Effects of a Colon-delivered Multivitamin Supplement on Brain Functioning, Immunometabolic- and Intestinal Markers in Ageing

Aging Clinical Trial

— COMBI  

Official title:

The Effects of a Colon-delivered Multivitamin Supplement on Brain Functioning and Its Relation With Immunometabolic and Intestinal Markers in Ageing: the COMBI Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05675007
• Other study ID #: 3033003.02
• Status: Completed
• Phase: N/A
• Start date: December 5, 2022
• Est. completion date: May 2, 2024

Study information

• Verified date: May 2024
• Source: Donders Centre for Cognitive Neuroimaging
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

COMBI is a multi-center, randomized controlled trial among 70 older adults at risk of cognitive decline. The main goal is to investigate the effect of a 6-week colon-delivered multivitamin supplementation on the gut-brain axis in older adults, by assessing changes in brain function as well as intestinal changes compared to placebo.

Description:

Growing evidence indicates an important role for intestinal health in development of cognitive decline in ageing. Intestinal health, and especially the gut microbiome, is assumed to affect brain health and functioning via immunometabolic pathways captured in the gut-brain axis. However, it is unclear whether changes in intestinal health markers causally relate to cognitive decline in older adults and how. Nutritional interventions specifically targeting the gut were found beneficial for human cognition and brain function. An intervention based on colon-delivered vitamins (B2, B3, B6, B9, C, D3) is proposed to affect gut health using microbiome-dependent and independent pathways. In this study, it will be investigated whether this intervention affects neurocognition in ageing humans, to reveal causal gut-brain relationships in aging.Therefore, the primary goal of the COMBI study is to investigate the effect of a 6-week colon-delivered multivitamin supplementation on the gut-brain axis in older adults, by assessing changes in brain function as well as intestinal changes compared to placebo. Secondary, the effects of this 6-week colon-delivered multivitamin supplementation in older adults on the following parameters related to potential gut-brain pathways will also be investigated: (1) other relevant brain parameters, (2) other relevant intestinal parameters, (3) immunometabolic parameters related to gut-brain pathways, and (4) neuropsychological test battery scoring.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 75
• Est. completion date: May 2, 2024
• Est. primary completion date: May 2, 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 60 Years to 75 Years

Eligibility

Inclusion Criteria:

• Written informed consent

• Age between 60-75 years (at pre-screening)

• Fluency in Dutch (speaking, reading and writing)

• Score =2 points on the risk factor scale below based on self report:

• BMI=25 (1 point)

• Physical inactivity (according to WHO guidelines) (1 point)

• Hypertension (1 point)

• Hypertension without medication (1 point)

• Hypercholesterolemia (1 point)

• Diabetes type II (1 point)

• Mild cardiovascular disease (1 point)

Exclusion Criteria:

• Food allergies or other issues with the vitamins included in the supplement

• Concurrent participation in other intervention trials

• Clinical diagnosis of =1 of the following:

• Stroke;

• Neurological disease(s) (e.g. MCI, dementia, MS, Parkinson's, epilepsy);

• Current malignant disease(s), with or without treatment;

• Current psychiatric disorder(s) (e.g. depression, psychosis, bipolar episodes, eating disorder);

• Symptomatic cardiovascular disease (e.g. stroke, angina pectoris, heart failure, myocardial infarction);

• Revascularisation surgery in the last 12 months at pre-screening;

• Gastrointestinal diseases (i.e., diarrhoea, Crohn's disease, ulcerative colitis, diverticulosis, stomach or duodenal ulcers) or having a history of gastrointestinal surgical events (e.g. stoma) that may influence the results of the study, as determined by the study team;

• Visual impairment (e.g. blindness);

• Hearing or communicative impairment.

• Use of antibiotics within the previous 3 months before the study start.

• Use of protonpump inhibitors within the study period (esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole)

• Not willing to refrain from taking other supplements (containing vitamin B2, B3, B6, B9, or C, prebiotic, or probiotic) that can interfere with the study outcomes, from at least 2 weeks before start of the intervention till the end of the intervention period.

• Answering "Yes" on =1 of the Donders Institute MRI safety screening protocol questions (see the 8 questions below):

1. Are there metal objects located in your upper body? Exception: tooth-fillings and/or dental crowns.

2. Are there metal splinters in your body, in particular within the eyes? For example: through labour work in the metal industry.

3. Are there jewellery items or piercings that you are unable to take off?

4. Have you had a brain surgery in the past?

5. Are there active implants present? For example: pacemaker, neurostimulator, insulin pump, hearing aid (that is unable to be removed).

6. Are there any medical plasters or patches that you can't or may not take off? For example: nicotine patch.

7. Do you suffer from epilepsy?

8. Do you suffer from claustrophobia?

• Cognitive impairment as determined by Telephone Interview for Cognitive Status (TICS-M1), performed during pre-screening before inclusion and defined as a score <23.

Related Conditions & MeSH terms

• Aging
• Cognitive Decline
• Cognitive Dysfunction

Intervention

Dietary Supplement:
• Colon-delivered multivitamin supplement
Colon-delivered multivitamin supplement containing the following dose of the indicated vitamin: vitamin B2 (10 mg), vitamin B3 (4.0 mg), vitamin B6 (1.4 mg), vitamin B9 (400 µg), vitamin C (200 mg) and vitamin D3 (15ug). Vitamin capsules are filled with microcrystalline cellulose and magnesium stearate up to 200 mg. Control of release in the colon is achieved by the Eudragit S 100 coating layer technology that surrounds the vitamins contained in the core capsules.
• Placebo capsule
Placebo capsule containing microcrystalline cellulose and magnesium stearate up to 200 mg. Placebo capsules are coated with the Eudragit S 100 coating layer.

Locations

Country	Name	City	State
Netherlands	Radboud University, Donders Centre for Cognitive Neuroimaging	Nijmegen	Gelderland
Netherlands	Wageningen University and Research, Division of Human Nutrition and Health	Wageningen	Gelderland

Sponsors (2)

Lead Sponsor	Collaborator
Donders Centre for Cognitive Neuroimaging	Wageningen University and Research

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Body mass index	Measured in kg/m^2	Baseline (T0)
Other	Waist circumference	Measured in cm	Baseline (T0)
Other	Hip circumference	Measured in cm	Baseline (T0)
Other	Blood pressure	Scores range from approximately (for diastolic) 60-120 and (for systolic) 100-180 mmHg, with higher scores indicating higher blood pressure.	Baseline (T0)
Other	Abdominal fat distribution	VAT(visceral adipose tissue)/SAT(subcutaneous adipose tissue) ratio based on abdominal MRI scan	Baseline (T0)
Other	Baseline Demographics and medical history (questionnaire)	Demographic information, medical history and medication use - qualitative assessment	Baseline (T0)
Other	4DKL (questionnaire)	(Psychosocial) complaints in daily life. Separate scores for distress (>10 moderate, >20 severe), depression (>2 moderate, >5 severe), anxiety (>3 moderate, >9 severe) and somatisation (>10 moderate, >20 severe)	Baseline (T0)
Other	EQ-5D-5L (questionnaire)	Quality of life. Scores range from 0-100, higher scores indicate better quality of life	Baseline (T0)
Other	Five Facet Mindfulness Questionnaire (questionnaire)	Self-assessment of mindfulness. Total scale ranges from 24 - 120, higher scores indicate more mindfulness	Baseline (T0)
Other	LIBRA (questionnaire)	Modifiable dementia risk using lifestyle for brain health. The score ranges from -5.9 (minimum score) to +12.7 (maximum score), with higher scores meaning a worse outcome (higher dementia risk)	Baseline (T0)
Other	Lubben Social Network Scale (questionnaire)	Social contact and perceived social support. The score ranges from 0 (minimum score) to 30 (maximum score), with higher scores meaning a better outcome (higher level of perceived social support)	Baseline (T0)
Other	SARC-F Sarcopenia questionnaire (questionnaire)	Sarcopenia. Scores range from 0 to 10 (i.e. 0-2 points for each component; 0 = best to 10 = worst).	Baseline (T0)
Other	Sedentary Behaviour Questionnaire (questionnaire)	Average hours and minutes of sedentary behavior a day, range from 0 to 24 hours. Higher scores (more hours) means a more sedentary behavior.	Baseline (T0)
Other	Change in Nutritional intake (questionnaire)	Nutritional intake measured with a Food Frequency Questionnaire, assessing food intake of the past month, qualitative assessment	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Other	Change in Perceived Stress Scale (questionnaire)	Stress perception. Total score, scale 0 - 40, higher scores indicate more perceived stress	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Other	Change in Pittsburgh Sleep Quality Index (PSQI) (questionnaire)	Sleep quality. Total score ranging from 0 to 21 with the higher total score (referred to as global score) indicating worse sleep quality	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Other	Change in SQUASH (questionnaire)	Physical activity. METs derived from the Ainsworth's compendium of physical activity will be used to classify physical activity intensity (<1.5METs- sedentary, 1.6-2.9 METs- light, 3.0-5.9METs- moderate, >6.0- vigorous physical activity).	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Other	Gastrointestinal symptoms questionnaire (questionnaire)	Gastrointestinal symptoms, qualitative assessment	Baseline (T0)
Other	Gastrointestinal symptoms questionnaire (questionnaire)	Gastrointestinal symptoms, qualitative assessment	Follow-up after 6 weeks (T1)
Other	Bristol stool chart (questionnaire)	Classification of faeces type, qualitative assessment	Baseline (T0)
Other	Bristol stool chart (questionnaire)	Classification of faeces type, qualitative assessment	Follow-up after 6 weeks (T1)
Other	Gut transit time	Gut transit time measured by blue muffin consumption and appearance in faeces	Baseline (T0)
Other	Gut transit time	Gut transit time measured by blue muffin consumption and appearance in faeces	Follow up after 6 weeks (T1)
Other	Change in Cognitive Failures Questionnaire (questionnaire)	Subjective cognitive functioning. Score ranges from 0-100. A higher total score indicates more subjective cognitive failure.	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Other	Change in Cognitive Emotions Regulation Questionnaire (questionnaire)	Cognitive coping strategies. Answers are scored on a 7-point Likert-type scale ranging from 1 (strongly disagree) to 7 (strongly agree). The scoring takes the average of all the scores in each subscale of cognitive reappraisal and expressive suppression	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Other	Change in Hospital Anxiety and Depression Scale (questionnaire)	Anxiety and depression. Separate scores for anxiety (max 21) and depression (max 21). For each domain, a score >8 indicates psychiatric condition of anxiety or depression.	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Other	Change in Memory Self-Efficacy MIA (questionnaire)	Self-evaluation and confidence of memory. Sum of Part 1 + Part 2A and B. Part 1: Strategy (scores 10 - 50, higher scores indicate more use of strategies), Part 2A: Subjective memory functioning, scores ranges from 23 - 115, with higher scores indicate better memory self-efficacy and 2B: Locus, scores ranges from 7 - 35, higher scores indicate better perceived personal control over remembering abilities.	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Other	Change in Starkstein Apathy Scale (questionnaire)	Screen and measure apathetic symptoms. A higher total score (range 0-42) indicates more severe apathy, with a score greater than 14 or greater is indicative of clinical apathy	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Other	User experiences (questionnaire)	User experiences of the supplement - qualitative assessment.	Follow up after 6 weeks (T1)
Other	COVID status (questionnaire)	Vaccination status, COVID history - qualitative assessment.	Baseline (T0)
Other	COVID status (questionnaire)	Vaccination status, COVID history - qualitative assessment.	Follow up after 6 weeks (T1)
Primary	Change in brain activity during working memory	Blood-oxygen level dependent activity in dlPFC and hippocampus during N-back fMRI task	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Primary	Change in working memory performance	Task accuracy during N-back fMRI task	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Primary	Change in faecal short-chain fatty acids	Total faecal short-chain fatty acid concentration measured by gas chromatograph mass spectrometry	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Secondary	Change in brain myo-inositol levels (neuroimaging)	Brain myo-inositol levels reflecting neuroinflammation in dlPFC and hippocampus, measured by magnetic resonance spectroscopy	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Secondary	Change in cerebral perfusion levels (neuroimaging)	Cerebral perfusion levels measured by arterial spin labelling	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Secondary	Change in neuropsychological test-battery scoring	Z-scoring on cognitive domains predominantly affected by cognitive ageing: executive function (incl. working memory), episodic memory and processing speed.	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Secondary	Change in microbiota profile (faecal)	16S rRNA based profile of gut microbiota in faeces	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Secondary	Change in individual short-chain fatty acids profile (faecal)	GCMS measurement to assess profile of individual SCFAs in faeces (acetic acid, formic acid, propionic acid, isobutyric acid, butyric acid, isovaleric acid, valeric acid, 4-methyl valeric acid, hexanoic acid, heptanoic acid)	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Secondary	Change in stool water content (faecal)	Water content of stool, based on wet- and dry weight.	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Secondary	Change in stool pH (faecal)	Faecal pH will be measured with a pH/redox meter in faeces	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Secondary	Change in stool redox potential (faecal)	Redox potential will be measured with a pH/redox meter in faeces	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Secondary	Change in intestinal inflammation profile (faecal)	Assay-based profile of intestinal inflammation measured in faeces	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Secondary	Change in C-reactive protein concentration (blood)	hsCRP measured via finger prick analysis	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Secondary	Change in white blood cell count (blood)	White blood cell count measured via finger prick analysis	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Secondary	Change in inflammation profile (blood)	Assay-based profile of systemic inflammation measured in plasma	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Secondary	Change in intestinal integrity profile (blood)	Assay-based profile of intestinal integrity measured in plasma	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Secondary	Change in anti-oxidant status profile (blood)	Assay-based profile of anti-oxidant status and oxidative stress measured in plasma	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Secondary	Change in metabolic profile (blood)	Assay-based profile of (energy) metabolism measured in plasma	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Secondary	Change in brain health profile (blood)	Assay-based profile of brain health measured in plasma	Change between Baseline (T0), Follow-up after 6 weeks (T1)
Secondary	Change in vitamin profile (blood)	Assay-based profile of circulating vitamins from supplement measured in plasma	Change between Baseline (T0), Follow-up after 6 weeks (T1)