Pilot Study - Cognition in Patients With Hypoglycemia, Without Diabetes
Conditions: Hypoglycemia, Cognition
Sponsor: Joslin Diabetes Center

Committee on Human Studies 
Research Protocol 
CHS Protocol Number 
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Protocol Version 
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Version Date 
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CHS Form, CHS-001, v2.00, 3/2020 
Principal Investigator 
Mary Elizabeth Patti, M.D. 
Study Title 
Pilot Study – Cognition in Patients with Hypoglycemia, without 
Diabetes 
I. Objectives
The goal of this study is to evaluate the effect of recurrent hypoglycemia on cognitive function in patients who 
do not have diabetes.    This pilot aims to identify the cognitive domains of interest, as well as inform the 
development of a future battery of assessments, which could be replicated in a larger sample.  Ultimately, 
this information may have important implications for assessment of risk, patient teaching methods, and 
treatment, to help avoid potential cognitive decline. We will test the hypotheses that (1) recurrent 
hypoglycemia in patients without diabetes is associated with impairment in cognition, and (2) patients with a 
history of post-bariatric hypoglycemia (PBH) have impaired performance on cognitive tests as compared with 
patients without known hypoglycemia.   
II. Background
Hypoglycemia in the absence of diabetes is generally classified in relation to its timing, and can manifest in 
the fasting state, with exercise, or most commonly, after meals (reactive hypoglycemia).  Some patients 
present with predominantly one type, while others may present with mixed patterns. While there are 
conditions which have been identified that cause, or contribute to hypoglycemia, diagnosis can be 
challenging, and for some the precise etiology of hypoglycemia remains unknown.   
Despite the heterogeneity of this population, hypoglycemia yields similar symptoms and may result in some 
common long-term outcomes.  When hypoglycemia is severe it causes not only distressing adrenergic and 
cholinergic symptoms, but also neuroglycopenia, with symptoms including changes in thinking, memory 
impairment, brain fog, headaches, and difficulty concentrating or maintaining attention.  When recurrent, 
hypoglycemia unawareness can develop, impairing safety and increasing risk for disability, syncope, 
arrhythmias, seizures, coma, and death. Patients often report multiple episodes with alteration in, or loss of 
consciousness.  Impaired cognition during acute hypoglycemia may result in inability to self-treat, thus, 
requiring assistance from others to both procure and administer treatment.  Moreover, many individuals with 
recurrent hypoglycemia are disabled due to inability to perform job-related tasks, or endorse difficulty in 
meeting the cognitive demands of their profession, or activities of daily life.      
Hypoglycemia has been extensively studied in the population of patients with diabetes; however, there is a 
paucity of literature describing cognition in patients with hypoglycemia, without diabetes.  For patients with 
diabetes, hypoglycemia is induced by medications, often in combination with behavioral factors such as 
reduced food intake or increased activity.   Hypoglycemia in the absence of diabetes can be unpredictable, 
even when patients are following all recommendations provided.  Management of this condition can be 
onerous for patients.  Options for therapy are limited, and medications available are not always well tolerated. 
Even with the best-available treatment, hypoglycemia can be a chronic, lifetime condition.  Thus, the effect 
that this repeated neurologic insult exerts on cognition is important to understand to assess risk, improve 
patient teaching methods, and optimize treatment, to help avoid potential cognitive decline.    

 
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Preliminary Data: 
Studies of cognition in relation to hypoglycemia have generally been focused on diabetes.  For example, in 
patients with type 1 diabetes, recurrent hypoglycemia is associated with impaired memory, executive 
function, language, and psychomotor speed. It is notable that severe hypoglycemia in patients with type 1 
diabetes has been positively correlated with the severity of depressive symptoms, and that a bi-directional 
relationship has been shown to exist between severe hypoglycemia and depressive symptoms.  Depression 
is known to have a deleterious effect on cognition.  In patients with obesity, BMI is negatively correlated with 
performance on cognitive assessments.  Moreover, obesity is an independent risk factor for poorer 
neurocognitive outcomes, and is associated with increased risk for dementia.   Inflammation, vascular effects, 
and higher adipose-derived cytokine / hormones have been implicated as potential mechanisms implicated 
in the white matter changes, disturbances of blood-brain barrier integrity, and brain atrophy observed in this 
population. 
Research has shown relatively prompt improvements in memory, executive function, and language with 
weight loss after bariatric surgery.  However, at least two studies have failed to show any improvement in 
cognition after bariatric surgery.  One limitation to the current literature is duration of follow-up, with most 
studies assessing cognition at one year or less post-surgery.  The longest duration of follow-up is in the 
Longitudinal Assessment of Bariatric Surgery (LABS) cohort; one study in this cohort reported improvements 
in executive function and attention after weight loss; contrary to expectations, post-operative improvements 
in HbA1c were not associated with improvements in cognitive function. The authors acknowledged that 
hypoglycemia following bariatric surgery could have been an unmeasured contributor to cognitive 
dysfunction.  
Thus, for patients who have hypoglycemia without diabetes, whether induced by bariatric surgery or due to 
other conditions, there is a paucity of data. There are no known published studies specifically investigating 
the potential effect of recurrent hypoglycemia on cognition in these patients. Also, the presence of depressive 
symptoms, as well as their potential relationship with cognitive function, has not been reported on in 
individuals with PBH, or in those with hypoglycemia in the absence of diabetes. 
Hypoglycemia Effect on the Brain:   
The brain is particularly vulnerable to the effects of hypoglycemia, as it is the organ in the body with the 
highest demand for glucose.  Neuronal function is compromised whenever the supply of glucose is not 
sufficient to meet the demand. Within the brain, the areas which are the most metabolically active have been 
found to be the most susceptible to the effects of low glucose, such as the hippocampus and prefrontal cortex 
– areas critical for memory, executive function, and attention.    
In healthy individuals hypoglycemia induces an adaptive neurohormonal, counterregulatory response, that 
results in alterations in metabolism aimed to restore normoglycemia.   Low glucose levels are sensed in the 
ventromedial hypothalamus, ultimately triggering release of counterregulatory hormones and activation of the 
parasympathetic and sympathetic nervous system.  
Research in animal models has revealed that when glucose depletion is sustained, cascade of impaired 
mitochondrial respiration, excitotoxicity, oxidative stress, generation of reactive oxygen species (ROS), lipid 
peroxidation, and microglial activation can result in cell death.  While the entire cortex is affected, the 
hippocampus has been found to be significantly more vulnerable to these effects.  Cellular damage can also 
occur during reperfusion with rising glucose concentrations. 
Hypoglycemia also induces a pro-inflammatory, pro-thrombotic state, as evidenced by increases in pro-
inflammatory mediators (IL6, IL-8, IL-1B, TNF-alpha), enhanced platelet activation, platelet aggregation, p-

 
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selectin, and decreased fibrinolysis.  Acutely, vasoconstriction, endothelial dysfunction, and white blood cell 
activation, also occur and may have cumulative effects on atherogenesis and thrombotic complications, 
including central ischemia.  Recurrent / moderate hypoglycemia has been found to aggravate brain damage 
in post-ischemic rats.  
Collectively, these data highlight several important points: 1) recurrent hypoglycemia can result in 
unawareness, with episodes possibly more frequent than appreciated by patients, leading to clandestine 
damage; 2) hypoglycemia can directly result in cell damage or death, neuroinflammation, and a pro-
thrombotic state; 3) hypoglycemia in patients with diabetes has been shown to have serious and detrimental 
cognitive consequences, both for short-term patient safety and long-term cognition; 4) it is possible that 
patients undergoing bariatric surgery may have a pre-existing neural vulnerability due to prior history of 
obesity, with subsequent  hypoglycemic insults;  5) understanding  the impact of recurrent hypoglycemia on 
cognition in this understudied group is essential for risk assessment, raising provider awareness, developing 
more effective patient teaching strategies, and informing treatment, to help avoid potential cognitive decline. 
In this study, we will assess and compare cognitive function in patients with hypoglycemia without a history 
of diabetes, as well as in RYGB patients with and without PBH. We will also assess and compare depressive 
symptoms between groups, and their potential relationship to cognition.  
 
 
III. Study Design 
a. Recruitment Methods 
Participants will be recruited into 4 groups: (1) patients with hypoglycemia after upper gastrointestinal surgery, 
recruited from the Joslin Hypoglycemia Clinic, (2) asymptomatic post-bariatric patients, recruited from 
postoperative surgical clinics at Brigham and Women’s Hospital, (3) patients with hypoglycemia and no 
history of upper gastrointestinal surgery, and NO current diagnosis of diabetes or pre-diabetes, recruited from 
the Joslin Hypoglycemia Clinic,  (4) participants without hypoglycemia or upper gastrointestinal surgery 
(controls),  recruited by local advertisement.  Some participants may be recruited from other hypoglycemia 
studies at Joslin.   
 
The Joslin Hypoglycemia Clinic has emerged as a referral clinic for patients with hypoglycemia from around 
the country, and particularly the New England region.  Over 300 individuals have been evaluated in this clinic 
since its inception, and new patient referrals continue to increase as the awareness of hypoglycemia is 
increasing among patients and physicians alike. Thus, we have immediate access to a large pool of highly 
motivated patients.  
 
Under a HIPAA waiver, a list of all potential candidates will be generated from the Joslin Electronic Medical 
Records every three months. Candidates will be sent a letter explaining the study in simple terms, including 
a phone number to call in order to “opt-out”. The letter may be mailed or given to the patient at the time of a 
clinic visit by clinic personnel. If the potential research subject does not decline further contact in two weeks, 
the study staff will invite him/her to participate in the study by telephone or at the time of their next visit. 
Prospective study subjects may also be informed of the study by their Joslin clinicians, who may provide 
them with information on how to contact study coordinators. Patients who agree to participate will be screened 
by telephone or in person to determine eligibility. Subjects who meet screening criteria will be mailed or given 
an informed consent form and will be invited to come to the Joslin CRC for the study visit. Written consent 
will be obtained after explaining again the purpose and procedures of the study. In the initial contact and 

 
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Protocol Version 
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Version Date 
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again at the time of the screening visit, study subjects will be encouraged to ask questions and they will be 
reassured that they may withdraw from the study at any time without impact on clinical care. 
 
Participants will also be recruited via Research Match, a secure online recruitment tool.  Research Match 
allows for recruitment searches for individuals who have registered on their site and are interested in being 
contacted with research opportunities.  An informational email about the study is then sent out through the 
Research Match portal to the potential participants whose information is de-identified in the initial search.  For 
those who respond to the initial email that they are interested (by clicking within the message), their contact 
email will be sent to the study specific Research Match portal (password protected), and the study team will 
respond to each person individually with a follow-up email to schedule phone screening.  For those that are 
not interested, they are able to click “not interested” and opt out of further communications, or not respond at 
all to the initial recruitment email.  
 
The hypoglycemia patient population is highly motivated by the frustration of this disease; we anticipate no 
difficulty in recruitment or retention for this population.  As involvement will include initial telephone or in-
person screening and a single study visit with history and testing, we do not anticipate significant attrition in 
this protocol. Our study team has extensive experience with recruitment and retention of post-bariatric 
patients in the context of the SLIMM-T2D and ARMMS-T2D longitudinal clinical trial, and in prior studies of 
post-bariatric hypoglycemia.   
 
b. Inclusion and Exclusion Criteria 
Initial general screening will be performed during an initial phone or in person visit (e.g. during a clinical visit), 
which will include administration of the Patient Health Questionnaire-2 (PHQ-2). 
Individuals who appear to meet criteria will be invited for the study visit, when a detailed history will be 
performed by study clinicians.  Inclusion and exclusion criteria will be reviewed after the visit to determine 
study eligibility. 
Inclusion criteria: 
1. For PBH group:  Males or females diagnosed with ongoing post-bariatric hypoglycemia with prior 
episodes of neuroglycopenia, unresponsive to dietary intervention (low glycemic index, controlled 
carbohydrate portions). 
2. For post-RYGB without hypoglycemia:  Males or females with history of RYGB and no history of 
symptomatic hypoglycemia. 
3. For hypoglycemia without a history of upper gastrointestinal surgery group: Males or females diagnosed 
with ongoing hypoglycemia with prior episodes of neuroglycopenia, and without a history of prediabetes 
or diabetes   
4. For non-surgical controls only:  Males or females with no history of upper gastrointestinal surgery and no 
history of hypoglycemia, prediabetes, or diabetes. 
5. Age 18-70 years of age, inclusive, at screening.   
6. Willingness to provide informed consent and attend one study visit.  
 
Exclusion criteria:  
1. Active treatment with any diabetes medications, except for acarbose.  
2. History of cerebrovascular accident.  
3. History of a traumatic brain injury not related to hypoglycemia.  
4. A score of 6 on the PHQ-2. 

 
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5. Active alcohol abuse or substance abuse. 
6. Known insulinoma, gastrinoma or other neuroendocrine tumor.  
7. Having undergone same / similar cognitive assessments within the last calendar year. 
 
There will be no involvement of special vulnerable populations such as fetuses, neonates, pregnant women, 
children, prisoners, institutionalized or incarcerated individuals, or others who may be considered vulnerable 
populations.   
 
Please note that duration of hypoglycemia will not be included in either inclusion or exclusion criteria, but will 
be included as a covariate in our analyses. 
 
 
c. Number of Subjects 
Participants will be recruited into 4 groups, (1) patients with PBH, recruited from the Joslin Hypoglycemia 
Clinic, (2) asymptomatic post-RYGB patients, recruited by advertisement flyers at  postoperative surgical 
clinics at local hospitals (e.g. Brigham and Women’s and Beth Israel Deaconess Hospitals), (3) patients with 
hypoglycemia and no history of upper gastrointestinal surgery, and NO current diagnosis of diabetes or pre-
diabetes, recruited from the Joslin Hypoglycemia Clinic,   (4) controls, recruited by local advertisement.  We 
anticipate screen failure and drop out rate of 20% each.  We plan to enroll patients with hypoglycemia 
continuously over the next 4 years.  We anticipate performing cognitive testing in up to 20 participants in each 
of the four groups, based on availability of grant funding. 
 
d. Study Timelines 
The total duration of the study will be one to three weeks: one screening call and one study visit. We 
anticipate recruitment to continue for up to 4 years, concurrent with grant funding. 
 
There is no plan in the current study to re-contact patients after the study has been completed.   
 
e. Study Endpoints 
Primary endpoints: 
• 
Assessment of memory 
 
Secondary endpoints:  
• 
Assessment of executive function, language and psychomotor speed 
• 
Assessment of depressive symptoms using the Beck Depression Inventory (BDI) 
Analysis to assess the effects of participant group, and BDI scores (depressive symptoms), on 
standardized quantitative scores for each cognitive domain assessed (memory, executive function, 
language and psychomotor speed). 
f. Study Procedures 
An initial pre-screening phone call will occur with focus on inclusion, and exclusion criteria.  The PHQ-2 will 
be administered as part of the screening process to assess for the presence, on a nearly daily basis, of both 
of the two cardinal symptoms of major depressive disorder.  Individuals will be told that as part of the 
screening process they will be asked 2 questions about symptoms related to their mood.  For individuals who 

 
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are ineligible due to their PHQ-2 score, the study physician or nurse practitioner will offer to contact their 
primary care physician and recommend referral for mental health assessment. PHQ-2 forms completed via 
phone for those who are not eligible or who do not want to participate will be disposed of in a secure waste 
bin (for shredding) immediately after screening. 
The study visit will then be scheduled for eligible participants.  At this visit, we will test the hypothesis that 
hypoglycemia is associated with changes in cognitive function in the domains of memory, language, 
executive function, and psychomotor speed.  Secondarily, we will also test the hypothesis that recurrent 
hypoglycemia is associate with higher scores on the BDI (depressive symptoms), and that BDI scores will be 
negatively correlated with cognitive function.  
Sites:  Participants will be recruited at Joslin Diabetes Center and via advertisement. All clinical evaluation 
will be performed on the clinical research unit of the Joslin Diabetes Center.   
Study Visit: After informed consent, patients will undergo a history, and EKG, with emphasis on 
inclusion/exclusion criteria. Blood glucose will be assessed by capillary glucose. Prior to cognitive testing, 
participants will also be asked to complete the BDI, measuring depressive symptoms.  Participants will be 
offered breaks of up to 10 minutes between components of the assessment. 
Cognitive Testing: Prior to cognitive assessment, blood glucose levels will be assessed by capillary glucose 
testing.  If glucose level is less than 70 mg/dL, glucose tablets and a snack will be provided, and glucose 
levels will be rechecked every 15 minutes until levels exceed 80 mg/dL.   If during the course of testing a 
patient develops symptoms of hypoglycemia, blood glucose levels will be checked, and if needed, treated as 
above.  Testing will not be resumed until glucose levels exceed 80 mg/dl. 
The neuropsychological tests include: 
a) Intelligence 
The National Adult Reading Test (NART) is composed of a list of 50 words that progress in level of difficulty. 
The participant is instructed to read each word aloud while the examiner tracks the number of errors made. 
This test was designed in order to estimate premorbid intelligence based on the test taker’s word familiarity.   
b) Working Memory and Attention 
To assess working memory, we will use the Letter-Number Sequencing subtest from the Wechsler Memory 
Scale III. In this task, the examiner instructs the participant to repeat a string of mixed letters and digits back 
in alphabetical and ascending numerical order. This string gets progressively longer and thus more difficult 
as the participant has more digits and letters to sort using working memory. 
c) Rey Auditory Verbal Learning Test  
The Rey Auditory-Verbal Learning Test (RAVLT) is a cognitive task aimed at assessing verbal memory and 
delayed memory. During this task, a list of 15 words is repeated 5 times. The participant is asked to recall as 
many words from the list as possible in no specific order. After the fifth cycle of repeating and recalling the 
first list, a second list of 15 words is read. The participant must recall as many words from the second list as 
possible. A delayed recall trial then occurs 20 minutes following the end of the previous trial where the 
participant is asked to recall as many words as possible from the first list.  
d) Delis-Kaplan Executive Function System 
The Delis-Kaplan Executive Function System (DKEFS) measures executive function and focuses on verbal 
and nonverbal concept formation, flexible thinking, and problem solving. We will administer Trail Making tests 
tasks (with Number-Letter Switching condition), the Stroop Task, and Verbal Fluency Task. Trail making tasks 

 
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are scored by time to complete the task plus errors, and allow us to assess cognitive flexibility and 
multitasking.  
e) Grooved Pegboard 
The grooved pegboard is a task to assess psychomotor speed and efficiency. It is scored according to time 
for completion combined with the number of dropped pegs. The validity of this task as a measure of motor 
speed and psychomotor processing comes from its demonstrated relationship to other tests of motor speed 
as well as to measures of attention and perceptual speed and nonverbal reasoning. 
Data Collection and Storage: Research material for this study will consist of data obtained during the study 
visit, including medical history, and cognitive testing. Data will be recorded on case report forms, as well as 
cognitive testing forms, and stored in participant-specific binders.  Data will be stored at the Joslin Diabetes 
Center in locked cabinets and rooms accessible only to study staff. All study participants will be assigned a 
unique study identifier. Publications or public presentations will not provide any information which could 
identify individual study participants or their families.  Data analysis will commence once the entire cohort 
has been studied. 
 
g. Data and Specimen Banking 
 
After study completion, primary written materials (cognitive battery scoring and answer sheets) will 
be stored in locked filing cabinets accessible only to current study team members, and data will be 
stored on shared drives accessible only to current study team members approved by IRB.  
Identifiers will not be shared with anyone beyond the study team.   
 
h. Data Management 
Study Records Retention and Storage 
Study documents will be retained for at least 10 years following study conclusion.  
Each participant will be assigned a unique study ID acrostic and number. Study data will be identified with 
this study ID, not with participant’s names. Study documents will be stored in locked file cabinets or locked 
storage rooms and only authorized study staff will have access to these files. Electronic data will be stored 
on a password-protected network accessible only to authorized staff.  Only deidentified information will be 
transferred between sites.  All data transfer between study sites will be performed via secure encrypted file 
transfer (e.g. MoveIt). 
 
Data Monitoring 
Designated personnel from the study site will be responsible for maintaining quality assurance (QA) and 
quality control (QC) systems to ensure that the study is conducted, and data are generated, documented, 
and reported, in compliance with the protocol, Good Clinical Practice (GCP), and the applicable regulatory 
requirements. Adverse events will be prioritized for monitoring. 
 
Analysis plan for the primary study endpoints 
(1) The distributions of relevant variables will be examined for outliers and to determine appropriate 
statistics for use. χ2, Kruskal-Wallis, and ANOVA tests will be used to examine categorical differences. 
(2) ANOVA tests will be used to assess the effects of group standardized quantitative score on 
each of the assessed cognitive domains.  
(3) Cohen’s delta (d) may be used to assess effect size between groups 

 
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Sample size and power.  
Since the cognitive assessments represent a pilot study, and no data are available in a similar population to 
guide power analysis, our sample size is guided by anticipated feasibility of recruitment. 
i. 
Confidentiality 
Representatives of the IRB or authorized representatives from Joslin Diabetes Center, and the NIH may 
inspect all documents and records required to be maintained by the investigator, including but not limited 
to, medical records (office, clinic, or hospital) for the participants in this study. The clinical study team will 
permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use during 
the study. At the end of the study, all records will continue to be kept in a secure location for as long a 
period as dictated by local IRB and Institutional regulations. 
 
j. 
Provisions to Monitor the Data to Ensure the Safety of Subjects 
Data safety and monitoring plan.  This plan will be implemented and strictly followed.  The PI will be 
responsible for ensuring that recruitment and phenotypic analyses are conducted in accordance with the IRB-
approved protocol and will review all adverse events and serious adverse events. The Joslin PI will also 
perform a periodic review of all data from phenotypic analyses. The members of the study team will conduct 
regularly scheduled meeting approximately weekly as well as on an as-needed basis to review status of the 
study inclusive of enrollment, oversight of informed consent, general conduct of the study as well as reporting 
of any complications as needed to the IRB. Safety data (including AE/SAE logs and protocol deviations) will 
be collected and reviewed every 3 months or as needed. 
Data quality. Interim analyses will be conducted on a quarterly basis to assess the quality of data through 
descriptive statistics.  Attempts will be made to fill missing data, verify outliers, and reconcile data 
discrepancies by assessing medical records or recontacting participants.  If data quality is not satisfactory, 
the need to follow GCP guidelines for data collection will be reinforced with study staff and retraining will be 
performed as needed.  Once a year, study staff will conduct an internal clinical monitoring to assess database 
accuracy relative to source documents, as well as adherence to regulatory and study procedures and 
maintenance of the study regulatory binder.  Emphasis will be placed on the process of consenting 
participants, compliance with regulatory requirements and study protocol, values of key endpoints, and 
identification of AE that may not have been reported.  Source documents will be stored for at least 10 years 
after the study ends. 
Definition of Adverse Events. Adverse events (AE’s) will be defined as untoward medical events related to 
the procedures done during the study visits.  A Serious Adverse Event (SAE) is any untoward medical 
occurrence that results in death, is life-threatening, requires hospitalization or prolongation of an existing 
hospitalization, results in persistent or significant disability, or is a congenital anomaly/birth defect. Important 
medical events that do not fall into the above categories may also be considered an SAE when, based on 
medical judgment, such events may jeopardize the patient’s safety and require medical/surgical intervention 
to prevent one of the outcomes listed in the SAE definition. The term SAE is not intended as a measure of 
severity or intensity. All AE or SAE that occur after the time of informed consent will be reported. The 
seriousness of adverse events will be ascertained by the study staff according to the criteria above and the 

 
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need for further evaluation, follow-up, or referral. The relationship between study participation and AEs will 
be determined according to the following criteria: 
• 
Not related – temporal relationship of the onset of the event, relative to study participation, is not 
reasonable or another cause can by itself explain the occurrence of the event. 
• 
Possibly related – temporal relationship of the onset of the event, relative to study participation, is 
reasonable but the event could have been due to another, equally likely cause. 
• 
Probably related – temporal relationship of the onset of the event, relative to study participation, is 
reasonable and the event is more likely explained by the study treatment than by another cause. 
• 
Definitely related – temporal relationship of the onset of the event, relative to study participation, is 
reasonable and there is no other cause to explain the event. 
 
Reporting of AE and safety analyses. AE and SAE will be recorded on an ongoing basis in an AE/SAE log, 
and tabulated yearly at the time of the annual report to the Joslin Committee on Human Studies (CHS), unless 
an SAE meets the criteria for immediate report to the CHS (i.e., an unexpected SAE that is deemed to be 
possibly/probably/definitely related to study participation). Since this is an observational study, we do not 
anticipate an excess of AEs/SAEs in one treatment group as compared to another. Nonetheless, if the 
number of AEs/SAEs occurring in relation to the study visit appears to be excessive in comparison to what 
one would reasonably expect, we will thoroughly review our study operations to identify and rectify possible 
problems and will report results to the Joslin CHS. 
 
Protocol Deviations and Violations. A Protocol Deviation is defined as any change, divergence, or 
departure from the approve study protocol that does not affect the participant’s safety, rights, welfare or the 
integrity of the study and its resultant data. A Protocol Violation is defined as a protocol deviation that may 
affect the participant's rights, safety, or wellbeing and/or the completeness, accuracy, and reliability of the 
study data. Deviation will be reported to the Joslin CHS at the time of continuing review whereas violations 
will be reported as soon as study personnel are aware of the event. The PI will keep an internal protocol 
deviation and violation log that will be forwarded to the IRB at the time of continuing review. 
 
Data and Safety Monitoring Board. Since this is a low-risk, single-center observational study, the oversight 
of an external Data Safety and Monitoring Board is not deemed necessary. 
 
Rules for stopping the trial. The trial may be stopped by the study team or CHS if the number of 
unanticipated study-related SAE appears to be excessive in comparison to expected numbers. 
k. Withdrawal of Subjects 
Subjects will be withdrawn from the research study without their consent for any of the following reasons:  
a. Subject decision to withdraw consent for study participation 
b. New diagnosis of exclusionary medical condition  
c. Intolerable adverse event as judged by investigator and participant 
d. If the PI feels the subject is not following the study protocol / instructions provided at the study visit 
 
Participants will be notified of the reasons for the termination.  Data collected until the point of withdrawal 
will be analyzed, unless the participant specifically requests that data be removed from analysis. 
 
 

 
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IV. Risks to Subjects 
Potential risks regarding participation include risks associated with:  
 
Depression Assessment:  
PHQ-2:  There may be a small potential risk of some discomfort or sadness when answering the 2 questions 
of the PHQ-2 during eligibility screening; however, investigators believe that the benefit of identifying 
symptoms of severe depression allowing for referral to treatment outweighs this risk.   
BDI:  Reading / responding to questions on the BDI about the presence and severity of depressive 
symptoms may cause sadness or be mildly distressing for some participants.  If concerns for depression 
are revealed during the study visit, the study physician or nurse practitioner will offer to contact the 
participant’s primary care physician so that they may work together on a mental health follow-up plan. 
 
Cognitive Testing: Certain assessments may be challenging, and possibly mildly distressing for some 
patients related to perception of their performance. Patients will be reassured during the testing that it is 
expected that the tasks they are asked to perform may be difficult, and their best effort is all that is required. 
Screening Tests and Procedures: It is possible that as a result of the screening process a subject may 
become aware of a health disorder.  Every effort will be made to help the participant obtain the care that they 
need. Results will be shared with participants, and if they consent, with their primary care providers. 
Breach of Confidentiality: While every effort will be made to protect the confidentiality of participant 
identifiable information, there is the potential loss of confidentiality by participating in this study. 
Inconvenience and Unknown Risks: Participants may be inconvenienced by the time commitment involved 
in participation in the study. There may be other risks from this study not yet identified.  
Participants can choose not to participate in this study and can withdraw consent at any time.  
 
V. Potential Benefits to Subjects 
The purpose of this study is to evaluate the effect of recurrent hypoglycemia on cognitive function in patients 
without diabetes. This project is not designed to be of direct benefit to any individual subject, although it is 
hoped that through the knowledge gained from these studies there will be general benefit to persons with or 
at risk of development of hypoglycemia, and in particular for those who report concerns about cognitive 
changes.  Patients will not be provided results of cognitive testing. . As such, risks are appropriate in relation 
to the potential significant benefits for the significant number of persons with or at risk for hypoglycemia.  
 
VI. Provisions to Protect the Privacy Interests of Subjects 
The participants will be provided adequate time and private space to review the consent document and as 
much time as needed to ask questions about procedures. All study procedures will be performed in a 
private space.  When reviewing participants’ medical records, study staff will access the minimum 
necessary information needed for the study. 
 
VII. Compensation for Research-Related Injury 

 
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There is no compensation provided to participants in the event of a research-related injury. 
 
VIII. Economic Burden to Subjects 
There will be no costs for subjects to participate in this study.  
Participants will receive a parking voucher for the study visit and will receive $20 compensation for 
completing study procedures.  If this testing is performed during a screening visit for another protocol, the 
$20 will be provided in addition to stipends from other studies.     
 
IX. Consent Process & Documentation 
Subjects will be recruited from the Joslin Hypoglycemia Clinic, and from local advertisements.  The study will 
be explained to the potential subject initially in the clinical setting (in a private location) or during a telephone 
screening session by the study coordinator/recruiter. The informed consent process will be inclusive of 
various types of education and counseling opportunities including an in-person or telephone screening, 
allowing for general overview of the procedures as well as options available for all subjects expressing 
interest in participation.  
Those still interested after in person or telephone screening will be scheduled for screening visit(s) at the 
clinical research center. The consent process will involve initial discussion of the purpose and scope of the 
research as well as risks and benefits. Ample opportunity will be provided for participants to read consent, 
share with family or other health care providers as well as have all questions answered by the Principal 
Investigator or their designated study staff prior to obtaining written informed consent using CHS- approved 
documents. The consent form will include a description of risks and benefits, alternative possible procedures, 
the availability of the investigating physicians throughout any study to discuss any concerns, the availability 
of CHS to discuss any concerns, and the fact that the patient can withdraw from the study at any time with 
no change in his/her standard treatment. There can be no changes in the protocol without the prior agreement 
of the CHS.  
If the patient consents to enroll in the study, and the consent form is signed, further evaluation in the form of 
the medical and screening visit will take place to determine eligibility. One copy of the consent form will be 
retained by the principal investigator and one copy will be provided to the subject. 
 
 
X. Vulnerable Populations 
Vulnerable populations will not be studied.  
 
XI. Drugs and/or Devices 
Not applicable. 
 
XII. Sharing of Results with Subjects 
If screening history reveals new medical diagnoses of clinical significance, information will be shared with 
the participant and primary care physician. Results of cognitive testing will not be shared with participants 
or primary care physicians.   

 
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