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| Name | Class |
|---|---|
| Mars, Inc. | INDUSTRY |
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to assess the effect of differing amounts of a cocoa-derived dietary flavanol (epicatechin ) on dentate gyrus function and corresponding cognitive function
In this double blinded trial, the participants, age 50-75 years, will be randomized to receive 0, 260, 510, or 770 mg daily* for 12 weeks and will be tested before and after the intervention. Cognitive testing will be conducted prior to randomization, and at weeks 4, 12, and 20 of the study.
In an optional substudy, fMRI (functional magnetic resonance imaging) with gadolinium contrast will be conducted to measure dentate gyrus function before randomization and then after completion of the 12-week intervention portion of the trial.
*see note in Record Log regarding the change in the method of assessment of cocoa flavanol content of the capsules
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| F 0 mg | Placebo Comparator | daily consumption of capsules containing 0 mg cocoa flavanol for 12 weeks |
|
| F 260 mg | Active Comparator | daily consumption of capsules containing 260 mg* cocoa flavanol for 12 weeks *see note in Record Log regarding the change in the method of assessment of cocoa flavanol content of the capsules |
|
| F 510 mg | Active Comparator | daily consumption of capsules containing 510 mg cocoa flavanol for 12 weeks |
|
| F 770 mg | Active Comparator | daily consumption of capsules containing 770 mg cocoa flavanol for 12 weeks |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Cocoa Flavanol | Dietary Supplement | 12 weeks administration of cocoa flavanol |
|
| Measure | Description | Time Frame |
|---|---|---|
| Modified Benton Recognition Task (ModBent) | The ModBent task is divided into two parts. During the matching trials (top), participants were shown a complex stimulus for 10 s. Following a 1-s inter-trial interval, they were required to select, via a key press, which of two stimuli matched the one they had just studied, as quickly and as accurately as possible. Following 41 matching trials, participants were shown a series of 82 stimuli (bottom), 41 of which appeared on the initial study set during the matching trials and 41 of which were foils. They were required to indicate, as quickly as possible, whether each stimulus appeared earlier (yes response) or was new (no response). The primary variable of the ModBent task is the mean RT for correct rejections of foils during the recognition trials | baseline and 12 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Dentate Gyrus Cerebral Blood Volume | measured in functional MRI. we generated high-resolution CBV brain maps using gadolinium-enhanced T1-weighted scans acquired perpendicular to the hippocampal long-axis, with sub-millimeter in-plane resolution of 0.68 × 0.68 mm and slice thickness of 3 mm. To perform group-wise voxel-based analyses on the whole hippocampal circuit, we first isolated hippocampal subfields using FreeSurfer segmentations and thresholded posterior probabilities to generate a composite mask of the bilateral hippocampal formation. These masked T1-weighted images were then used to generate a group-wise template to which individual images were co-registered using a diffeomorphic technique that maximizes cross-correlation among images. |
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Inclusion Criteria:
1. Signed and dated informed consent obtained before any trial-related activities. (Trial-related activities are any procedure that would not have been performed during normal management of the subject). Telephone Screen
2. Healthy Male or Female subjects. (Females must be post-menopausal) Telephone Screen
3. Age between 50 and 75 years, both inclusive. Telephone Screen
4. Body mass index between 18.0 and 35 kg/m², both inclusive. Telephone Screen
Exclusion Criteria:
Currently undergoing medical treatment, including prescription drugs/medication. Medical History Interview
Clinically significant abnormal hematology, biochemistry, urinalysis, or coagulation screening tests, as judged by the Investigator. Medical History Interview
History or presence of cancer (except basal cell skin cancer or squamous cell skin cancer), or any clinically significant cardiovascular, respiratory, metabolic, renal, hepatic, gastrointestinal, endocrinological (with the exception euthyroid struma), haematological, dermatological, venereal, neurological, psychiatric diseases or other major disorders as judged by the Investigator. Medical History Interview
Seated blood pressure at screening (after resting for 5 min in seated position) outside the range of 90-140 mmHg for systolic or 50-90 mmHg for diastolic (excluding white-coat hypertension; therefore, if a repeated measurement shows values within the range, the subject can be included in the trial) and/or resting supine heart rate outside the range 50-90 beats per minute. Measurement taken at consent before eligibility is determined
Current Depression or Anxiety Symptoms using PHQ-8 (eight-item Patient Health Questionnaire depression scale) and GAD-7 (Generalized Anxiety Disorder 7-item scale). PHQ-8 score >= 10 and/or GAD-7 score >= 10 are excluded.
(Past history of disorders not exclusionary). Interview
Currently taking SSRI (selective serotonin reuptake inhibitor) medications for any reason. Interview
Heart Diseases. Medical History Interview
Hepatitis B or C positive status. Medical History Interview
HIV positive status. Medical History Interview
History of multiple and/or severe allergies to drugs or foods or a history of severe anaphylactic reaction. Medical History Interview
Use of non-prescription medication, herbal products or nutritional supplements during the study, and within the last 4 weeks before the start of the study (screening), as judged by the Investigator; occasional use of aspirin, ibuprofen, acetaminophen is permitted. Interview
Adherence to a vegan or vegetarian diet or to specialty/uncommon diets. Interview
Food Allergies to tree nuts, soy, cocoa and cocoa-containing products. Interview
People who choose to avoid caffeine intake. Interview
Current or history of alcoholism or drug/chemical abuse as per Investigator's judgment. Medical History Interview
Hormone Replacement Therapy; Currently pregnant; Pregnant or lactating within past 6 mos; Hormonal birth control (pill). Interview
Smoking. Interview
Unwilling to have blood drawn or anxiety/nausea during a blood draw. Interview.
Uncomfortable completing memory and attention tasks in the English language. Interview
MoCA (Montreal Cognitive Assessment) score less than 26. Montreal Cognitive Assessment
Inability to swallow study capsules. Interview (at consent).
Did not complete the two weeks Run-In Period (Participants who missed more than 2 intake occasions out of 14 days (28 occasions total) or if there are > 8 capsules left in the bottle after the two weeks will be excluded). Run-In Period.
MRI RELATED
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| Name | Affiliation | Role |
|---|---|---|
| Scott A Small, MD | Columbia University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Columbia University Medical Center | New York | New York | 10032 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 25344629 | Background | Brickman AM, Khan UA, Provenzano FA, Yeung LK, Suzuki W, Schroeter H, Wall M, Sloan RP, Small SA. Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults. Nat Neurosci. 2014 Dec;17(12):1798-803. doi: 10.1038/nn.3850. Epub 2014 Oct 26. | |
| 31932823 | Background | Bussy U , May BR , Olanrewaju Y , Hewitt G , Anderson N , Crozier A , Ottaviani JI , Kwik-Uribe C . Reliable, accessible and transferable method for the quantification of flavanols and procyanidins in foodstuffs and dietary supplements. Food Funct. 2020 Jan 29;11(1):131-138. doi: 10.1039/c9fo02762a. |
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first consent; 1/13/2016 Final data collection session: 11/21/2018
All data collected at Columbia University Medical Center
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| ID | Title | Description |
|---|---|---|
| FG000 | 0 mg Cocoa Flavanol | daily consumption of capsules containing 0 mg cocoa flavanol for 12 weeks |
| FG001 | 260 mg Cocoa Flavanol | daily consumption of capsules containing 260 mg cocoa flavanol for 12 weeks; |
| FG002 | 510 mg Cocoa Flavanol | daily consumption of capsules containing 510 mg cocoa flavanol for 12 weeks; |
| FG003 | 770 mg Cocoa Flavanol | daily consumption of capsules containing 770 mg cocoa flavanol for 12 weeks; |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 0 mg | daily consumption of capsules containing 0 mg cocoa flavanol for 12 weeks |
| BG001 | 260 mg | daily consumption of capsules containing 260 mg cocoa flavanol for 12 weeks; |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Modified Benton Recognition Task (ModBent) | The ModBent task is divided into two parts. During the matching trials (top), participants were shown a complex stimulus for 10 s. Following a 1-s inter-trial interval, they were required to select, via a key press, which of two stimuli matched the one they had just studied, as quickly and as accurately as possible. Following 41 matching trials, participants were shown a series of 82 stimuli (bottom), 41 of which appeared on the initial study set during the matching trials and 41 of which were foils. They were required to indicate, as quickly as possible, whether each stimulus appeared earlier (yes response) or was new (no response). The primary variable of the ModBent task is the mean RT for correct rejections of foils during the recognition trials | Posted | Mean | Standard Deviation | ms | baseline and 12 weeks |
|
adverse events were monitored each week throughout the study and for the MRI substudy, at each of the two MRI sessions
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 0 mg Cocoa Flavanol | daily consumption of capsules containing 0 mg cocoa flavanol for 12 weeks |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Scott A. Small, MD | Columbia University Medical Center | 212-305-1269 | sas68@columbia.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_ICF | Yes | No | Yes | Study Protocol and Informed Consent Form | Dec 17, 2019 | Jan 31, 2020 | Prot_ICF_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Oct 23, 2019 | Feb 3, 2020 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D008569 | Memory Disorders |
| ID | Term |
|---|---|
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
| D012816 | Signs and Symptoms |
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| baseline and 12 weeks |
| Modified Benton Recognition Task (ModBent) | The ModBent task is divided into two parts. During the matching trials (top), participants were shown a complex stimulus for 10 s. Following a 1-s inter-trial interval, they were required to select, via a key press, which of two stimuli matched the one they had just studied, as quickly and as accurately as possible. Following 41 matching trials, participants were shown a series of 82 stimuli (bottom), 41 of which appeared on the initial study set during the matching trials and 41 of which were foils. They were required to indicate, as quickly as possible, whether each stimulus appeared earlier (yes response) or was new (no response). The primary variable of the ModBent task is the mean RT for correct rejections of foils during the recognition trials | 20 weeks |
| Modified Rey Auditory Verbal Learning Test | In learning Trials 1 to 3 the participant is read 20 unique, semantically/phonemically unrelated words (List A) and is to free recall those words after each trial. Next the participant is read a list of 20 unique words (List B) and is to recall as many as possible. This trial is followed by a short delay free recall trial: the participant is to recall as many words as possible from List A. After a 1.5-hour, the participant is asked to long delay free recall words from List A and then from List B. This is followed by a 66-item forced recognition trial: the participant is read a list of 66 words and asked to distinguish List A words from semantic and phonemic distractors, including words from List B. Finally, a source memory trial is administered: the examiner serially reads words from List A and B. The participant is to specify from which list each word came.Higher score indicates better performance. score ranges from 0 to 60. | Baseline and 12 Weeks |
| NIH Toolbox Cognition Battery (NIHTB-CB): The List Sorting Test | Participants are presented with a series of stimuli, each of which is both visually and auditorily presented by computer. A picture of each stimulus is displayed on the computer monitor for 2 seconds while the name of the stimulus is simultaneously being read via a computerized voice; stimuli are presented one after another. The participant must remember each stimulus in a series, mentally reorder them from smallest to largest, and recite the names of the stimuli in this order. List Sorting scores are based upon Total Score. Higher score indicated better performance.Score ranges from 0-100. | Baseline and 12 Weeks |
| 29959422 | Background | Ottaviani JI, Fong R, Kimball J, Ensunsa JL, Britten A, Lucarelli D, Luben R, Grace PB, Mawson DH, Tym A, Wierzbicki A, Khaw KT, Schroeter H, Kuhnle GGC. Evaluation at scale of microbiome-derived metabolites as biomarker of flavan-3-ol intake in epidemiological studies. Sci Rep. 2018 Jun 29;8(1):9859. doi: 10.1038/s41598-018-28333-w. |
| BG002 | 510 mg | daily consumption of capsules containing 510 mg cocoa flavanol for 12 weeks; |
| BG003 | 770 mg | daily consumption of capsules containing 770 mg cocoa flavanol for 12 weeks; |
| BG004 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants | No |
|
| alternative Healthy Eating Index (aHEI) | We used the Block 2005 food frequency questionnaire (FFQ) (NutritionQuest, Berkeley CA) to estimate customary dietary intake. The food list for this questionnaire was developed from the NHANES III dietary recall data. The nutrient database was developed from the USDA (United States Department of Agriculture) Nutrient Database for Standard Reference. Individual portion size was measured using pictures provided. From these data, we computed the alternative Healthy Eating Index (aHEI). The total aHEI score ranged from 0 (nonadherence) to 110 (perfect adherence). | Mean | Standard Deviation | units on a scale |
|
| 5-(3',4'-dihydroxyphenyl)-γ-valerolactone (gVLM) | gVLM is a nutritional biomarker of flavan-3-ol intake. Detection was achieved with a Waters Quattro Micromass spectrometer fitted with an electrospray interface (ESI; Waters). MS analysis was carried out in negative ionization mode by multiple reaction monitoring (MRM). Detection of gVL-3'-sulphate and -3'-O- glucuronide utilized transitions from 287 m/z to 207 m/z and 383 m/z to 207 m/z, respectively, and both with a dwell time of 0.02 s, a cone voltage of 32 V, and a collision energy of 20 V. | Mean | Standard Deviation | nM |
|
| OG001 | 260 mg Cocoa Flavanol | daily consumption of capsules containing 260 mg cocoa flavanol for 12 weeks; |
| OG002 | 510 mg Cocoa Flavanol | daily consumption of capsules containing 510 mg cocoa flavanol for 12 weeks; |
| OG003 | 770 mg Cocoa Flavanol | daily consumption of capsules containing 770 mg cocoa flavanol for 12 weeks; |
|
|
|
| Secondary | Dentate Gyrus Cerebral Blood Volume | measured in functional MRI. we generated high-resolution CBV brain maps using gadolinium-enhanced T1-weighted scans acquired perpendicular to the hippocampal long-axis, with sub-millimeter in-plane resolution of 0.68 × 0.68 mm and slice thickness of 3 mm. To perform group-wise voxel-based analyses on the whole hippocampal circuit, we first isolated hippocampal subfields using FreeSurfer segmentations and thresholded posterior probabilities to generate a composite mask of the bilateral hippocampal formation. These masked T1-weighted images were then used to generate a group-wise template to which individual images were co-registered using a diffeomorphic technique that maximizes cross-correlation among images. | Posted | Mean | Standard Deviation | % cerebral blood volume | baseline and 12 weeks |
|
|
|
| Secondary | Modified Benton Recognition Task (ModBent) | The ModBent task is divided into two parts. During the matching trials (top), participants were shown a complex stimulus for 10 s. Following a 1-s inter-trial interval, they were required to select, via a key press, which of two stimuli matched the one they had just studied, as quickly and as accurately as possible. Following 41 matching trials, participants were shown a series of 82 stimuli (bottom), 41 of which appeared on the initial study set during the matching trials and 41 of which were foils. They were required to indicate, as quickly as possible, whether each stimulus appeared earlier (yes response) or was new (no response). The primary variable of the ModBent task is the mean RT for correct rejections of foils during the recognition trials | Posted | Mean | Standard Deviation | ms | 20 weeks |
|
|
|
| Secondary | Modified Rey Auditory Verbal Learning Test | In learning Trials 1 to 3 the participant is read 20 unique, semantically/phonemically unrelated words (List A) and is to free recall those words after each trial. Next the participant is read a list of 20 unique words (List B) and is to recall as many as possible. This trial is followed by a short delay free recall trial: the participant is to recall as many words as possible from List A. After a 1.5-hour, the participant is asked to long delay free recall words from List A and then from List B. This is followed by a 66-item forced recognition trial: the participant is read a list of 66 words and asked to distinguish List A words from semantic and phonemic distractors, including words from List B. Finally, a source memory trial is administered: the examiner serially reads words from List A and B. The participant is to specify from which list each word came.Higher score indicates better performance. score ranges from 0 to 60. | Posted | Mean | Standard Deviation | units on a scale | Baseline and 12 Weeks |
|
|
|
| Secondary | NIH Toolbox Cognition Battery (NIHTB-CB): The List Sorting Test | Participants are presented with a series of stimuli, each of which is both visually and auditorily presented by computer. A picture of each stimulus is displayed on the computer monitor for 2 seconds while the name of the stimulus is simultaneously being read via a computerized voice; stimuli are presented one after another. The participant must remember each stimulus in a series, mentally reorder them from smallest to largest, and recite the names of the stimuli in this order. List Sorting scores are based upon Total Score. Higher score indicated better performance.Score ranges from 0-100. | Posted | Mean | Standard Deviation | units on a scale | Baseline and 12 Weeks |
|
|
|
| 0 |
| 53 |
| 0 |
| 53 |
| 0 |
| 53 |
| EG001 | 260 mg Cocoa Flavanol | daily consumption of capsules containing 260 mg cocoa flavanol for 12 weeks; | 0 | 53 | 0 | 53 | 0 | 53 |
| EG002 | 510 mg Cocoa Flavanol | daily consumption of capsules containing 510 mg cocoa flavanol for 12 weeks; | 0 | 53 | 0 | 53 | 0 | 53 |
| EG003 | 770 mg Cocoa Flavanol | daily consumption of capsules containing 770 mg cocoa flavanol for 12 weeks; | 0 | 52 | 0 | 52 | 0 | 52 |
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| D013568 | Pathological Conditions, Signs and Symptoms |
| 12 Weeks |
|
| 12 Weeks |
|
| 12 Weeks |
|