ACCORD-Memory IN Diabetes (MIND) Sub-study
I.
Study Overview
The primary aim of this study is to test whether the rate of cognitive decline and
structural brain change in people with diabetes treated with standard care guidelines is
different than in people with diabetes treated with intensive care guidelines. This
comparison will be made in a sub-sample of 2800 people with diabetes participating in
the already funded National Heart Lung and Blood Institute (NHLBI) randomized factorial
clinical trial Action to Control Cardiovascular Risk in Diabetes (ACCORD).
II.
Background
Type 2 diabetes and cognitive impairment are two of the most common chronic
conditions found in persons 60 years and older. Approximately 18%-20% of older
persons suffer from diabetes. And, in the general population, the prevalence of cognitive
impairment, measured with the simple Mini-Mental State Exam, increases steadily from
5% at 65 years to 15% percent at 80 years of age. Many persons with cognitive
impairment go on to develop dementia, which doubles in incidence and prevalence
every additional 5 years of age. Studies suggest diabetes is one risk factor for cognitive
impairment and dementia.
Further, the brains of people with diabetes are at risk for adverse sequelae
following repeated hypoglycemic events. Magnetic Resonance Imaging (MRI) provides a
measure of the structural changes in the brain that form the anatomical substrate for
cognitive decline and dementia. At present there are a few MRI studies showing people
with diabetes have increased risk for brain atrophy and (mainly silent) lacunae.
A. Need for Proposed Randomized Trial
To date there are no randomized trials of long-term glycemic control,
cognitive function, and structural brain changes in people with type 2 diabetes, let
alone trials in older patients who are at the greatest risk for cognitive decline.
The NHLBI-funded ACCORD trial is an ideal vehicle and unique opportunity
to investigate the relationship between diabetes, treatment intensity, and cognition in
this population. Data on the possible beneficial/adverse effects of treatment on
cognitive function will be generated. There is also an added benefit to ACCORD if
cognitive tests are included because they may provide important insights into why
some persons with type 2 diabetes develop difficulties in compliance with and
management of their treatment regimen and can provide important safety data in
regards to the effects of hypoglycemia which may be more frequent and severe on
average in those randomized to intensive glucose management. In addition, the MRI
data can be used to estimate the effect of treatment on “subclinical” cerebrovascular
endpoints that may not be detected by study personnel and clinicians.
III.
Study Hypotheses and Aims
A. Cognitive Decline
Primary hypothesis: Over a four year period, compared to the standard
glycemic treatment group, the rate of decline in tests of memory and executive
function will be less in the intensively treated group.
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1. Secondary hypothesis: Over a four year period, compared to the standard
blood pressure treatment group, the rate of decline in tests of memory and
executive function will be less in the intensively treated group.
2. Secondary hypothesis: Over a four year period, compared to the standard
lipid treatment group, the rate of decline in tests of memory and executive
function will be less in the intensively treated group.
The cognitive sub-study will be based on all eight cells in the ACCORD trial.
B. MRI Brain Changes
1. Primary hypothesis: Over a four year period, compared to the standard
glycemic treatment group, total brain volume will be greater (thus less cerebral
atrophy) in the intensively treated group.
2. Secondary hypothesis: Over a four year period, compared to the standard
blood pressure group total brain volume will be greater (thus less cerebral
atrophy) in the intensively treated group.
The MRI sub-study will be conducted in the four BP/glycemic treatment cells.
C. Additional Aims
We will also address secondary questions that are particularly relevant to the
questions posed in the main trial and to physicians treating older people with
diabetes:
1. Regardless of treatment group, do the number of severe hypoglycemic events
adversely affect cognitive and MRI outcomes?
2. Are brain outcomes associated with protocol compliance and/or baseline
cognitive function?
IV.
Study Design
A. Study Population
We propose to study 2,800 subjects recruited from participants enrolled in
four of the ACCORD trial networks (Southeast, Northeast, Minnesota/Iowa, and
Northwest). Participants in this sub-study, ACCORD-MIND (Memory in
Diabetes), will have already been randomly assigned to either the intensive or
standard care glycemic arm of the ACCORD trial. They will also have been
randomized to either the blood pressure or lipid intervention arms of the
ACCORD trial as outlined in the ACCORD trial protocol.
1. Inclusion Criteria
The following should be present in all participants in the study:

Willing to participate in the average 5-year follow-up of the ACCORD
trial plus this sub-study.

At least 55 years of age.

English or Spanish is usual language.
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
Agree to identify a person who will serve as a contact for the participant .
Ideally, the contact should have frequent interaction with the participant in
order to provide data if necessary.
2. Exclusion Criteria
 Cancer diagnosed and treated within the past five years that, in the judgment
of clinical study staff, would compromise a participant’s ability to comply with
the protocol and complete the trial (exceptions could include non-melanoma
skin cancer, early-stage prostate cancer, etc.)
 Any condition that, in the judgment of clinical study staff, would preclude full
participation in the study (e.g., clinical evidence of dementia, excessive use
of alcohol, any visual or hearing impairment that could compromise
assessment of cognitive function).
B. Enrollment of Participants
1. Recruitment of Participants into the Cognition Sub-Study
a. Eligible Populations and Approaches to Recruitment
Participants will be recruited from four of the ACCORD trial networks
(Southeast, Northeast, Minnesota/Iowa, and Northwest). Each network will
contribute 6-12 field sites from which ACCORD-MIND participants will be
recruited. The ACCORD-MIND Principal Investigator for each network will
work with the field site Principal Investigators and staff, the main ACCORD
Network Principal Investigator, and the ACCORD Network Coordinators to
facilitate recruitment and implementation of the sub-study within each
network.
b. Sequence of Participant Recruitment
The ACCORD-MIND sub-study will be described to potential
participants who have consented to participate in ACCORD. They will be
given a letter and brochure introducing and describing ACCORD-MIND
which will be followed by a telephone call from a clinic staff member familiar
with ACCORD-MIND. If the participant is interested, additional time will be
allotted at their next ACCORD clinic visit to again review the cognition substudy, emphasizing the commitment to an additional 30 minutes of memory
testing every 2 years. Consent will be obtained. Study staff will then
administer the 30-minute baseline ACCORD-MIND testing. Participants will
be asked to provide the name of a contact able to answer questions about
their memory and executive function during the study if this becomes
necessary.
2. Recruitment of Participants for the MRI Sub-Study
Three of the ACCORD-MIND Networks will participate in the MRI substudy (Columbia University, Wake Forest University School of Medicine, and
University of Minnesota). Each network will have one MRI center. Recruited
participants that reside within 2 hours of the MRI scanner for the network will
be asked to participate in the MRI sub-study. Recruitment into the MRI substudy will follow similar guidelines as the recruitment into the cognitive substudy. MRI will be offered to all ACCORD-MIND participants randomized to
the blood pressure treatment arm of the main trial until the full subset of MRIscanned participants is completed (N=640). Consent for the MRI portion of
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the study will be administered at the time of the baseline appointment and the
MRI scan will be scheduled to take place within 45 days.
There are certain absolute exclusion criteria for the MRI. These will be
reviewed when the participant is recruited into the MRI study.
C. Baseline Visit
There will be a 45-day window allowed between ACCORD randomization and
the MIND baseline visit. This should allow for doing the cognition questions at the
next scheduled visit, i.e. there need not be a special visit scheduled for the
purpose of doing the memory testing.
The major goals of the baseline visit are to: 1) administer consent for the substudy; 2) fingerstick blood glucose for pre-cognitive testing performed (to avoid
testing any participant with a serum glucose < 60 mg/dl); 3) administer the
cognitive battery (a brief self-report questionnaire [4 questions] on cognitive
ability to manage diabetes, the Mini-Mental State Exam [MMSE], Digit-Symbol
Substitution Text [DSST], Rey Auditory Verbal Memory Test, the Stroop Test,
and PHQ Depression Inventory); and 4) arrange MRI testing for the
subpopulation of ACCORD-MIND participants agreeing to MRI testing.
D. Follow-up Visit Description and Schedule
The major goals of the 24- and 48-month follow-up visits are to measure
cognitive function and cognitive decline using the same measures as at baseline
evaluation and to administer the same questions as at baseline on perceived
ability to self-manage diabetes in compliance with the clinical trial study protocol.
There will be a +/- 1-month window surrounding each 24-month and 48month follow-up visit. The 24-month follow-up will be performed no earlier than
23 months after baseline and no later than 25 months after the baseline exam.
The 48-month follow-up visit will be performed no earlier than 47 months after
baseline and no later than 49 months after baseline. Participants or their contacts
will be encouraged to call the clinic anytime to address issues of concern. Clinic
staff will also schedule the follow-up MRI Scan after the 48-month visit.
E. Training and Quality Assurance of Neuropsychologic (NP) Technicians
Cognitive testing training will be conducted by the Coordinating Center (CC) at
each network site. Training includes a presentation on each test, detailed
instruction in the administration and scoring of each test, discussion of
challenges to data fidelity, direct observation of a criterion administration, and
practice administrations with feedback. Training will be provided for assessing
participants speaking either English or Spanish.
F. Ascertainment of Response Variables
1. Assessment of Cognitive Function
The cognitive test battery should measure early, subtle cognitive
changes that could progress to grossly apparent, intellectually disabling
conditions. Thus, a battery was formulated to meet several objectives: 1)
sensitivity to alterations in memory storage and retrieval, and in informationprocessing speed and executive function that appear affected by global
gray and white matter changes; 2) standardized and well-validated in the
target age groups; 3) ease of administration that would ensure reliable data
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collection across a large number of clinical sites; and 4) availability of a
comparable Spanish version.
Table 1. The Battery and Order of Administration
Domain
Global Mental
Status
Time
(min)
5
English
Spanish
Outcome Score
MMSE
Total Score
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Rey Auditory
Verbal Learning
Test
Digit Symbol
Substitution Test
(DSST)
Stroop Test
MMSE (Spanish
Version)
Spanish-English
Verbal Learning
Test
Symbol-Digit
Stroop Test
(Spanish Version)
Spanish-English
Verbal Learning
Test
Interference Score
PHQ
Total Score
Memory I
Mental
Speed
2
Executive
Function
Memory II
7
Depression
3
4
Rey Auditory
Verbal Learning
Test-Delayed
Recall
PHQ
Total Immediate
Recall
Number of correct
entries
Delayed Recall
Score
V. Trial Organization
A.
National Institutes Of Health
1. National Institute on Aging (NIA) Program Office
As the initiating institute, the NIA Program Officer will provide administrative
and scientific oversight for the project. The NIA Program Officer and the
ACCORD-MIND Principal Investigator (PI) will work closely with the NHLBI
Program Officer (see below) and the ACCORD Steering Committee on
implementation of all facets of the ACCORD-MIND trial and its interactions with
the main ACCORD trial. The NIA Program Officer along with the ACCORDMIND PI will review the progress of each Network Field Center through review
of the annual reports, site visits, DSMB reports, etc. As required for these
activities, the Program Officer will be assisted by other NIA staff and contractors.
This review may include, but is not limited to, compliance with protocol,
specifications, participant accrual, adherence to uniform data collection
procedures, data management and quality control, and the timeliness of data
reporting.
2. National Heart, Lung, and Blood Institute (NHLBI)
The NHLBI will, through an inter-agency agreement, oversee distribution of
the research funds for the ACCORD-MIND trial in conjunction with the NIA
program office. In accordance with the main ACCORD trial protocol, the NHLBI
Program Officer reviews all DSMB reports and participates in DSMB meetings
as outlined. As necessary, the NHLBI program office will provide advice to the
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ACCORD-MIND study leadership (NIA Program officer and study PI) on study
protocol and implementation issues arising over the course of study. The NHLBI
Program Officer will be solely responsible for facilitating implementation of
DSMB recommendations and conveying DSMB recommendations and requests
to the NIA Program Officer and the ACCORD-MIND PI.
B. ACCORD-MIND Coordinating Center (CC)
The ACCORD-MIND Coordinating Center is located at Wake Forest
University School of Medicine. Tasks include; 1) coordinating development of the
study protocol; 2) training, retraining and certifying study personnel; 3) monitoring
recruitment, adherence, retention, timeliness of data collection, and
completeness and accuracy of study data; 4) assisting network coordinators with
performing clinical center audits; 5) taking the lead in developing the MOP; 6)
monitoring all study data; 7) preparing data summary reports for review by the
ACCORD DSMB the NIA project office, the investigators, or various committees/
subcommittees; 8) providing statistical and other support in the preparation of
study publications and presentations; 9) organizing study meetings and
conference calls; and 10) participating in dissemination of the trial findings.
C. Regional Networks
The four ACCORD-MIND Regional Network PI’s (located at Columbia
University, The University of Minnesota, The Wake Forest University, The
University of Washington) are each responsible for the conduct of the study
within their respective ACCORD networks. They will oversee in-network
recruitment, data collection, and site visits. Network PI’s and coordinators will
also assist the Coordinating Center at Wake Forest with the retraining of current
plus initial training of new staff. For those networks participating in the MRI substudy, the network coordinator will oversee scheduling and implementation of the
MRI testing by working closely with the field centers, the Network radiologist, and
the radiologist’s staff.
D. Field Centers
The ACCORD-MIND Field Centers are each responsible for: 1) screening
and recruiting eligible participants; 2) administration of the cognitive testing and
(for three centers) the MRI protocol, monitoring adherence/retention; 3) collecting
participant data on standardized case report forms; 4) submitting this information
to the Coordinating Center; and 5) participating in dissemination of the trial
findings.
E. MRI Reading Center
The Central ACCORD-MIND MRI Center will be located at the University
of Pennsylvania School Of Medicine, Department of Radiology and will be under
the direction of Nick Bryan, MD. All ACCORD-MIND MR Field Centers will be
American College of Radiology (ACR) MR QC accredited sites. MR QC will be
based on the ACR MR Quality Control Program that is fully detailed in the MR
Quality Control Manual.
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