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Proof of Mechanism of a New Ketogenic Supplement Using Dual Tracer PET (Positron Emission Tomography) (BENEFIC)

Primary Purpose

Mild Cognitive Impairment

Status
Completed
Phase
Not Applicable
Locations
Canada
Study Type
Interventional
Intervention
ketogenic drink
placebo
Sponsored by
Université de Sherbrooke
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Mild Cognitive Impairment focused on measuring mild cognitive impairment, ketones, medium chain triglycerides, Positron emission tomography, magnetic resonance imaging, cognition, brain, neuroimaging

Eligibility Criteria

55 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • subjective memory complaint
  • Montreal Cognitive Assessment (MoCA) score of 18-26/30 or a Mini-mental state exam (MMSE) score of 24-27/30
  • autonomy for activity of daily living
  • absence of depression

Exclusion Criteria:

  • diagnosis of a major cognitive disorder
  • diseases or psychiatric disorders that could interfere with participation
  • uncontrolled diabetes (fasting plasma glucose >7 mM or glycated hemoglobin >6.5%)
  • major depression or history of alcohol or substance abuse within the past 2 years,
  • already supplementing with coconut oil or MCT
  • vitamin B12 deficiency
  • uncontrolled hypertension, dyslipidemia, or thyroid disease,
  • visual or hearing impairment impeding comprehension
  • participation in another intervention trial
  • inability to lie down without moving for 60 min (for the brain imaging)
  • presence of implanted metal objects or devices contraindicated for MRI (phase 1)

Sites / Locations

  • Research Center on Aging

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

ketogenic drink

Placebo

Arm Description

MCT ketogenic drink: ketogenic drink providing 30 g/d of MCT oil in 250 ml of lactose-free skim milk for 6 months supplementation

Lactose-free skim milk-based placebo drink containing high-oleic sunflower oil of equivalent energy value to the active arm for a 6 months supplementation

Outcomes

Primary Outcome Measures

Change in global ketone (11C-AcAc) uptake in grey matter
The change in brain ketone uptake will be quantified by PET and expressed as cerebral metabolic rate of AcAc (CMR-A)
Change in plasma ketone
The change in plasma ketone will be measure to obtain a ketone chronic response

Secondary Outcome Measures

Change in global brain FDG uptake in grey matter (CMR-G)
The change in brain glucose uptake will be quantified by PET and expressed as cerebral metabolic rate of glucose (CMR-G)
Change in regional CMR-A
The change in brain ketone uptake will be quantified by PET in different regions of the brain
regional brain volumes by vMRI
Change in brain volume measure by MRI
Change in cognitive status - episodic memory
Change in episodic memory assessed by the 16-item free/cued word learning (Buschke and Grober test- Z score of trial 1, 2, 3 and delay) and the Brief Visuospatial Memory Test-revised (Z score of trial 1)
Change in cognitive status- language domain
Change in language assessed by Boston Naming Test (Z score)
Change in cognitive status - executive function
Change in executive function assessed by condition 4 of the trail making test, condition 3 and 4 of the Stroop test and the 4 conditions of verbal fluency test (all Z score)
Change in cognitive status - processing speed
Change in processing speed assessed by global score of Digit Span (WAIS III), Digit Symbol (WAIS III), condition 1 and 2 of Stroop test and condition 1,2,3,5 of the trail making test (all Z score)
Blood metabolite profile triglycerides
Changes in Triglycerides (mM)
Blood metabolite profile Glucose
Changes in Glucose (mM)
Blood metabolite profile cholesterol
Changes in Total cholesterol (mM)
Derived cerebral metabolic rate of total ketones
Cerebral metabolic rate of total ketone derived from ketone PET (dCMRket, μmol/100 g/min)
Pharmacokinetic ketone response (phase 2)
Area under the curve of pharmacokinetic of blood ketone

Full Information

First Posted
September 15, 2015
Last Updated
March 24, 2020
Sponsor
Université de Sherbrooke
Collaborators
Alzheimer's Association
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1. Study Identification

Unique Protocol Identification Number
NCT02551419
Brief Title
Proof of Mechanism of a New Ketogenic Supplement Using Dual Tracer PET (Positron Emission Tomography)
Acronym
BENEFIC
Official Title
Effect of a Ketogenic Supplement on Brain Energy Metabolism Measured by Neuroimaging in Mild Cognitive Impairment
Study Type
Interventional

2. Study Status

Record Verification Date
November 2019
Overall Recruitment Status
Completed
Study Start Date
June 2015 (Actual)
Primary Completion Date
December 2019 (Actual)
Study Completion Date
December 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Université de Sherbrooke
Collaborators
Alzheimer's Association

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
A six month, placebo-controlled, parallel group project in which MCI participants will receive 30 g/day of a custom-made MCT-based ketogenic supplement or a matching placebo. Uptake of both the brain's fuels - ketones (as 11C-AcAc) and glucose (as FDG) - both before and after the intervention will be assessed by PET (position emission tomography) ; imaging and ketone pharmacokinetic as primary objective as well as fMRI, diffusion MRI and cognition.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Mild Cognitive Impairment
Keywords
mild cognitive impairment, ketones, medium chain triglycerides, Positron emission tomography, magnetic resonance imaging, cognition, brain, neuroimaging

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
82 (Actual)

8. Arms, Groups, and Interventions

Arm Title
ketogenic drink
Arm Type
Experimental
Arm Description
MCT ketogenic drink: ketogenic drink providing 30 g/d of MCT oil in 250 ml of lactose-free skim milk for 6 months supplementation
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Lactose-free skim milk-based placebo drink containing high-oleic sunflower oil of equivalent energy value to the active arm for a 6 months supplementation
Intervention Type
Dietary Supplement
Intervention Name(s)
ketogenic drink
Intervention Description
6 months' supplementation with the ketogenic drink . Product will be taken daily - 125 ml will be consumed at the morning meal, and 125 ml at the evening meal.
Intervention Type
Dietary Supplement
Intervention Name(s)
placebo
Intervention Description
6 months' supplementation with the placebo drink . Product will be taken daily - 125 ml will be consumed at the morning meal, and 125 ml at the
Primary Outcome Measure Information:
Title
Change in global ketone (11C-AcAc) uptake in grey matter
Description
The change in brain ketone uptake will be quantified by PET and expressed as cerebral metabolic rate of AcAc (CMR-A)
Time Frame
Baseline and 6 months of intervention
Title
Change in plasma ketone
Description
The change in plasma ketone will be measure to obtain a ketone chronic response
Time Frame
Baseline and 6 months of intervention
Secondary Outcome Measure Information:
Title
Change in global brain FDG uptake in grey matter (CMR-G)
Description
The change in brain glucose uptake will be quantified by PET and expressed as cerebral metabolic rate of glucose (CMR-G)
Time Frame
Baseline and 6 months of intervention
Title
Change in regional CMR-A
Description
The change in brain ketone uptake will be quantified by PET in different regions of the brain
Time Frame
Baseline and 6 months of intervention
Title
regional brain volumes by vMRI
Description
Change in brain volume measure by MRI
Time Frame
Baseline and 6 months of intervention
Title
Change in cognitive status - episodic memory
Description
Change in episodic memory assessed by the 16-item free/cued word learning (Buschke and Grober test- Z score of trial 1, 2, 3 and delay) and the Brief Visuospatial Memory Test-revised (Z score of trial 1)
Time Frame
Baseline and 6 months of intervention
Title
Change in cognitive status- language domain
Description
Change in language assessed by Boston Naming Test (Z score)
Time Frame
Baseline and 6 months of intervention
Title
Change in cognitive status - executive function
Description
Change in executive function assessed by condition 4 of the trail making test, condition 3 and 4 of the Stroop test and the 4 conditions of verbal fluency test (all Z score)
Time Frame
Baseline and 6 months of intervention
Title
Change in cognitive status - processing speed
Description
Change in processing speed assessed by global score of Digit Span (WAIS III), Digit Symbol (WAIS III), condition 1 and 2 of Stroop test and condition 1,2,3,5 of the trail making test (all Z score)
Time Frame
Baseline and 6 months of intervention
Title
Blood metabolite profile triglycerides
Description
Changes in Triglycerides (mM)
Time Frame
Baseline and 6 months of intervention
Title
Blood metabolite profile Glucose
Description
Changes in Glucose (mM)
Time Frame
Baseline and 6 months of intervention
Title
Blood metabolite profile cholesterol
Description
Changes in Total cholesterol (mM)
Time Frame
Baseline and 6 months of intervention
Title
Derived cerebral metabolic rate of total ketones
Description
Cerebral metabolic rate of total ketone derived from ketone PET (dCMRket, μmol/100 g/min)
Time Frame
Baseline and 6 months of intervention
Title
Pharmacokinetic ketone response (phase 2)
Description
Area under the curve of pharmacokinetic of blood ketone
Time Frame
Baseline and 6 months of intervention

10. Eligibility

Sex
All
Minimum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: subjective memory complaint Montreal Cognitive Assessment (MoCA) score of 18-26/30 or a Mini-mental state exam (MMSE) score of 24-27/30 autonomy for activity of daily living absence of depression Exclusion Criteria: diagnosis of a major cognitive disorder diseases or psychiatric disorders that could interfere with participation uncontrolled diabetes (fasting plasma glucose >7 mM or glycated hemoglobin >6.5%) major depression or history of alcohol or substance abuse within the past 2 years, already supplementing with coconut oil or MCT vitamin B12 deficiency uncontrolled hypertension, dyslipidemia, or thyroid disease, visual or hearing impairment impeding comprehension participation in another intervention trial inability to lie down without moving for 60 min (for the brain imaging) presence of implanted metal objects or devices contraindicated for MRI (phase 1)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Stephen Cunnane, Ph.D.
Organizational Affiliation
Université de Sherbrooke
Official's Role
Principal Investigator
Facility Information:
Facility Name
Research Center on Aging
City
Sherbrooke
State/Province
Quebec
ZIP/Postal Code
J1H 4C4
Country
Canada

12. IPD Sharing Statement

Citations:
PubMed Identifier
25147107
Citation
Castellano CA, Nugent S, Paquet N, Tremblay S, Bocti C, Lacombe G, Imbeault H, Turcotte E, Fulop T, Cunnane SC. Lower brain 18F-fluorodeoxyglucose uptake but normal 11C-acetoacetate metabolism in mild Alzheimer's disease dementia. J Alzheimers Dis. 2015;43(4):1343-53. doi: 10.3233/JAD-141074.
Results Reference
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PubMed Identifier
24735889
Citation
Nugent S, Castellano CA, Goffaux P, Whittingstall K, Lepage M, Paquet N, Bocti C, Fulop T, Cunnane SC. Glucose hypometabolism is highly localized, but lower cortical thickness and brain atrophy are widespread in cognitively normal older adults. Am J Physiol Endocrinol Metab. 2014 Jun 1;306(11):E1315-21. doi: 10.1152/ajpendo.00067.2014. Epub 2014 Apr 15.
Results Reference
background
PubMed Identifier
24388785
Citation
Nugent S, Tremblay S, Chen KW, Ayutyanont N, Roontiva A, Castellano CA, Fortier M, Roy M, Courchesne-Loyer A, Bocti C, Lepage M, Turcotte E, Fulop T, Reiman EM, Cunnane SC. Brain glucose and acetoacetate metabolism: a comparison of young and older adults. Neurobiol Aging. 2014 Jun;35(6):1386-95. doi: 10.1016/j.neurobiolaging.2013.11.027. Epub 2013 Dec 1.
Results Reference
background
PubMed Identifier
23274095
Citation
Courchesne-Loyer A, Fortier M, Tremblay-Mercier J, Chouinard-Watkins R, Roy M, Nugent S, Castellano CA, Cunnane SC. Stimulation of mild, sustained ketonemia by medium-chain triacylglycerols in healthy humans: estimated potential contribution to brain energy metabolism. Nutrition. 2013 Apr;29(4):635-40. doi: 10.1016/j.nut.2012.09.009. Epub 2012 Dec 28.
Results Reference
background
PubMed Identifier
21035308
Citation
Cunnane S, Nugent S, Roy M, Courchesne-Loyer A, Croteau E, Tremblay S, Castellano A, Pifferi F, Bocti C, Paquet N, Begdouri H, Bentourkia M, Turcotte E, Allard M, Barberger-Gateau P, Fulop T, Rapoport SI. Brain fuel metabolism, aging, and Alzheimer's disease. Nutrition. 2011 Jan;27(1):3-20. doi: 10.1016/j.nut.2010.07.021. Epub 2010 Oct 29.
Results Reference
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Proof of Mechanism of a New Ketogenic Supplement Using Dual Tracer PET (Positron Emission Tomography)

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