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Gut-Brain-axis: Targets for Improvement of Cognition in the Elderly (SmartAge)

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ClinicalTrials.gov Identifier: NCT04841668
Recruitment Status : Recruiting
First Posted : April 12, 2021
Last Update Posted : May 20, 2021
Sponsor:
Information provided by (Responsible Party):
José Manuel Fernández-Real, Institut d'Investigació Biomèdica de Girona Dr. Josep Trueta

Brief Summary:

Cognitive disorders increase with age and in the presence of metabolic diseases such as Type 2 Diabetes Mellitus (T2DM). In addition, digestive disorders, changes in dietary pattern and decreased activity negatively influence the microbiome.

The hypothesis is that pharmacological intervention with metformin will modify the composition of the gut microbiota and cognition.

The study has a pilot longitudinal design, where each patient with T2DM will be followed for one year. Two groups will be recruited:

  1. Group A: The aim will be to evaluate the associations between glucose (measured by continuous glucose monitoring (CGM)), cognitive function (by means of cognitive tests and magnetic resonance imaging (MRI)), physical activity (recorded by activity and sleep tracker devicer), metformin, diet (evaluated by nutritional survey) and composition of the microbiota (evaluated by metagenomics), during 12 months (6 months without metformin and 6 months with metformin treatment).
  2. Group B: The aim will be to evaluate the associations between glucose, diet (evaluated by nutritional survey), cognitive function (by means of cognitive tests), physical activity (measured by activity and sleep tracker device), the treatment and composition of the microbiota (evaluated by metagenomics), during 12 months.

Condition or disease Intervention/treatment
Type 2 Diabetes Mellitus Drug: Metformin

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Study Type : Observational
Estimated Enrollment : 136 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Gut-Brain-axis: Targets for Improvement of Cognition in the Elderly
Actual Study Start Date : April 10, 2021
Estimated Primary Completion Date : December 1, 2023
Estimated Study Completion Date : August 1, 2024

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
Patients with recently diagnosed T2DM
This group will consist of 36 recently diagnosed T2DM, according to the World Health Organization (WHO) patients (last 6 months), who have not received treatment with metformin.
Drug: Metformin
Patients will begin treatment with metformin administered orally at a starting dose of 425 mg / day every 12 hours for the first 15 days and then continue with a dose of 850 mg / day until the end of the study. The beginning of this treatment phase will be following the recommendations of the clinical guidelines (Comprehensive Approach to Type 2 Diabetes Mellitus, SEEN V2019.2)

Patients with long-term T2DM
The group will consist of 100 patients with long-term T2DM, according to the WHO classification, regardless of whether they take metformin or another treatment.



Primary Outcome Measures :
  1. Gut microbiota composition. [ Time Frame: 12 months ]
    It will be identified in the stool by cultures and DNA and mRNA expression after metformin treatment.

  2. Cognitive impairment [ Time Frame: 12 months ]
    It will be measured by Mini-Examen Cognoscitivo (MEC).

  3. Audioverbal memory [ Time Frame: 12 months ]
    It will be measured by Test aprendizaje verbal-TAVEC.

  4. Visual memory [ Time Frame: 12 months ]
    It will be measured by Rey-Osterrieth Complex Figure.

  5. Depressive symptomatology [ Time Frame: 12 months ]
    It will be measured by Patient Health Questionnaire-9 (PHQ-9).

  6. Impulsivity [ Time Frame: 12 months ]
    It will be measured by UPPS Impulsive Behavior Scale.

  7. Food Addiction [ Time Frame: 12 months ]
    It will be measured by Yale Food Addiction Scale.

  8. Behavioral inhibition [ Time Frame: 12 months ]
    It will be measured by Sensitivity to Punishment and Sensitivity to Reward (SPSRQ).

  9. Behavioral activation [ Time Frame: 12 months ]
    It will be measured by Sensitivity to Punishment and Sensitivity to Reward (SPSRQ).

  10. Visoconstructive function [ Time Frame: 12 months ]
    It will be measured by Rey-Osterrieth Complex Figure.

  11. Visuospatial perception [ Time Frame: 12 months ]
    It will be measured by Judgment Line Orientation.

  12. Naming [ Time Frame: 12 months ]
    It will be measured by Boston Naming Test.

  13. Selective and alternating attention [ Time Frame: 12 months ]
    It will be measured by Trail making test (Part A y B).

  14. Attention and working memory [ Time Frame: 12 months ]
    It will be measured by the Wechsler Adult Intelligence Scales, Fourth Edition (WAIS-IV).

  15. Inhibition [ Time Frame: 12 months ]
    It will be measured by Stroop Color-Word Test.

  16. Phonemic verbal fluency [ Time Frame: 12 months ]
    It will be measured by PMR

  17. Semantic verbal fluency [ Time Frame: 12 months ]
    It will be measured by Animals


Secondary Outcome Measures :
  1. The percentage of time in glucose target range (glucose level 70mg/dl-180mg/dl) [ Time Frame: 12 months ]
  2. Effect on gut microbiota [ Time Frame: 12 months ]
    Gut microbiota will be analysed by metagenomics and metabolomics.

  3. The percentage of time in glucose range (glucose level below 100 mg/dl) [ Time Frame: 12 months ]
  4. The percentage of time in glucose range (glucose level between 100-125 mg/dl) [ Time Frame: 12 months ]
  5. The percentage of time in glucose range (glucose level between 126-139 mg/dl) [ Time Frame: 12 months ]
  6. The percentage of time in glucose range (glucose level between 140-199 mg/dl) [ Time Frame: 12 months ]

Other Outcome Measures:
  1. Integrity of the brain gray matter [ Time Frame: 12 months ]
    It will be assessed using magnetic resonance imaging (T1-weighted)

  2. Integrity of the white matter tracts [ Time Frame: 12 months ]
    It will be assessed using magnetic resonance imaging with diffusion tensor imaging (DTI)

  3. Brain iron accumulation [ Time Frame: 12 months ]
    It will be assessed using magnetic resonance imaging using (R2*)

  4. Resting-state functional brain sequences [ Time Frame: 12 months ]
    It will be assessed using magnetic resonance imaging (T2*-weighted echo-planar imaging)

  5. Insulin resistance [ Time Frame: 12 months ]
    It will be measured by HOMA

  6. Markers of chronic inflammation: C-reactive protein, IL-6, adiponectin and soluble, tumor necrosis factor-α receptor fractions. [ Time Frame: 12 months ]
    Enzyme-linked immunosorbent assay (ELISA) and quantitative polymerase chain reaction (qPCR)

  7. Glycosylated hemoglobin (HbA1c) value [ Time Frame: 12 months ]
    Glycosylated hemoglobin (HbA1c) in % or mmol/mol

  8. The percentage of time in hyperglycaemia (glucose level above 180 mg/dl) [ Time Frame: 12 months ]
  9. The percentage of time in hypoglycaemia (glucose level below 70 mg/dl) [ Time Frame: 12 months ]
  10. The glycaemic risk measured with low blood glucose index (LBGI) [ Time Frame: 12 months ]
    Low blood glucose index (LBGI) is a parameter that quantifies the risk of glycaemic excursions in non-negative numbers.

  11. The glycaemic risk measured with high blood glucose index (HBGI) [ Time Frame: 12 months ]
    High blood glucose index (HBGI) is a parameter that quantifies the risk of glycaemic excursions in non-negative numbers.

  12. The glycaemic variability measured with mean amplitude of glycaemic excursions (MAGE) [ Time Frame: 12 months ]
    measured in mg/dl

  13. Burned calories [ Time Frame: 12 months ]
    Mean and standard deviation of burned calories measures by activity and sleep tracker device.

  14. Steps [ Time Frame: 12 months ]
    Mean and standard deviation of steps measures by activity and sleep tracker device.

  15. Distance [ Time Frame: 12 months ]
    Mean and standard deviation of distance measures by activity and sleep tracker device.

  16. Plants [ Time Frame: 12 months ]
    Mean and standard deviation of plants measures by activity and sleep tracker device.

  17. Minutes null activity [ Time Frame: 12 months ]
    Mean and standard deviation of minutes null activity measures by activity and sleep tracker device.

  18. Minutes slight activity [ Time Frame: 12 months ]
    Mean and standard deviation of minutes slight activity measures by activity and sleep tracker device.

  19. Minutes mean activity [ Time Frame: 12 months ]
    Mean and standard deviation of minutes mean activity measures by activity and sleep tracker device.

  20. Minutes high activity [ Time Frame: 12 months ]
    Mean and standard deviation of minutes high activity measures by activity and sleep tracker device.

  21. Calories consumption [ Time Frame: 12 months ]
    Mean and standard deviation of calories measures by activity and sleep tracker device.

  22. Minutes asleep [ Time Frame: 12 months ]
    Mean and standard deviation of minutes asleep measures by activity and sleep tracker device.

  23. Minutes awake [ Time Frame: 12 months ]
    Mean and standard deviation of minutes awake measures by activity and sleep tracker device.

  24. Bed time [ Time Frame: 12 months ]
    Mean and standard deviation of bed time measures by activity and sleep tracker device.

  25. Minutes light sleep [ Time Frame: 12 months ]
    Mean and standard deviation of minutes light sleep measures by activity and sleep tracker device.

  26. Minutes deep sleep [ Time Frame: 12 months ]
    Mean and standard deviation of minutes deep sleep measures by activity and sleep tracker device.

  27. Minutes rapid eye movement (REM) [ Time Frame: 12 months ]
    Mean and standard deviation of minutes REM measures by activity and sleep tracker device.

  28. Number time awake [ Time Frame: 12 months ]
    Mean and standard deviation of number time awake measures by activity and sleep tracker device.



Information from the National Library of Medicine

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Ages Eligible for Study:   65 Years to 80 Years   (Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

Group A Study population Adult patients (≥ 65 years of age) recently diagnosed with T2DM according to the WHO and who have not been treated with metformin.

Group B Study population Adult patients (≥ 65 years of age) diagnosed with long-term T2DM according to the WHO classification, regardless of whether they take metformin or other treatment.

Criteria

Group A

Inclusion Criteria:

  1. Age between 65 and 80 years.
  2. Patients with recently diagnosed T2DM (last 6 months), according to the WHO classification.
  3. Patients in whom written informed consent has been obtained for participation in the study.

Exclusion Criteria:

  1. HbA1c ≥ 9%
  2. Metformin treatment in the past 6 months
  3. Creatinine greater than 1.2 and glomerular filtration rate less than 40
  4. Serious systemic disease not related to obesity, including any type of cancer, severe kidney disease or liver disease, and known type 1 diabetes.
  5. Systemic diseases with intrinsic inflammatory activity such as rheumatoid arthritis, Crohn's disease, asthma, or chronic infection (e.g., HIV, active tuberculosis) or any type of infectious disease.
  6. Current treatment for malignant neoplasia, other than basal cell or squamous cell skin cancer.
  7. Class III or IV heart disease, known ischemic cardiovascular disease
  8. Kidney failure, history of kidney transplant, or current dialysis treatment
  9. Serum liver enzymes (GOT, GPT) above twice the upper limit of normal. Obvious signs or symptoms of liver disease, acute or chronic hepatitis.
  10. Chronic constipation (stool habit ≥ 7 days)
  11. Pregnancy or breastfeeding
  12. Treatments that affect glucose metabolism or the intestinal microbiota with biguanides, sulfonylurea secretagogues or non-sulfonylurea secretagogues, insulin sensitizers, insulin, thiazolidinediones, alpha glucosidase inhibitors, incretin mimetics, Dipeptidyl peptidase IV inhibitors, use of cathartics.
  13. Chronic anti-inflammatory treatment with steroidal drugs (during the previous 3 months).
  14. Symptoms and / or clinical signs of infection in the previous month.
  15. Antibiotic, antifungal or antiviral treatment active in the previous 3 months.
  16. Treatment with glucocorticoids chronic or during the 2 months prior to inclusion in the study.
  17. Treatment with a weight loss product during the previous two months
  18. Immunosuppressant treatment.
  19. Excessive alcohol consumption (alcohol intake greater than 40 g per day (women) or 80 g / day (men)) either acute or chronic, or drug use. History of drug or alcohol abuse.
  20. Patients with severe eating disorders
  21. History of alterations in iron balance (known chronic hemoglobinopathies or anemia, genetic hemochromatosis, hemosiderosis from any cause, atransferrinemia, paroxysmal nocturnal hemoglobinuria).
  22. Important psychiatric history.
  23. Participation in any other study.
  24. People whose freedom is under legal or administrative requirement.

Group B

Inclusion Criteria:

  1. Age between 65 and 80 years.
  2. Patients with long-term T2DM according to the WHO classification
  3. Patients in whom written informed consent has been obtained for participation in the study.

Exclusion Criteria:

  1. HbA1c ≥ 9%
  2. Creatinine greater than 1.2 and glomerular filtration rate less than 40
  3. Serious systemic disease not related to obesity, including any type of cancer, severe kidney disease or liver disease, and known type 1 diabetes.
  4. Systemic diseases with intrinsic inflammatory activity such as rheumatoid arthritis, Crohn's disease, asthma, or chronic infection (e.g., HIV, active tuberculosis) or any type of infectious disease.
  5. Current treatment for malignant neoplasia, other than basal cell or squamous cell skin cancer.
  6. Class III or IV heart disease, known ischemic cardiovascular disease.
  7. Kidney failure, history of kidney transplant, or current dialysis treatment
  8. Serum liver enzymes (GOT, GPT) above twice the upper limit of normal. Obvious signs or symptoms of liver disease, acute or chronic hepatitis.
  9. Chronic constipation (stool habit ≥ 7 days)
  10. Pregnancy or breastfeeding
  11. Chronic anti-inflammatory treatment with steroidal drugs (during the previous 3 months).
  12. Symptoms and / or clinical signs of infection in the previous month.
  13. Antibiotic, antifungal or antiviral treatment active in the previous 3 months.
  14. Treatment with glucocorticoids chronic or during the 2 months prior to inclusion in the study.
  15. Treatment with a weight loss product during the previous two months.
  16. Immunosuppressant treatment.
  17. Excessive alcohol consumption (alcohol intake greater than 40 g per day (women) or 80 g / day (men)) either acute or chronic, or drug use. History of drug or alcohol abuse.
  18. Patients with severe eating disorders
  19. History of alterations in iron balance (known chronic hemoglobinopathies or anemia, genetic hemochromatosis, hemosiderosis from any cause, atransferrinemia, paroxysmal nocturnal hemoglobinuria).
  20. Important psychiatric history.
  21. Participation in any other study.
  22. People whose freedom is under legal or administrative requirement.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04841668


Contacts
Layout table for location contacts
Contact: José M. Fernández-Real, Ph.D. +34 972 94 02 00 ext 2325 jmfreal@idibgi.org
Contact: Marisel Rosell Díaz, M.D. +34 972 94 02 00 ext 2325 mrosell@idibgi.org

Locations
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Spain
Institut d'Investigació Biomèdica de Girona (IDIBGI) Recruiting
Girona, Spain, 17007
Contact: Yenny Leal, Ph.D.    0034 972940200 ext 2325    yleal@idibgi.org   
Principal Investigator: José M. Fernández-Real, M.D., Ph.D.         
Sponsors and Collaborators
Institut d'Investigació Biomèdica de Girona Dr. Josep Trueta
Investigators
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Principal Investigator: José M Fernández-Real, Ph.D. Institut d'Investigació Biomèdica de Girona (IDIBGI)
Publications:
Metformin in Longevity Study (MILES). - Full Text View - ClinicalTrials.gov [Internet]. [cited 2020 May 19]. Availablefrom: https://clinicaltrials.gov/ct2/show/NCT02432287
Cohen, J. (1977). Statistical power analysis for the behavioral sciences. New York:Academic Press)

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Responsible Party: José Manuel Fernández-Real, Principal investigator, clinical professor, section chief of Endocrinology and Nutrition Department of Josep Trueta University Hospital, Institut d'Investigació Biomèdica de Girona Dr. Josep Trueta
ClinicalTrials.gov Identifier: NCT04841668    
Other Study ID Numbers: SmartAge
First Posted: April 12, 2021    Key Record Dates
Last Update Posted: May 20, 2021
Last Verified: May 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by José Manuel Fernández-Real, Institut d'Investigació Biomèdica de Girona Dr. Josep Trueta:
Type 2 Diabetes Mellitus
Continous Glucose Monitoring
Cognition
Metformin
Gut microbiome
Magnetic resonance imaging
Physical activity monitor
Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs