, higher point attainment signifies worse outcome | 6 months to 9 months | 
| Difference in mood in Geriatric Depression Scale at 3 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | A self-report measure of mood, measured on 0-15 point scale, higher point attainment signifies worse outcome | 3 months | 
| Difference in mood in Geriatric Depression Scale at 6 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | A self-report measure of mood, measured on 0-15 point scale, higher point attainment signifies worse outcome | 6 months | 
| Change from baseline self-sufficiency self-reported in Questionnaire of functional state (abbreviation in original language: subjective FAQ-CZ) at 3 months | FAQ-CZ is a self-report measure of self-sufficiency, it is measured on a scale of 0-30 with higher point attainment signalling worse outcome | baseline to 3 months | 
| Change from baseline self-sufficiency self-reported in Questionnaire of functional state (abbreviation in original language: subjective FAQ-CZ) at 6 months | FAQ-CZ is a self-report measure of self-sufficiency, it is measured on a scale of 0-30 with higher point attainment signalling worse outcome | baseline to 6 months | 
| Change from 3 month self-sufficiency self-reported in Questionnaire of functional state (abbreviation in original language: subjective FAQ-CZ) at 6 months | FAQ-CZ is a self-report measure of self-sufficiency, it is measured on a scale of 0-30 with higher point attainment signalling worse outcome | 3 months to 6 months | 
| Change from 6 month self-sufficiency self-reported in Questionnaire of functional state (abbreviation in original language: subjective FAQ-CZ) at 9 months | FAQ-CZ is a self-report measure of self-sufficiency, it is measured on a scale of 0-30 with higher point attainment signalling worse outcome | 6 months to 9 months | 
| Difference in self-sufficiency self-reported in Questionnaire of functional state (abbreviation in original language: subjective FAQ-CZ) at 3 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | FAQ-CZ is a self-report measure of self-sufficiency, it is measured on a scale of 0-30 with higher point attainment signalling worse outcome | 3 months | 
| Difference in self-sufficiency self-reported in Questionnaire of functional state (abbreviation in original language: subjective FAQ-CZ) at 6 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | FAQ-CZ is a self-report measure of self-sufficiency, it is measured on a scale of 0-30 with higher point attainment signalling worse outcome | 6 months | 
| Changes in tau protein | Measured in pg/ml; 2x10ml samples collected to assess tau protein, neurofilament light and immunocomplex antibody levels | baseline to 3 months | 
| Changes in tau protein | Measured in pg/ml; 2x10ml samples collected to assess tau protein, neurofilament light and immunocomplex antibody levels | baseline to 6 months | 
| Changes in tau protein | Measured in pg/ml; 2x10ml samples collected to assess tau protein, neurofilament light and immunocomplex antibody levels | 3 months to 6 months | 
| Changes in tau protein | Measured in pg/ml; 2x10ml samples collected to assess tau protein, neurofilament light and immunocomplex antibody levels | 6 months to 9 months | 
| Changes in neurofilament light levels | Measured in pg/ml; 2x10ml samples collected to assess tau protein, neurofilament light and immunocomplex antibody levels | baseline to 3 months | 
| Changes in neurofilament light levels | Measured in pg/ml; 2x10ml samples collected to assess tau protein, neurofilament light and immunocomplex antibody levels | baseline to 6 months | 
| Changes in neurofilament light levels | Measured in pg/ml; 2x10ml samples collected to assess tau protein, neurofilament light and immunocomplex antibody levels | 3 months to 6 months | 
| Changes in neurofilament light levels | Measured in pg/ml; 2x10ml samples collected to assess tau protein, neurofilament light and immunocomplex antibody levels | 6 months to 9 months | 
| Changes in immunocomplex antibody levels | Measured in ng/ml; 2x10ml samples collected to assess tau protein, neurofilament light and immunocomplex antibody levels | baseline to 3 months | 
| Changes in immunocomplex antibody levels | Measured in ng/ml; 2x10ml samples collected to assess tau protein, neurofilament light and immunocomplex antibody levels | baseline to 6 months | 
| Changes in immunocomplex antibody levels | Measured in ng/ml; 2x10ml samples collected to assess tau protein, neurofilament light and immunocomplex antibody levels | 3 months to 6 months | 
| Changes in immunocomplex antibody levels | Measured in ng/ml; 2x10ml samples collected to assess tau protein, neurofilament light and immunocomplex antibody levels | 6 months to 9 months | 
| Biochemical parameters in blood | Change from baseline Blood metabolome assessed using mass spectrometry at 3 months | baseline to 3 months | 
| Biochemical parameters in blood | Change from baseline Blood metabolome assessed using mass spectrometry at 6 months | baseline to 6 months | 
| Biochemical parameters in blood | Change from 3 months Blood metabolome assessed using mass spectrometry at 6 months | 3 months to 6 months | 
| Biochemical parameters in blood | Change from 3 months Blood metabolome assessed using mass spectrometry at 6 months | 6 months to 9 months | 
| Biochemical parameters in urine | 15ml sample collected twice at each visitation time point (at home in the morning, during centre visit); Change from baseline Urine metabolome assessed using mass spectrometry at 3 months | baseline to 3 months | 
| Biochemical parameters in urine | 15ml sample collected twice at each visitation time point (at home in the morning, during centre visit); Change from baseline Urine metabolome assessed using mass spectrometry at 6 months | baseline to 6 months | 
| Biochemical parameters in urine | 15ml sample collected twice at each visitation time point (at home in the morning, during centre visit); Change from 3 months Urine metabolome assessed using mass spectrometry at 6 months | 3 months to 6 months | 
| Biochemical parameters in urine | 15ml sample collected twice at each visitation time point (at home in the morning, during centre visit); Change from 3 months Urine metabolome assessed using mass spectrometry at 6 months | 6 months to 9 months | 
| Biochemical parameters in stool | Change from baseline Stool metabolome assessed using mass spectrometry at 3 months | baseline to 3 months | 
| Biochemical parameters in stool | Change from baseline Stool metabolome assessed using mass spectrometry at 6 months | baseline to 6 months | 
| Biochemical parameters in stool | Change from 3 months Stool metabolome assessed using mass spectrometry at 6 months | 3 months to 6 months | 
| Biochemical parameters in stool | Change from 3 months Stool metabolome assessed using mass spectrometry at 6 months | 6 months to 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline Questionnaire of adverse events (abbreviation in original language: DNU) at 3 months | DNU is a self-report measure of adverse events, scale ranges from 0-22 points with higher point outcome indicating more adverse events | baseline to 3 months | 
| Change from baseline Questionnaire of adverse events (abbreviation in original language: DNU) at 6 months | DNU is a self-report measure of adverse events, scale ranges from 0-22 points with higher point outcome indicating more adverse events | baseline to 6 months | 
| Change from 3 months Questionnaire of adverse events (abbreviation in original language: DNU) at 6 months | DNU is a self-report measure of adverse events, scale ranges from 0-22 points with higher point outcome indicating more adverse events | 3 months to 6 months | 
| Change from 6 months Questionnaire of adverse events (abbreviation in original language: DNU) at 9 months | DNU is a self-report measure of adverse events, scale ranges from 0-22 points with higher point outcome indicating more adverse events | 6 months to 9 months | 
| Difference in the Questionnaire of adverse events (abbreviation in original language: DNU) at 3 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | DNU is a self-report measure of adverse events, scale ranges from 0-22 points with higher point outcome indicating more adverse events | 3 months | 
| Difference in the Questionnaire of adverse events (abbreviation in original language: DNU) at 6 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | DNU is a self-report measure of adverse events, scale ranges from 0-22 points with higher point outcome indicating more adverse events | 6 months | 
| Change from baseline Self-assessment of memory at 3 months | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling better outcome | baseline to 3 months | 
| Change from baseline Self-assessment of memory at 6 months | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling better outcome | baseline to 6 months | 
| Change from 3 months Self-assessment of memory at 6 months | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling better outcome | 3 months to 6 months | 
| Change from 6 months Self-assessment of memory at 9 months | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling better outcome | 6 months to 9 months | 
| Difference in Self-assessment of memory at 3 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling better outcome | 3 months | 
| Difference in Self-assessment of memory at 6 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling better outcome | 6 months | 
| Change from baseline Self-assessment of digestion at 3 months | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling better outcome | baseline to 3 months | 
| Change from baseline Self-assessment of digestion at 6 months | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling better outcome | baseline to 6 months | 
| Change from 3 months Self-assessment of digestion at 6 months | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling better outcome | 3 months to 6 months | 
| Change from 6 months Self-assessment of digestion at 9 months | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling better outcome | 6 months to 9 months | 
| Difference in Self-assessment of digestion at 3 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling better outcome | 3 months | 
| Difference in Self-assessment of digestion at 6 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling better outcome | 6 months | 
| Change from baseline Self-assessment of overall health at 3 months | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling better outcome | baseline to 3 months | 
| Change from baseline Self-assessment of overall health at 6 months | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling better outcome | baseline to 6 months | 
| Change from 3 months Self-assessment of overall health at 6 months | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling better outcome | 3 months to 6 months | 
| Change from 6 months Self-assessment of overall health at 9 months | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling better outcome | 6 months to 9 months | 
| Difference in Self-assessment of overall health at 3 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling better outcome | 3 months | 
| Difference in Self-assessment of overall health at 6 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling better outcome | 6 months | 
| Change from baseline Self-assessment of sleep quality at 3 months | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling better outcome | baseline to 3 months | 
| Change from baseline Self-assessment of sleep quality at 6 months | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling better outcome | baseline to 6 months | 
| Change from 3 months Self-assessment of sleep quality at 6 months | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling better outcome | 3 months to 6 months | 
| Change from 6 months Self-assessment of sleep quality at 9 months | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling better outcome | 6 months to 9 months | 
| Difference in Self-assessment of sleep quality at 3 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling better outcome | 3 months | 
| Difference in Self-assessment of sleep quality at 6 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling better outcome | 6 months | 
| Change from baseline Self-assessment of anxiety at 3 months | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling worse outcome | baseline to 3 months | 
| Change from baseline Self-assessment of anxiety at 6 months | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling worse outcome | baseline to 6 months | 
| Change from 3 months Self-assessment of anxiety at 6 months | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling worse outcome | 3 months to 6 months | 
| Change from 6 months Self-assessment of anxiety at 9 months | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling worse outcome | 6 months to 9 months | 
| Difference in Self-assessment of anxiety at 3 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling worse outcome | 3 months | 
| Difference in Self-assessment of anxiety at 6 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling worse outcome | 6 months | 
| Change from baseline Self-assessment of fatigue at 3 months | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling worse outcome | baseline to 3 months | 
| Change from baseline Self-assessment of fatigue at 6 months | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling worse outcome | baseline to 6 months | 
| Change from 3 months Self-assessment of fatigue at 6 months | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling worse outcome | 3 months to 6 months | 
| Change from 6 months Self-assessment of fatigue at 9 months | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling worse outcome | 6 months to 9 months | 
| Difference in Self-assessment of fatigue at 3 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling worse outcome | 3 months | 
| Difference in Self-assessment of fatigue at 6 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling worse outcome | 6 months | 
| Change from baseline Self-assessment of pain at 3 months | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling better outcome | baseline to 3 months | 
| Change from baseline Self-assessment of pain at 6 months | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling better outcome | baseline to 6 months | 
| Change from 3 months Self-assessment of pain at 6 months | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling better outcome | 3 months to 6 months | 
| Change from 6 months Self-assessment of pain at 9 months | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling better outcome | 6 months to 9 months | 
| Difference in Self-assessment of pain at 3 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling better outcome | 3 months | 
| Difference in Self-assessment of pain at 6 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | Self-reported on a visual scale ranging from 1-10 with higher point attainment signalling better outcome | 6 months | 
| Change from baseline physical condition assessment in 30 second sit stand test at 3 months | Number of sits and stands during 30 seconds | baseline to 3 months | 
| Change from baseline physical condition assessment in 30 second sit stand test at 6 months | Number of sits and stands during 30 seconds | baseline to 6 months | 
| Change from 3 months physical condition assessment in 30 second sit stand test at 6 months | Number of sits and stands during 30 seconds | 3 months to 6 months | 
| Change from 6 months physical condition assessment in 30 second sit stand test at 9 months | Number of sits and stands during 30 seconds | 6 months to 9 months | 
| Difference in physical condition assessment in 30 second sit stand test at 3 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | Number of sits and stands during 30 seconds | 3 months | 
| Difference in physical condition assessment in 30 second sit stand test at 6 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | Number of sits and stands during 30 seconds | 6 months | 
| Change from baseline physical condition assessment in 30 second dumbell lift tests at 3 months | Number lifts during 30 seconds | baseline to 3 months | 
| Change from baseline physical condition assessment in 30 second dumbell lift tests at 6 months | Number lifts during 30 seconds | baseline to 6 months | 
| Change from 3 months physical condition assessment in 30 second dumbell lift tests at 6 months | Number lifts during 30 seconds | 3 months to 6 months | 
| Change from 6 months physical condition assessment in 30 second dumbell lift tests at 9 months | Number lifts during 30 seconds | 6 months to 9 months | 
| Difference in physical condition assessment in 30 second dumbell lift tests at 3 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | Number lifts during 30 seconds | 3 months | 
| Difference in physical condition assessment in 30 second dumbell lift tests at 6 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | Number lifts during 30 seconds | 6 months | 
| Change from baseline physical condition assessment in 30 meters walk at 3 months | Time untill completion | baseline to 3 months | 
| Change from baseline physical condition assessment in 30 meters walk at 6 months | Time untill completion | baseline to 6 months | 
| Change from 3 months physical condition assessment in 30 meters walk at 6 months | Time untill completion | 3 months to 6 months | 
| Change from 6 months physical condition assessment in 30 meters walk at 9 months | Time untill completion | 6 months to 9 months | 
| Difference in physical condition assessment in 30 meters walk at 3 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | Time untill completion | 3 months | 
| Difference in physical condition assessment in 30 meters walk at 6 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | Time untill completion | 6 months | 
| Change from baseline Structured nutritional questionnaire about long-term eating habits (abbreviation in original language: STRADO) at 3 months | Structured self-report questionnaire | baseline to 3 months | 
| Change from baseline Structured nutritional questionnaire about long-term eating habits (abbreviation in original language: STRADO) at 6 months | Structured self-report questionnaire | baseline to 6 months | 
| Change from 3 months Structured nutritional questionnaire about long-term eating habits (abbreviation in original language: STRADO) at 6 months | Structured self-report questionnaire | 3 months to 6 months | 
| Change from 6 months Structured nutritional questionnaire about long-term eating habits (abbreviation in original language: STRADO) at 9 months | Structured self-report questionnaire | 6 months to 9 months | 
| Difference in Structured nutritional questionnaire about long-term eating habits (abbreviation in original language: STRADO) at 3 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | Structured self-report questionnaire | 3 months | 
| Difference in Structured nutritional questionnaire about long-term eating habits (abbreviation in original language: STRADO) at 6 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | Structured self-report questionnaire | 6 months | 
| Change in baseline Beck's Anxienty Inventory at 3 months | Beck's Anxenty Inventory is a validated self-report measure of anxiety. The scale ranges from 0-63 points, higher point attainment signals worse outcome | baseline to 3 months | 
| Change in baseline Beck's Anxienty Inventory at 6 months | Beck's Anxenty Inventory is a validated self-report measure of anxiety. The scale ranges from 0-63 points, higher point attainment signals worse outcome | baseline to 6 months | 
| Change in 3 months Beck's Anxienty Inventory at 6 months | Beck's Anxenty Inventory is a validated self-report measure of anxiety. The scale ranges from 0-63 points, higher point attainment signals worse outcome | 3 months to 6 months | 
| Change in 6 months Beck's Anxienty Inventory at 9 months | Beck's Anxenty Inventory is a validated self-report measure of anxiety. The scale ranges from 0-63 points, higher point attainment signals worse outcome | 6 months to 9 months | 
| Difference in Beck's Anxienty Inventory at 3 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | Beck's Anxenty Inventory is a validated self-report measure of anxiety. The scale ranges from 0-63 points, higher point attainment signals worse outcome | 3 months | 
| Difference in Beck's Anxienty Inventory (BAI) at 6 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | Beck's Anxenty Inventory is a validated self-report measure of anxiety. The scale ranges from 0-63 points, higher point attainment signals worse outcome | 6 months | 
| Change in baseline Beck's Depression Inventory - II (BDI-II) at 3 months | BDI-II is a validated self-report measure of depression with scale ranging from 0-63 points, higher point attainment signals worse outcome | baseline to 3 months | 
| Change in baseline Beck's Depression Inventory - II (BDI-II) at 6 months | BDI-II is a validated self-report measure of depression with scale ranging from 0-63 points, higher point attainment signals worse outcome | baseline to 6 months | 
| Change in 3 months Beck's Depression Inventory - II (BDI-II) at 6 months | BDI-II is a validated self-report measure of depression with scale ranging from 0-63 points, higher point attainment signals worse outcome | 3 months to 6 months | 
| Change in 6 months Beck's Depression Inventory - II (BDI-II) at 9 months | BDI-II is a validated self-report measure of depression with scale ranging from 0-63 points, higher point attainment signals worse outcome | 6 months to 9 months | 
| Difference in Beck's Depression Inventory - II (BDI-II) at 3 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | BDI-II is a validated self-report measure of depression with scale ranging from 0-63 points, higher point attainment signals worse outcome | 3 months | 
| Difference in Beck's Depression Inventory - II (BDI-II) at 6 months between the Probiotics C2P/Placebo and Placebo/C2P Probiotics group | BDI-II is a validated self-report measure of depression with scale ranging from 0-63 points, higher point attainment signals worse outcome | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Probiotics, Microbiome, Gut Microflora, Cognitive Health