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MAP will be a multisite phase II/III 1:1 randomized controlled trial of long acting metformin (Glucophage XR) vs. matching placebo among 370 men and women with early and late aMCI, without diabetes, not treated with metformin, overweight or obese, aged 55 years to 90 years. The duration of the trial will be 24 months and will have 5 visits: baseline, 6-months, 12-months, 18-months, and 24-months. The trial will be preceded by a screening phase followed by randomization and a titration period in which long-acting metformin will be titrated from 500 mg a day (one tablet) to 2,000 mg a day (4 tablets), in increments of 500 mg (one tablet) every 10 days. During this titration period subjects will also undergo repeated cognitive testing (3 times in addition to baseline) to account for practice effects and establish a cognitive baseline. We expect the attrition rate to be 10% a year. Neuropsychological battery, clinical interviews, physical exam, and phlebotomy will be conducted at baseline and repeated every 6 months during 24 months, for a total of 5 visits. Brain MRI will be conducted in approximately half of the participants (186). The baseline MRI will be conducted after the end of the titration period and after the 24 months assessment. Medication compliance will be assessed every 6 months. Adverse events will be checked every month via telephone call, text, or email, or in person during the scheduled in-person assessments every six months. The primary clinical outcome of the study will be changes in the Free and Cued Selective Reminding Test. The secondary clinical outcome will be changes in the Alzheimer's Disease Cooperative Study Preclinical Alzheimer's Cognitive Composite. Secondary subclinical outcomes will be changes in hippocampal volume and white matter hyperintensity volume. The data coordinating center and Imaging Core will be located at John Hopkins University. The Clinical Coordinating and Monitoring Center and the central laboratory will be located at Columbia. The Research pharmacy function will be shared by the University of Rochester, which will dispense randomization kits, and the University of Iowa, which will receive bulk metformin and identical matching placebo from EMD Serono.
STUDY PROCEDURES AT THE LEVEL OF THE PARTICIPANT.
1. Screening. We propose a 2-tier approach for screening, including telephone pre-screening followed by in-person screening. Telephone screening includes questions about inclusion and exclusion criteria including demographics (age, language), medical history, contraindications to metformin, and medications. At the time of telephone contact for screening, we will conduct the Telephone Interview for Cognitive Status (TICS) if the potential participant agrees, as was conducted in the MetMCI study. A Score > 34 on the TICS out of 41 is considered normal cognition. Persons with this score will not be invited to participate. Only persons that meet inclusion criteria and do not meet exclusion criteria are invited for in-person screening. In-person screening includes consent, in-person anthropometric measurements (height, weight, waist and hip circumference), vital signs (blood pressure and heart rate), EKG, laboratory tests (TSH, RPR, vitamin B12, complete blood count [CBC], basic metabolic panel [BMP], Hepatic panel, Lipid panel, and Hemoglobin A1c [HbA1c]), and the in person-neuropsychological battery that is used to determine aMCI. At the time of screening the tester may choose to complete other assessments that would be scheduled for the first visit; otherwise, these assessments will be done in the baseline visit.
2. Baseline/screening study visit. The baseline study visit will include the following assessments.
History includes age, handedness, education, occupation and employment history, past medical history, and all medications utilized, including a judgment as to whether they affect cognition (positively or negatively). Referral source is also documented. Psychiatric history, current and past history of depression, current anxiety, alcohol and other substance use, head injury, hypertension, cardiac disease, thyroid disease, other major medical conditions, and surgery are evaluated at screening. A full medical history will be obtained only at screening. Any report of events, or side effects will prompt a full history and physical exam at any visit.
Physical exam will be conducted at screening, with particular emphasis on signs of congestive heart failure, pulmonary, liver, or renal disease for contraindications to metformin, and neurologic examination for the presence of neurologic diseases. Vital signs including blood pressure and heart rate will also be ascertained. Standing height will be measured using a stadiometer calibrated in cm. Body weight is measured using a balance beam scale calibrated in kg. With the participant standing, measurements are taken to the nearest 0.1 kg of weight with a balance scale and height without shoes to nearest 0.5 cm, to calculate BMI (weight in k/height in m2). Waist circumference (WC) is measured at the level of the umbilicus. Hip circumference (HP) is measured at the level of maximal protrusion of the gluteal muscles. Resting Blood Pressure (BP) will be measured using an automated oscillometric device, 3 measurements will be obtained at 1-minute intervals in a seated position after 5 minutes of rest. The average of the 2nd and 3rd measurements will be recorded.
Neuropsychological battery. For neuropsychological testing verbatim instructions for administration and specific scoring guidelines will be available. All tests are validated in English and Spanish. We will use different versions of the tests when available (e.g. different word lists) to account for learning effects. The following is an expanded description of the neuropsychological battery:
Total Recall Score of the Free and Cued Selective Reminding Test (FCSRT). The FCSRT is a 16 item word list with visual and auditory presentation that uses semantic cuing to facilitate encoding and retrieval. The test has a score range of 0 to 48.
Paragraph Recall on the Logical Memory IIa (episodic memory): Free recall of 1 short story that consists of 25 bits of information will be elicited immediately after it is read aloud to the subject and again after approximately 30-minute delay. The total bits of information from the story that are recalled immediately (maximum score = 25) and after the delay interval (maximum score = 25) are recorded. The delay score (0-25 story units) will be used in the composite.
Digit-Symbol Substitution Test: The Digit Symbol Substitution test is a subset from the WAIS-R. The test consists of 110 small blank squares presented in 7 rows with 1 of 9 numbers (1-9) randomly printed directly above each blank square. A "key" is printed above the rows of blank squares. The "key" pairs numbers 1 through 9 with an unfamiliar symbol. The subject must work as fast as possible for 90 seconds. The measure of interest is number of squares filled in correctly within the time limit (maximum raw score = 110).
Mini Mental Status Exam (MMSE). The MMSE scale evaluates orientation, memory, attention, concentration, naming, repetition, comprehension, and ability to create a sentence and to copy 2 overlapping pentagons. The MMSE is scored as the number of correctly completed items with a lower score indicative of poorer performance and greater cognitive impairment. The total score ranges from 0 (worse) to 30 (perfect).
Trail-Making Test, Part A: This test of visuoperceptual ability, attention and speed consists of 25 circles distributed over a white sheet of 8 1/2" X 11" paper that are numbered. The participant is instructed to connect the circles with a pencil line as quickly as possible all numbers in an ascending order (e.g., 1 to 2; 2 to 3; etc). The participant's performance is judged in terms of the time (in seconds) required to complete the task and by the number of errors of commission and omission. The time to complete the trial will be the measures of interest.
Trail-Making Test, Part B: This test of visuoperceptual ability, attention and set-shifting ability consists of 25 circles distributed over a white sheet of 8 1/2" X 11" paper that are either numbered (1 through 13) or contain letters (A through L). The participant is instructed to connect the circles with a pencil line as quickly as possible while alternating between numbers and letters in an ascending order (e.g., A to 1; 1 to B; B to 2; 2 to C). The participant's performance is judged in terms of the time (in seconds) required to complete the task and by the number of errors of commission and omission. The time to complete the trial will be the measures of interest. Trail-Making Test, Part B is available in multiple forms of equal difficulty for purposes of repeated evaluations.
ADAScog12. This test will be used as part of the core battery and assesses memory, reasoning, naming, orientation, ideational praxis, constructional praxis, spoken language, language comprehension, word finding difficulty, and ability to remember test instructions. The addition of a 10 word delay recall adds sensitivity in aMCI and yields maximum score of 80.
Functional abilities: ADCS-ADL-PI:The ADCS-ADL-PI was developed in the ADCS Prevention Instruments Trial. The subject rates his/her performance of 18 IADL tasks over the past 2 months. Questions about use of technology (e.g., computers and cell phones) are included. Responses for each IADL include improved IADL performance (fewer errors, faster completion, less need to refer to notes or instructions), no change ('as well as usual'), various levels of impaired performance, and non-performance. Clinical Dementia Rating (CDR). The CDR is a clinical scale that rates the severity of dementia as absent, questionable, mild, moderate, or severe (CDR score of 0, 0.5, 1, 2, or 3, respectively). The score is based on interviews with the subject and study partner, using a structured interview that assesses 6 domains: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. The ratings of degree of impairment obtained on each of the 6 categories of function are synthesized into 1 global rating of dementia (ranging from 0 to 3), with more refined measure of change available by use of the Sum of Boxes (CDR-SB). Reliability and validity has been established, as has high inter-rater reliability.
Memory Complaint Questionnaire (MAC-Q): The MAC-Q consists of six items. The first five items relate to specific situations that are frequently reported as troublesome for those with declining memory, and the last item broadly measures overall self-perceived memory decline.
Cognitive diagnoses. The research physician will complete the National Alzheimer's Coordinating Centers (NACC) Assessment and Uniform Data Set (UDS), which takes 35 minutes and includes detailed medical and family history, and neurological exam, including the Unified Parkinson's Disease Rating Scale for extrapyramidal signs, psychiatric assessment with the short version of the Geriatric Depression Scale and Neuropsychiatric Inventory (NPI) questions, assessment of vascular risk factors plus the Hachinski scale, and a Clinical Dementia Rating (CDR). Cognitive diagnosis will be examined for inclusion and exclusion purposes and will also be examined as an exploratory outcome. For cognitive diagnosis transitions (i.e. conversion from MCI to dementia), an adjudication panel at the CCMC will conduct monthly consensus meetings or calls. This panel will be comprised of co-investigators Luchsinger, Goldberg, Devanand, Manly, and Brickman. During the meeting information of all the cognitive, functional and other clinical information of the subjects will be presented, blind to study allocation. Evidence of cognitive deficits (based on the neuropsychological scores), evidence of impairment in social or occupational function (as assessed by the functional measures), and evidence of cognitive and social-occupational function decline will be the criteria used for the diagnosis of dementia.
3. Randomization. Eligible participants will be randomized in 1:1 ratio to receive either metformin or placebo, using randomly permuted block randomization of size two or four by each site to achieve balance of treatment assignment overall and by site. The distribution of kits of active metformin or placebo were previously described.
4. Titration and repeated neuropsychological testing. After participants consent, are deemed eligible, and complete the baseline assessment, they will complete a 30-day titration period in which the metformin dose will be increased from 500 mg a day at randomization in increments of 500 mg every 10 days to a maximum of 2,000 mg a day. The metformin tablets are taken together as a single dose, usually recommended once at night. Participants unable to tolerate at least 1,000 mg a day will be excluded from the study. Participants will have in person visits every 10 days to check on their metformin tolerance and to conduct repeated neuropsychological testing. During this titration period, participants will have repeated cognitive tests at day 10, 20, and 30 after randomization.
5. Baseline Brain MRI. Participants who remain in the study after titration be invited to have a baseline brain MRI without contrast. We expect that approximately half of participants will be willing to do MRI and will not have contraindications, based on our current experience at Columbia. Brain Magnetic Resonance Imaging (MRI) with 3T magnets will be conducted in 186 participants across all sites. MRI sequences will include 3Plane Gradient Echo Localizer, 3D MPRAGE T1 (Morphological), 3D T2 (Morphological), DTI 30 direction (anisotropy, mean diffusivity), DTI 30 direction (anisotropy, mean diffusivity), pCASL Axial(Arterial Spin Labeling/CBF), pCASL Axial Calibration. Acquisition of these sequences will take approximately 50 minutes.
6. Monthly and ad-lib follow-up calls, text messages, or mails. We will conduct monthly follow-up calls to inquire about adverse events and issues with metformin tolerance. We will prefer voice calls, but will provide the options to participants of receiving and replying to text messages or emails. We will encourage participants to communicate with the site staff ad-lib in case of contingencies, comments, or questions. We will use the ADCS Adverse Event Checklist to monitor adverse events. In this case we will emphasize potential adverse effects of metformin such as gastrointestinal side effects (e.g. diarrhea), and development of contraindications (class III or IV congestive heart failure, renal insufficiency, hepatic insufficiency). We will also inquire about potential situations in which metformin needs to be held temporarily such as surgery and the administration of intravenous contrast.
7. Follow-up visits: We will repeat all clinical (non-brain imaging) assessments at months 6, 12, 18, and 24. The only exception is that we will test TSH and RPR only at baseline. All other laboratory tests will be repeated. Pill counts will be conducted to assess compliance with metformin and placebo. In addition, we will administer the adverse events checklist. All remaining study drug or placebo will be retrieved to assess compliance and for disposal.
8. Follow-up Brain MRI. Participants who undergo a baseline MRI will be invited to have a follow-up brain MRI with the same sequences after the completion of the last visit at month 24. The MRI will be completed within one month of the last visit.
Amnestic Mild Cognitive Impairment (aMCI)
Placebo oral tablet, extended release metformin
District of Columbia
Not yet recruiting
Published on BioPortfolio: 2019-09-26T05:42:37-0400
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