Conditions: Type 2 Diabetes Mellitus
Keywords: Type 2 Diabetes Mellitus Intranasal Insulin Placebo Memory Gait Non diabetic older controls
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 289
Healthy volunteers: yes

Brief summary:
The main purpose of this study is to find the long-term effects of daily administration of 40 IU of intranasal insulin (INI) as compared to placebo (sterile saline) on cognition and memory in people with type 2 diabetes mellitus (DM), and non-diabetic controls over 24 weeks with a follow-up period for 24 weeks. Four groups will be tested: DM group treated with INI; DM group treated with placebo; control group treated with INI and the control group treated with placebo. The INI or placebo will be delivered into the nose. The investigators are interested to see whether INI can improve memory and cognition and blood flow in the brain in the type 2 DM group as compared to placebo and to the non-diabetic group over a long-term period.

Detailed description:
The investigators propose a randomized controlled trial determining the long-term effects of intranasal insulin (INI) on cognition and memory in type 2 diabetes (DM) and non-DM groups. The investigators hypothesize that: 1) INI-treated adults with DM have better memory and functioning of specific cognitive domains and faster walking during a dual task than those treated with placebo and the control group; 2) Glycemic and insulin resistance and genetic markers for Alzheimer's disease (Apolipoprotein E4 \[ApoE4\]) may serve as predictors of positive responses to INI therapy; 3) INI treatment neither adversely affects systemic glycemic levels or the cardiovascular system nor causes weight gain.

Aim 1: To determine whether INI-treated type 2 DM adults have a) better memory and functioning of specific cognitive domains and b) faster dual-task gait speed and better daily living functioning than the placebo-treated and non-DM groups. Four groups will be tested: 60 DM subjects treated with insulin; 60 DM subjects treated with placebo; 45 control subjects treated with INI and 45 control subjects treated with placebo. These 210 patients are expected to complete treatment and 168 are expected to complete study by the study completion anticipated date.

The investigators will conduct a randomized, double-blind, placebo-controlled study in 120 older adults with type 2 DM and 90 non-DM controls examining whether 40 IU INI once daily over a 24-week period improves:

* Specific domains of visuospatial attention and memory, verbal learning (primary outcomes);
* Gait speed during a dual task (which is an excellent predictor of overall health), daily living functionality, and depression as compared to the DM group receiving sterile saline and the non-DM groups. The non-DM groups will provide reference of INI effects in a clinical phenotype of cognitive decline and insulin resistance that occurs with normal aging.

Aim 2: To identify a phenotype and long-term trajectory predicting clinically relevant response to INI therapy based on glycemic control, insulin resistance, endothelial and genetic markers.

1. The investigators will determine a phenotype predicting a clinically relevant response to INI therapy and identify time-dependent trajectories of INI effects on cognition in the DM group vs. the placebo and the non-DM groups. Clinical predictors will be based on associations between cognitive function and/or gait and demographic, glycemic control, insulin resistance, endothelial and genetic (ApoE4) measures.
2. The investigators will evaluate the dose-escalating trajectory of cognition, gait speed, and functionality during the 24 weeks of therapy and 24 weeks post-treatment and their dependence on the above-mentioned factors, and determine the time point when maximum effect was reached. INI therapy response is defined as a clinically relevant improvement on cognitive tests or in gait speed (as a continuous variable) or as responders vs. non-responders as compared to placebo within DM and non-DM groups (as a categorical variable).
3. MRI substudy: The investigators will explore the long-term INI effects on regional perfusion, vasodilatation, and resting functional connectivity in 40 DM subjects pre- and post- INI/placebo administration at the beginning and at the end of intervention and their relationships to cognitive outcomes. Regional perfusion and vasodilatation will be measured by pseudo-continuous arterial spin labeling (PCASL) MRI at 3 Tesla, and resting-state functional connectivity will be quantified from low-frequency (0.01-0.08 Hz) fluctuations (LFF) of the whole-brain blood-oxygen-level dependent (BOLD) functional Magnetic Resonance Imaging (fMRI).

Aim 3: To determine the long-term safety of INI vs. placebo with regard to glycemic control (fasting glucose, hemoglobin A1c \[HbA1c\], hypoglycemic episodes), vital signs, and body mass.

1. The investigators will obtain measurements of fasting glucose, insulin, vital signs, and body mass at baseline, 2-months, 4-months, and 6-months follow-up and keep weekly logs monitoring glucose and adverse events.
2. Safety substudy: In the first 20 DM patients treated with subcutaneous insulin, the investigators will conduct continuous glucose monitoring (CGM) OR 5 finger sticks/day (effective after 9/25/2017) for 1 week during baseline and during the first week of INI or placebo treatment to evaluate the INI effects on glycemic control, hypoglycemic episodes, and body weight.

This study may pave the way to potential treatment and/or cure of DM- and age-related cognitive decline.

Arms:
arm 1: 40 IU of regular human insulin once daily over 24 weeks arm 2: Intranasal sterile saline once daily over 24 weeks arm 3: 40 IU of regular human insulin once daily over 24 weeks arm 4: Intranasal sterile saline once daily over 24 weeks

Interventions: intervention 1: Regular Human Insulin intervention 2: Placebo
Intervention descriptions: intervention 1: Regular human insulin 40 IU daily over 24 weeks intervention 2: Intranasal sterile saline 40 IU daily over 24 weeks

Protocol document:
Prot_SAP_001.pdf: 
1 
 
Memory Advancement by Intranasal Insulin in Type 2 Diabetes (MemAID) 
RCT Trial 
 
 
Study Protocol and Statistical Analysis Plan 
 
 
 
NCT#: 0241556 
IRB Approval Date: 7/20/2021 
 
 


2 
 
 
Hypotheses and Aims: 
Memory Advancement by Intranasal Insulin in Type 2 Diabetes (MemAiD)  
Type 2 diabetes mellitus (DM) accelerates brain aging(1), alters neurovascular coupling(2-6) and increases the risk 
for dementia and Alzheimer's disease (AD)(7-9). Insulin is a key neurotrophic factor in the brain, where it modulates 
cognition through regulation of energy metabolism, neurovascular coupling, and neuroprotection (10-13). Intranasal 
insulin (INI) binds to the receptors in the limbic system and cognitive networks including the hippocampus, 
hypothalamus, and insular cortex(14),(13),(15). Short-term administration of INI improved learning and memory in 
both healthy and cognitively impaired non-diabetic adults.(16-24) Our pilot randomized, cross-over, placebo-
controlled study (5R21-DK-084463-02, IND 107690, NCT01206322)(24, 25) has shown that a single 40 IU dose of 
INI improved visuospatial memory in DM and controls. In the DM group, INI improved perfusion and resting state 
functional connectivity(25), and better visuospatial memory was associated with greater vasodilatation. No serious 
adverse events (AEs) or hypoglycemic episodes occurred. This study provided proof-of-concept supporting the 
potential usefulness and safety of INI and laid the groundwork to expand on these findings to determine the long-
term effects and safety of INI treatment.  
We propose a randomized controlled trial determining the long-term effects of INI on cognition and memory 
in DM and non-DM groups. We hypothesize that: 1) INI-treated adults with DM have better memory and functioning 
of specific cognitive domains and faster walking during a dual task than those treated with placebo and the control 
group; 2) Glycemic and insulin resistance and genetic markers for AD (ApoE4) may serve as predictors of positive 
responses to INI therapy; 3) INI treatment neither adversely affects systemic glycemic levels or the cardiovascular 
system nor causes weight gain.  
 
Aim 1: To determine whether INI-treated type 2 DM adults have a) better memory and functioning in specific 
cognitive domains and b) faster dual-task gait speed and better daily living functioning than the placebo-
treated and non-DM groups. 
We will conduct a randomized, double-blinded, placebo-controlled study in 120 older adults with type 2 DM and 90 
non-DM controls examining whether 40 IU INI once daily over a 24-week period improves:  
 
Specific domains of visuospatial attention and memory, verbal learning (primary outcomes);  
 
Gait speed during a dual task (which is an excellent predictor of overall health (26)), daily living functionality, and 
depression as compared to the DM group receiving sterile saline and the non-DM groups. The non-DM groups 
will provide reference of INI effects in a clinical phenotype of cognitive decline and insulin resistance that occurs 
with normal aging.  
 
Aim 2: To identify a phenotype and long-term trajectory predicting clinically relevant response to INI 
therapy based on glycemic control, insulin resistance, endothelial and genetic markers. 
a. We will determine a phenotype predicting a clinically relevant response to INI therapy and identify time-dependent 
trajectories of INI effects on cognition in the DM group vs. the placebo and the non-DM groups. Clinical predictors 
will be based on associations between cognitive function and/or gait and demographic, glycemic control, insulin 
resistance, endothelial and genetic (ApoE4) measures.  
b. We will evaluate the dose-escalating trajectory of cognition, gait speed, and functionality during the 24 weeks of 
therapy and 24 weeks post-treatment and their dependence on the above- mentioned factors, and determine the 
time point when maximum effect was reached. INI therapy response is defined as a clinically relevant 
improvement on cognitive tests or in gait speed (as a continuous variable) or as responders vs. non-responders 
as compared to placebo within DM and non-DM groups (as a categorical variable). 
c. MRI substudy: We will explore the long-term INI effects on regional perfusion, vasodilatation, and resting 
functional connectivity in 40 DM subjects pre- and post- INI/placebo treatment at baseline  and at the end of 
intervention and their relationships to cognitive outcomes. Regional perfusion and vasodilatation will be measured 
by pseudo-continuous arterial spin labeling (PCASL) MRI at 3 Tesla, and resting-state functional connectivity will 
be quantified from low-frequency (0.01–0.08 Hz) fluctuations (LFF) of the whole-brain blood-oxygen-level 
dependent (BOLD) fMRI. 
 


3 
 
Aim 3: To determine the long-term safety of intranasal insulin vs. placebo with regard to glycemic control 
(fasting glucose, Hb1Ac, hypoglycemic episodes), vital signs, body mass, appetite feelings and food intake.  
a. We will obtain measurements of fasting glucose, insulin, vital signs, body mass measurements, waist and hip 
circumference, appetite feelings using visual analogue scales (VAS) at baseline, 2-months, 4-months, and 6-
months follow-up and keep weekly logs monitoring glucose and AEs.  
b.  Safety substudy: In the first 20 DM patients (ICF signed, enrolled) treated with subcutaneous insulin, we will 
conduct safety substudy with five glucose measurements per day using finger sticks  (FS) for one week during 
baseline and during the first week of INI or placebo treatment, to evaluate the INI effects on glycemic control and 
hypoglycemic episodes. The enrollment has stopped per Amd #21 9/25/2017. 
 
This study may pave the way to potential treatment and/or cure of DM- and age-related cognitive decline. 
 
Primary Endpoints:  
 
Aim 1: To determine whether INI-treated type 2 DM adults have a) better memory and functioning in specific 
cognitive domains and b) faster dual-task gait speed and better daily living functioning than the placebo-
treated and non-DM groups. 
 
Specific domains of visuospatial attention and memory, verbal learning, normal and dual task gait speed (Primary 
outcomes). 
 
Gait speed during a dual task (which is an excellent predictor of overall health (26), daily living functionality, and 
depression as compared to the DM group receiving sterile saline and the non-DM groups.  
 
These measures will be collected at baseline, during 4 on-treatment (at V2-intervention week 1, V4 –week 8, V6 
week 16, V8  week 24)  and 4 post-treatment visits (V9 week 25, V10 week 32, V11 week 40 and V12 week 48). 
V9 will be a virtual visit conducted over the phone with an abbreviated assessment. 
 
Aim 2: To identify a phenotype and long-term trajectory predicting clinically relevant response to INI therapy 
based on glycemic control, insulin resistance, endothelial and genetic markers. 
 
Clinical predictors will be based on associations between cognitive function and/or gait and demographic, 
glycemic control, insulin resistance, endothelial and genetic (ApoE4) measures.  
The dose-escalating trajectory of cognition, gait speed, and functionality during the 24 weeks of therapy and 24 weeks 
post-treatment and their dependence on the above-mentioned factors, and determine the time point when maximum 
effect was reached. INI therapy response is defined as a clinically relevant improvement on cognitive tests or in gait 
speed (as a continuous variable) or as responders vs. non-responders as compared to placebo within DM and non-
DM groups (as categorical variable). 
 
Secondary End Points  
Aim 3: To determine the long-term safety of intranasal insulin vs. placebo with regard to glycemic control 
(fasting glucose, Hb1Ac, hypoglycemic episodes), vital signs, body mass, appetite feelings and food intake.  
We will obtain measurements of fasting glucose, insulin, vital signs, body mass measurements, waist and hip 
circumference, and appetite feelings using VAS at baseline, on-treatment and post-treatment and keep weekly logs 
monitoring glucose and AEs (V1-V8). 
 
 
 
 
 
 
 
 
 


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METHODS 
 
DESIGN AND RATIONALE  
 
Design: We propose a prospective double-blind, placebo-controlled study with 210 subjects with or without type 2 
DM randomized into 4 groups (60 DM–INI, 60 DM–PLACEBO, 45 CONTROL–INI, and 45 CONTROL–PLACEBO) 
examining whether 40 IU INI (Novolin®R Novo Nordisk, Bagsvaerd, Denmark) once daily over 24 weeks improves 
cognition, daily functionality and walking speed, as compared to placebo (Aim 1). We aim to identify a phenotype and 
predictors of best response (Aim 2) and investigate long-term safety (Aim 3).  
 
Rationale: Outcome measures were selected based on positive reports of INI effects on cognition.(16-24, 27) The 
INI dose of 40 IU has shown promise for long-term improvement of cognition in DM and non-DM people.  
The 24-week INI treatment extends beyond previous studies (11, 16, 20, 22, 28) to maximize potential benefits, 
optimize duration and dose-escalating effect, and evaluate long-term safety.  
Study Groups: Broader inclusion criteria permit to enroll a diverse DM and non-DM population to generalize the 
results. The matched design of DM vs. non-DM is essential to elucidate: 1) Long-term safety and INI effects; 2) INI 
impact on specific cognitive domains that may differ in DM vs. normal aging; 3) The effects of insulin resistance and 
glucose levels on brain aging and cognitive decline where longitudinal data are lacking; 4) The role of demographics 
(age, sex), cardiovascular risks (hypertension, obesity), and genetic markers (ApoE4) for prediction of an INI-
responsive phenotype; 5) Sex-specific outcomes; 6) Furthermore, our Aim 3 will also explore the impact of INI on 
weight, waist and hip circumference, appetite feelings and food intake as another potentially beneficial mechanism 
of INI on food and brain reward system and potential benefits for weight management. 
 
Rationale for Study Population 
Diabetes mellitus affects >44 million people and 27% of older adults in the U.S. It accelerates brain atrophy and 
promotes earlier onset of cognitive impairment (5, 29, 30), vascular dementia (31) and AD (1, 32-35).  
Currently, there is no cure for DM-related cognitive impairment. Even a tight glycemic control did not improve 
cognitive function in participants of the large clinical trials (36, 37). Insulin resistance, altered insulin transport and 
signaling in the brain may mediate DM-related cognitive decline. Older adults are the most rapidly growing segment 
of T2DM population, which is also at greater risk for cognitive decline. Recently, intranasal insulin (INI) therapy 
has emerged as a potential solution to deliver insulin safely to the brain and treat DM-related cognitive 
impairment. 
 
DM management: Insulin/placebo will be added to participants’ medication regimen for diabetes, and for any co-
morbidities DM participants will receive the usual care from their providers. Primary care providers will receive the 
study description, and laboratory results upon enrollment and after each intervention visit during the treatment period 
(V2, V4, V6, V8), and if an adverse event occurs to adjust medication regimen. They will be required to inform the 
investigators about any changes in their regimen or health status during the follow-up visits. Glycemic control and 
other potential confounders will be monitored, and their effects will be tested and accounted for in the analyses. 
Insulin/placebo will be administered once daily in the morning before breakfast. Participants will receive two or three 
10-mL vials containing 100 units/mL of insulin (Novolin® R Novo Nordisk, Bagsvaerd, Denmark) or sterile saline that 
will be used over three to four weeks. Insulin/saline will be delivered over two minutes using a ViaNase electronic 
atomizer (Kurve Technology, Inc., Seattle, WA). The device is easy to operate, and it allows precise preprogrammed 
dosing and targeted delivery into the olfactory region with minimal peripheral deposition.  
 
Compliance: Participants will be asked not only to bring their devices and vials to the follow-up visits every 3-4 
weeks, but also to keep detailed diaries of drug usage and of any AEs daily and weekly measures of glucose before 
and after INI. The volume remaining in the vial will be measured at each visit to document medication usage. 
 
.  
 


5 
 
DM management: Insulin/placebo will be added to participants’ medication regimen for diabetes, and for any co-
morbidities DM participants will receive the usual care from their providers. Primary care providers will receive the 
study description, and laboratory results upon enrollment and after each intervention visit during the treatment period 
(V2, V4, V6, V8), and if an adverse event occurs to adjust medication regimen. They will be required to inform the 
investigators about any changes in their regimen or health status during the follow-up visits. Glycemic control and 
other potential confounders will be monitored, and their effects will be tested and accounted for in the analyses. 
Insulin/placebo will be administered once daily in the morning before breakfast. Participants will receive two or three 
10-mL vials containing 100 units/mL of insulin (Novolin® R Novo Nordisk, Bagsvaerd, Denmark) or sterile saline that 
will be used over three to four weeks. Insulin/saline will be delivered over 1 minute using a ViaNase electronic 
atomizer (Kurve Technology, Inc., Seattle, WA). The device is easy to operate, and it allows precise preprogrammed 
dosing and targeted delivery into the olfactory region with minimal peripheral deposition. People with mild AD (22) 
have used this device successfully.  
 
Compliance: Participants will be asked not only to bring their devices and vials to the follow-up visits every 3-4 
weeks, but also to keep detailed diaries of drug usage and of any AEs daily and weekly measures of glucose before 
and after INI. The volume remaining in the vial will be measured at each visit to document medication usage. 
  
Recruitment & retention & enrollment:  
We plan to screen up to 800 subjects over the phone. We anticipate that we will need to recruit (sign ICF) in 360 
subjects, to allow for attrition during the longitudinal study assuming 33% drop out in the DM and control groups. 
However, the insulin treated DM subjects have 66.7% drop-out rate which negatively affected the overall recruitment 
goals. Subjects will be recruited consecutively. We aim that 210 participants (90 controls and 120 DM) will complete 
the Visit 8 (end-of treatment) upon the study completion (May 31, 2020) (Aim 1).  As of 8.1.2017, 55 participants 
completed V8 and 36 completed also the follow-ups (V12) at BIDMC. We plan to enroll 50 subjects per year in years 
3 and 4 and 24 in year 5 across both sites (30 or more at BIDMC and up to 20 subjects at BWH).Aim 3b- safety 
substudy enrollment of IDDM participants was closed for futility in October 2017. 
 
We will also attempt to complete the six-month follow-up (V12) in as many participants as possible (Aim 2), we 
estimate that 168 participants may complete the six month  follow up. However, we may need to shorten the 
duration of the follow-up and further reduce the number of follow-up visits to meet our primary recruitment goal. We 
will leverage the existing resources at Harvard Catalyst and our experience with successful recruitment and 
retention in the greater Boston area for previous studies (PIs CREED, TRACT, Look Ahead). We will use 
community recruitment within a 3-mile radius of BIDMC greater Boston area and Joslin Diabetes Clinic. We will use 
BIDMC records, city censuses, senior centers and TrialX databases. Emphasis on recruitment of minorities:  
Type 2 DM is common in African Americans and Hispanics, who are underrepresented in clinical trials. We will use 
community advertisement and activities, e.g., targeting barbershops and beauticians, churches and educational 
sessions.  The PI has established a recruitment repository with >300 records of participants with T2DM older than 
50 years and controls who are eligible and potentially interested in participating. 
 
Retention strategies: 1) The PI or the study physicians are present during the consent process and are available to 
further answer any questions or concerns. 2) Participants who previously failed phone screening can be re-screened 
with the new inclusion/exclusion criteria.  3) Participants have 24/7 contact for investigators phone numbers and 
pager with contact for the PI and MDs; 4) Skipping visits: Participants will be allowed to miss two assessment visits 
during the treatment period and two during the long-term follow up for serious reasons. Minimum requirements: 
assessment visits V2, V8 or V10, V12 to complete the study due to serious reasons. Participants will be allowed to 
skip visits V4, V6, V9 or V10, V11. Post-treatment 4 (Visit 9) will be replaced by a phone interview. The follow-up 
visits 3,5,7 may be replaced by a phone interview of drug supply, device functionality, FS measures and calendar if 
necessary due to significant reasons.  In special circumstances, functional assessments (WHODAS and GDS) can 
be done over the phone (V9 or skipped assessment or post-intervention visits). Interim visits can be  scheduled if the 
procedures cannot be completed or re-training on the study procedures is needed. For patients running out of 


6 
 
medication that cannot come to the hospital for refill the BIDMC/BWH pharmacies will dispense the filled prescriptions 
to the study team to mail them out to subjects. 5) Appointment reminders: reminders are mailed a week before the 
visits; appointment reminder phone calls are made on the night before each visit); After V2- a phone call is made 
within one week to welcome participants to the study and meet our team cards. 6) Prior to V1 “Welcome on board” 
packages are mailed (study brochures and materials, overview, ICF, directions and instructions etc.). 7) New 
incentives: gift cards, key chains, mugs, totes, pens, etc. will be provided. 8) Meals are provided. 9) Transportation 
is reimbursed (parking and MBTA reimbursement, taxi in special circumstances, Uber/Lyft, pilot Lyft concierge 
service). 10) Visit 8 assessment will be performed even after treatment end date if patient cannot make it on time for 
that visit. Study team will ask the patient to stop study medication on the treatment end date and come for the 
assessment visit as soon as possible after that date. 
FDA assurance: Current active FDA-IND 107690 has been amended to follow FDA regulations; ViaNase is a 
minimum risk device and therefore IDE is not required. We will obtain renewed authorization to cross-reference Novo 
Nordisk IND 29089 Novolin® R, Regular, Human Insulin Injection (rDNA origin).  
Data and Safety Monitoring Board was established and the trial was registered at Clinical Trials.gov 
(NCT02415556). 
 
STUDY PROTOCOL   
Studies will be conducted at the SAFE Laboratory at the BIDMC and Brigham and Women Hospital  
(BWH) Harvard Catalyst Clinical Research Center (CRC). Joslin Diabetes Center will serve only for advertisement. 
Harvard Medical Center will serve for cognitive training. 
The PI and co-investigators have extensive experience in clinical studies in older vulnerable adults and all 
procedures that we propose. The protocol involves 24 weeks of treatment and 24 weeks of 
long-term follow-up, and it includes 12 visits (Table 1). There are 9 assessment visits (baseline, 4 on-treatment 
assessments , and 4 post-treatment assessments) and 3 short follow-up visits during the on-treatment . An interim  
visits can be scheduled in case participants are not able to come fasting for visit, or physical exam cannot be 
scheduled, or all activities for a given visit cannot be completed for any reason or for participants in the MRI and 
safety substudies. Participants in MRI substudy may be required to complete MRI exam on a special visit. Potential 
participants will be screened by a phone interview.  
 
Screening –V1 will include: informed consent, medical history, medications, vital signs, ECG, MMSE, metabolic panel 
(fasting glucose, HbA1c, lipids, CBC panel, C-peptide for insulin-treated diabetic subjects), height, weight, and waist 
and hip circumferences (HWC), demonstration of the ViaNase device. Participants of the MRI substudy will complete 
the MRI safety checklist and their head circumference and shoulder width will be measured. 
Participants of the safety substudy will begin baseline glucose monitoring for one week. 
The physical and neurological exam has to be completed on V1 or during in the interim visit or at the V2 baseline 
prior to  beginning of intervention (V2 Intervention 1). 
Enrollment, Randomization: The final eligibility and approval for participation is determined after completion of V1 
procedures or during the V2 (baseline) prior to V2 (Intervention 1).  
Baseline, Intervention 1-V2 will include: vital signs, physical and neurological exam, Toronto Neuropathy Scale (if not 
done before), medical history, fasting glucose, insulin and metabolic panels, endothelial and DNA markers, HWC, 
VAS for appetite feelings. Two blood draws will be obtained during this visit, one at baseline assessment and one 
during intervention 1.  
 
Visit 2 should be completed within 3 months after screening visit 1. The assessment visits should be completed within 
2 weeks of the scheduled visit, unless there are serious reasons to justify longer period. The end of treatment visit 
must be <168 days after the treatment started. The study completion visit must be on or before the study date.  
 
BASELINE ASSESSMENT will include: a neuropsychological assessment, a short WTAR IQ test 
(http://www.pearsonclinical.com/psychology/products/100000256/wechsler-test-of-adult-reading-wtar.html ), 6-min 
normal walk and performance of a dual task (a 6-min walk while counting backward), 30-second balance test with 


7 
 
eyes open, 30-second balance test with eyes closed, functional measures and depression scale. INTERVENTION 1 
will be done during V2, and will begin after ~30-min rest. INI or placebo will be administered and followed by blood 
draws for glucose and insulin, neuropsychological, depression and functional assessments, normal walk and walk 
with a dual task.  
ASSESSMENT VISITS – V2, V4, V6, V8, (V9*), V10, V11, V12 – will include the same laboratory panels, 
anthropometric measurements, VAS, cognitive, functional, and gait testing procedures as V2. One week after V2 the 
study team will call patients to check compliance and assess any problems with device usage and other study 
procedures. Visit 9 (V9*) will be a virtual visit that will be done over the phone and will include updates on medical 
history, medications, AEs and one fasting glucose finger stick measurement at one week post treatment and  
functional assessments (WHODAS and GDS), and complete Visual analog scale (VAS). Participants will receive the 
functional assessment forms, VAS at V8 and will be asked to mail the forms back. 
 
There will be a baseline assessment and 4 assessments during on-treatment  (ON-TREATMENT  V2 week 1, V4  week 
8, V6 week16, V8 week 24 and 4 assessments during post-treatment (POST-TREATMENT V9 week 25, V10 week 32, 
V11 week 40 and V12 week 48)  On-treatment, there will be 3  medication refill follow-ups   (V3 week 4, V5 week 12 and 
V7 week 20)  which will include: vital signs, glucose measurements using a finger stick, drug inventory and refill, 
compliance checks, AEs monitoring. Subjects will continue their usual daily activities and treatment plans, will measure 
fasting glucose with a finger stick once a week and when symptomatic for hypoglycemia, and keep a detailed diary of 
physical activities (38). V3 will be 3 weeks after enrollment (V2) as a run-in period to ensure compliance and 
understanding of procedures and proper device use.  
If patients are diabetic treated with medications or insulin and they take their medications in the morning, they will be 
asked to hold their morning dose of sugar control medications before the visits that require to come fasting  (V2, V4, 
V6, V8,V10, V11, V12). They should bring their medications with them for the visit and they will take them after the 
fasting blood draw.  If they cannot come  fasting to these visits, they will be asked to come early morning next day for 
fasting blood draws only.    
 
INTERIM VISIT- The subject may be asked to come on a separate visit if study procedures cannot be completed during 
any of the study visits for any reason. For example, if they are not able to come fasting for their first visit or other study 
visits, we will ask them to come back for an extra visit; or any scheduling issues for physical exam. Safety substudy, MRI 
study walk test, cognitive tests or other reasons. 
Safety Substudy: A subset of 20 insulin-treated subjects will also complete  FS glucose monitoring  five times per 
day for 1 week before and 1 week after INTERVENTION 1 (V2) using our established protocol.(39). C-peptide 
levels will be measured in patients enrolled in this substudy in order to select type 2 DM subjects with greater beta 
cell reserve and thus lesspropensity to experience hypoglycemic events improving subject’s retention. Patients with 
type 2 DM pts on insulin with a C-peptide of <0.8 nmol/L and a corresponding blood glucose > 150 mg/dl should be 
excluded from the substudy, even without history of hypoglycemia during FS measurements  or otherwise. Insulin-
treated type 2 diabetics with a C-peptide of <0.8 nmol/L and blood glucose >150 mg/dl will be excluded even 
without history of hypoglycemia during finger stick measurements. The study was terminated for futility in 2017). 
 
MRI Substudy: 40 DM subjects will also complete an MRI scan at baseline (within ten days before V2) and at or 
within ten days before V8 INTERVENTION 4. 
 
 
 
 
 
 
 
 
 


8 
 
Table 1: Protocol and procedures 
 
 
 
Table Abbreviations: ICF: informed consent; INI vs. PL:  insulin vs. placebo; Med Hx: Medical. History; Phys: 
Physical; d: day Cogn test; Cognitive tests * MMSE only;  **FS: Finger Sticks; AE, SE: Adverse  and Serious  
Events. Ass: Assessment, PTASS: post-treatment assessment. 
 
Insulin/placebo administration 
Insulin/saline will be delivered using ViaNase electronic atomizers (Kurve Technology, Inc. Lynnwood, WA). The 
ViaNase electronic atomizers allow precise electronic dosing for each administration and will be pre-programmed by 
the company. They also allow for targeted delivery into the olfactory region with efficient and effective nasal cavity 
saturation; and with minimal peripheral deposition to the lungs and stomach. Clinical results showed that the average 
area of intranasal deposition is almost 300 percent greater than with spray pumps. Each administration device will 
contain a pre-programmed daily dose of 40 IU insulin (Novolin® R Novo Nordisk, Basvearg, Denmark )  or sterile 
saline to be administered once daily in the morning before breakfast, a process that takes about 1 minute. The device 
dispenses 0.1ml per 20 seconds, so participants will have to press the devices twice for each nostril to receive 0.4ml 
dose. Each vial will contain 10 ml of insulin (100 IU/mL) or placebo and will be used over a 3-week period, to be 
refrigerated between daily treatments. Placebo, the sterile saline, will be stored in identical vials. Participants will be 
required to bring the device with the INI/placebo vial for each study visit. During the study visit the device usage will 
be reviewed and the vial will be replaced. The volume of remaining insulin or placebo will be measured to quantify 
usage and assess compliance with the study. Research participants will stay on intranasal insulin/placebo treatment 
for a maximum of 168 days. Participants that use the device 65% of the days will be considered compliant. If this 
compliance rule is not met, participants will we excluded from the study and analyses.  
 


9 
 
Packaging and Labelling of Study Medication(s) 
BIDMC research pharmacy will handle insulin and placebo storage, labelling and dispensing, randomization 
documentation and tracking of medications shipment and packaging using the BIDMC online tracking system for the 
BIDMC site.  
 
BWH hospital pharmacy will handle insulin and placebo storage, labelling and dispensing, randomization 
documentation and tracking of medications shipment and packaging using their online tracking system for the BWH 
site. 
 
Storage and Drug Accountability of Study Medication(s) 
Insulin/placebo will be stored at the BIDMC research pharmacy and refrigerated at 2-8OC. To ensure blinding study 
participants, insulin/ placebo will be placed in the sterile vials extended stability dating to will be performed according 
to USP.  Participants will be required to store the devices with the insulin/placebo vials in the refrigerator. 
Depending on the site, BIDMC and BWH pharmacy online tracking systems will be used to track medications. 
Participants will be requested to bring their devices with used and un-used vials to the study visits. BIDMC/BWH 
pharmacy will measure the residual vial volumes as a part of the compliance procedures. Un-used insulin will be 
returned to Novo Nordisk. Unused placebo-sterile saline will be disposed using the disposal guidelines.  
 
Auxiliary Supply 
Insulin/placebo will be administered using the ViaNase device (Kurve technology, Inc Lynnwood WA). 
 
Potential limitation  
Meta-cresol which is used as a preservative in insulin has a distinct smell that may be recognizable by the subjects 
using insulin, and therefore diabetic subjects treated with SC insulin may be familiar with the smell. However, the 
ViaNase device itself has a distinct odor that is noticeable during device operation (air only) and even during the 
saline administration. Participants will be trained with a device that operates on air only, and there is noticeable 
distinct smell due to the device operation that appears to mask other odors. The investigators are present during the 
first INI/placebo administration during V2 intervention. Participants record any unusual events and observations in 
the home diaries, which are reviewed at each visit.   
 
 
EXPERIMENTAL PROCEDURES AND MEASURES 
A neurocognitive assessment battery  will be administered using the Cambridge Cognition computerized system 
(CANTAB) http://www.cambridgecognition.com). CANTAB enables simplified data collection, standardized 
administration, 
and 
computerized 
grading 
that 
increases 
reliability 
of 
the 
data 
collected 
(see 
http://www.cantab.com/cantab-tests.asp for test details). CANTAB provides multiple validated parallel versions of 
these tests to minimize practice effects in a complex repeated measures design. The CANTAB brief 
neuropsychological battery correlates with traditional measures that showed on-insulin improvement (24) and has 
been extensively used in cognitively impaired(40),(41) and AD populations(42). The CANTAB will be administered at 
BASELINE, during ON-TREATMENT  (V2, V4, V6, V8)  and POST-TREATMENT VISITS (V9,V10,V11,V12) (Table 
2). 
 
Paired Associates Learning (PAL): PAL, a measure of visuospatial memory and learning, uses a pattern recognition 
task useful for assessing older adults with MCI or AD. Outcome Measure: PAL Total Errors (adjusted): is the total 
number of errors across all assessed problems and all stages.  
 
Spatial Working Memory (SWM): SWM that tests the participant’s ability to retain spatial information in the working 
memory by identifying the boxes with and without tokens, is a sensitive measure of executive dysfunction in DM.(43) 
The SWM strategy includes errors and latency measures (44). SWM showed that DM patients have slower 
processing speed and worse spatial planning than controls (45),(43). 
Outcome Measures: Between Errors are number of times the subject revisits a box to find a token.  


10 
 
  
Rapid Visual Information Processing (RVP): RVP is a test of sustained attention and a sensitive measure of 
general cognitive performance. Slower RVP speed detected DM-related cognitive impairment in the frontal and 
parietal lobes.(29, 46) Task: Participants are asked to detect and register target sequences of digits. Outcome 
Measures: A′ (A prime) and Response Latency. A′ is the signal detection measure or sensitivity to the target, 
regardless of response tendency (range 0.00 to 1.00; worse to better).  
Verbal Recognition Memory (VRM): The VRM assesses immediate and delayed verbal memory (a list of words) 
information under free recall and forced choice recognition conditions. Outcome measures: VRM Free Recall: total 
correct of a word list, which is a measure of immediate verbal learning. VRM Recognition: total correct is a measure 
of delayed verbal learning.  
 
Executive function composite z score is a sum of individual z scores of PAL, SWM-total errors and strategy). Verbal 
memory composite z score is a sum of individual VRM z scores (immediate free recall and immediate and delayed 
recognition). 
 
WTAR- premorbid verbal IQ test. http://www.pearsonclinical.com/psychology/products/100000256/wechsler-test-
of-adult-reading-wtar.html. Brief (under 5 minutes) measure of premorbid verbal IQ, which provides a correlate of 
verbal intelligence and is well-normed. The manual provides conversions from verbal IQ (VIQ) to full scale IQ 
(FSIQ). 
 
The Mini Mental State Examination (MMSE) will be administered at V1 to screen for clinically significant 
dementia,(47-51) using age- and education-adjusted norms. Therefore, we will adopt relatively liberal criteria for 
inclusion of individuals with MCIs, as these are likely to be prevalent and representative of the targeted cohort, 
particularly at the higher age range, and exclude only individuals with MMSE ≤20 (total score =30).  
 
Functional measures: Geriatric Depression Scale (GDS) is a self-report measure of overall mood, activity, 
sadness, and worry. Outcome measure: a total score (up to 30 points) that reflects level of depression.  
 
WHO Disability Assessment Schedule 2.0 (WHODAS  2.0) (http://www.who.int/classifications/icf/whodasii/en/) is 
a short, easy-to-administer and widely used self-report measure of function and disability that is valid across a 
broad age range and across all diseases. Outcome measures: Standardized disability levels and profiles for: 
Cognition, understanding and communicating; Mobility, moving and getting around; Self-care, hygiene, dressing, 
eating, and staying alone; Getting along, interacting with other people; Life activities, domestic responsibilities, 
leisure, work, and school; Participation, joining in community activities. The summary score will be converted into a 
percentage score – WHODAS Complex score. 
 
Gait speed and step characteristics will be measured with a Mobility Lab System (APDM, Inc., Portland, OR) during 
6-min walking at usual speed and 6-min walking with a dual task counting backwards subtracting 7.  
 
Balance will be measured with a Mobility Lab System (APDM, Inc., Portland, OR) during a 30-second standing 
position with eyes open and 30 seconds with eyes closed. 
Laboratory measures: routine blood and urine panels including fasting glucose, HbA1c, fructosamine, insulin, CBC, 
lipid panels and genetic markers (ApoE4), markers of endothelial function (soluble intracellular adhesion molecule, 
and vascular adhesion molecule, C-reactive protein, and matrix metallopeptidase 1-10)  that have a demonstrated 
relationship to gray matter atrophy and cognition (5). Insulin resistance will be quantified using an updated HOMA-2 
model (http://www.dtu.ox.ac.uk/homacalculator/)(52). C-peptide will be measured only in insulin-treated DM type 2 
participants. 
 
DNA samples: Serum samples will be obtained to measure genetic markers (ApoE4), that have been linked to 
greater risk for Alzheimer’s disease. Genetic and DNA markers (ApoE4) collection was requested by NIH, and was 


11 
 
approved by BIDMC IRB in the protocol and ICF. Blood samples will be stored, and analyzed upon the study 
completion. The results will not be available until un-blinding of the study. Acutely, INI enhances verbal memory in 
memory-impaired ApoE4-adults (20, 27, 53). All of the above is contained in the ICF with an option to opt from 
providing a sample for DNA analyses. 
 
Anthropometric measurements: Participants’ body weight, height, waist and hip circumferences will be measured 
by  the study team at V1 and assessment visit  V2, 4, 6, 8,10, 11 and 12. 
 
 
Visual Analogue Scales (VAS): Appetite feelings will be assessed with the use of VAS at V2, 4, 6, 8, 9, 10, 11 and 
12. Participants will be asked to rate their appetite feeling on 10 cm visual analogue scales before and after meal 
and/or INI/placebo administration.  
 
 
Magnetic resonance imaging (MRI) substudy:  anatomical, perfusion, vasoreactivity, functional MRI. 
We will conduct an exploratory substudy in 40 randomly selected DM subjects to determine the long-term INI effects 
on cerebral perfusion, vasodilatation, and functional connectivity. MRI will be done at baseline (before treatment 
initiation) and at end of treatment (during or within 10 days before V8. Brain scans will be acquired using a GE 3 
Tesla MR750 scanner with 32-head coil in 3–D plane. Subjects for the MRI substudy should have a head 
circumference less than 65 cm and shoulder width less than 60 cm in order to fit to the machine. Pseudo-continuous 
arterial spin labeling (PCASL)  
and 3D stack of spirals Rapid Acquisition with Relaxation Enhancement (RARE) sequences will be used to measure 
cerebral blood flow (CBF) and vasoreactivity (mL/100g/min) and (54-56) resting-state fMRI blood-oxygen-level 
dependent (BOLD) will be used to measure intrinsic brain activity. 
Protocol: High-resolution anatomical images will include T1-weighted anatomical images were acquired with a 
3D BRAVO sequence and T2 and fluid attenuation inversion recovery (FLAIR) to improve image registration and 
to review images to detect brain lesions. Subjects will complete PCASL (6 min) and BOLD (8 min) during supine rest 
in normocapnia, and PCASL during hypercapnia (rebreathing of a mixture of 5% CO2 and 95% air for about 2 min), 
hypocapnia (hyperventilation for 2 min), with vital signs and CO2 monitoring. 3DCASL is a noninvasive technique 
utilizing electromagnetic labeling of water in arterial blood. Reference images will be acquired with the same PCASL 
sequence for quantification of CBF brain map. CBF images will be automatically reconstructed and stored in the 
scanner database. Quantification of CBF: CBF will be quantified from PCASL during normocapnia, hypercapnia, 
and hypocapnia, as reported.(57-61) Regional CBF will be quantified via a voxel-based approach complemented with 
region-based analyses using a template of anatomical regions (e.g., insular cortex).The average difference between 
control and label images and the intensity in the reference image acquired with the same sequence will be used to 
calculate  
 
CBF (Formula 1),
CBF 
b (S c S l )
2aT1aC exp w
T1a



1 exp 
T1a










    [1] 
where b is the density of brain tissue, 1.05 g/ml (62),  is the labeling efficiency, assumed to be 70% due to efficiency 
of background suppression and labeling, w is the post-labeling delay of 1.5 seconds (57),  is the labeling duration of 
1.5 seconds, T1a is the T1 of arterial blood(63), a is the density of water in blood, 0.85 g/ml,(62) and Sl and Sc are 
the signal intensities in the labeled and control images, respectively, and C is the reference image. The equation 
assumes that the labeled blood remains in the arterioles and capillaries and does not reach the tissue.  
 
Vasodilatation reactivity: will be calculated as a regional perfusion difference between hypercapnia and baseline 
divided by the difference in CO2 between hypercapnia and baseline.  
 


12 
 
Vasoconstriction reactivity will be calculated as perfusion difference between hypocapnia and baseline divided by 
the difference in CO2 between hypocapnia and baseline. 
For vasoreactivity we will use only the first 2 min of PCASL data during baseline to match the signal-to-noise ratio at 
the other 2 conditions.  
 
Functional connectivity: Resting state functional connectivity will be measured using fractional amplitude of low 
frequency fluctuation (fALFF) from BOLD fMRI data (see Analyses Section). 
 
 
 
SAFETY: 
 
DM management: Insulin/placebo will be added to participants’ medication regimen for diabetes and any co-morbidities 
DM participants will receive a usual care from their providers. They will be required to inform the investigators about any 
changes in their regiment or health status during the follow-up visits. Glycemic control and other potential confounders 
will be monitored and their effects will be tested and accounted for in the analyses. Primary care providers will receive 
study description and laboratory results upon enrollment and after each intervention visit during the treatment period (V2, 
V4, V6, and V8) and if an AE occurs. 
 
Medical Oversight: All patients are seen by a physician (study physician or CRC medical research officer (MRO)) 
during screening visits.  The study physicians review all materials from the screening visit (including the physical 
exam by MRO) and provide approval for the study. CRC nurse will perform medication reconciliation at each visit. In 
accordance with the study procedures subject will be asked if they experience adverse events at all visits post 
baseline measurements. During the study visits the CRC nurse meeting the patient will identify adverse events and 
will discuss these with the study MD, while the patient is present.  
 
Concomitant illnesses and medications: 
INI/placebo will be used as add on medication to current  medications for treatment of concomitant illnesses per 
definition below. Concomitant illness: any illness that is present at the start of the trial (i.e. at the first visit). 
Concomitant medication: any medication other than the trial product(s) that is taken during the trial, including the 
screening and run-in periods. 
 
Safety substudy: DM participants treated with subcutaneous insulin will be required to complete one week of glucose 
finger stick monitoring five times per day prior to V2 baseline and one week after beginning of V2 intervention. 
Participants will be requested to document the time of INI/placebo administration the time and doses of medications 
administration, meals and  activities in diaries (39). Finger stick glucose will be measured in the morning before 
breakfast after INI/placebo administration, 2 hours after breakfast, before lunch, dinner and at bedtime. The C-peptide 
blood levels will be measured as an additional measure to select type 2 DM subjects with greater beta cell reserve 
and thus less propensity to experience hypoglycemic events improving subject’s retention. 
 
Glucose measurements using a finger sticks:  All study Participants will be required to measure fasting glucose 
once a week using a finger sticks including one week post-treatment (V9). 
 
 
 
DATA MANAGEMENT AND STATISTICAL ANALYSES PLAN  
Data Management: The electronic data capture system ScienceTRAX (FDA, HIPAA compliant) will be used for the 
questionnaires, assignment of variable names and coding and verification. Cognitive and gait data will be captured 
electronically (CANTAB, Mobility Lab), and laboratory data will be uploaded. The data will be converted to SAS 
datasets for analysis.  


13 
 
Table 3 lists outcome variables and analytical methods. 
 
 
 
 
Table 3: DEPENDENT AND INDEPENDENT OUTCOME VARIABLES, TIME POINTS,  AND ANALYSES 
Aim  
Dependent Variable 
Independent Variables 
Data Collection 
Times 
Method of Analysis 
Aim 
1a 
Visuospatial learning and 
memory; Learning  and 
sustained attention 
(all continuous variables) 
PAL : Total errors -
adjusted 
SWM: Between errors 
and Strategy 
RVP: A′ (A prime) 
responses & latency 
VRM: Recognition - total 
correct  
VRM: Free recall – total 
correct 
TREATMENT_ARM, 
TIMEG, 
TREATMENT_ARM*TIME 
Baseline,  
4 On-treatment   
(V2,V4,V6,V8) 
Post-treatment 
 4 Post-treatment 
(V9,V10,V11,V12) 
 
*V9 no Cantab data 
Linear Mixed Effects Models 
Aim 
1b 
Gait speed, WHODAS, 
GDS 
(all continuous variables) 
TREATMENT_ARM, 
TIMEG, 
TREATMENT_ARM*TIME 
Baseline 
4 On-treatment 
(V2,V4, V6, V8) 
4 Post-treatment 
 (V10, V11,V12) 
 
V9 has only 
WHODAS and 
GDS 
Linear Mixed Effects Models 
Aim 
2a 
Responses to INI therapy  
(binary) 
INI_RESPONSE  
 
 
 
Age, sex, adiposity  
Fasting glucose, insulin, 
HbA1c, Insulin resistance 
(HOMA-2), DM_duration 
Endothelial function 
Genetic markers (ApoE4) 
VBaseline 
4 On-treatment 
(V2,V4, V6, V8) 
4 Post-treatment 
 (V10,V11,V12)  
 
V9* only glucose FS 
Generalized Linear Model with Log Link 
and Binary Error term 
Aim 
2b 
Trajectory of INI therapy 
response 
 
(all continuous variables 
from Aim 1a) 
TREATMENT_ARM, 
TIMEG 
V2,V4, V6, V8, 
V10,V11,V12 
V9* limited dataset 
Mixture Modeling Generalized Logit 
Model & General Linear Models 
Aim 2c  
MRI –Perfusion, vasodilation  
reactivity Functional 
connectivity 
TREATMENT_ARM* TIME , 
V2 baseline, V8 end of 
treatment 
Mixture Modeling Generalized Logit Model & 
General Linear Models 
Aim 
3a,  
 
 
 
 
 
3b 
Safety of INI therapy  
(all continuous variables)  
fasting glucose*; HbA1c, 
insulin resistance, blood 
pressure, number of 
hypoglycemic episodes 
TREATMENT_ARM, 
TIMEG, 
TREATMENT_ARM*TIMEG 
V2,V4, V6, 
V8,V10,V11,V12 
weekly glucose finger 
stick V2-V9 
V9*limited dataset 
 
 
 
IDDM baseline and 
post V2 one week FS 
5xdaily  
Linear Mixed Effects Models 


14 
 
Aim 1a and b: To determine whether INI improves long-term cognition and memory in specific domains and normal 
and dual task gait speed in type 2 DM subjects as compared with the placebo and non-DM groups.  
Primary efficacy variables are cognitive outcomes and gait (executive function and verbal learning composite scores, 
NW and DTW).  We will use 5 summary measures of the 4 computerized CANTAB tests. PAL Total errors (adjusted) 
and SWM -Between errors and Strategy are 2 assessments of visuospatial learning and memory, previously tested using 
a Brief  Visuospatial Memory test (BVMT_Trial 2 and BVMT_Total recall). We will also use 3 measures of learning and 
sustained  attention: RVP: A′ (A prime) and responses latency, VRM Recognition - total correct,  and VRM Free recall – 
total correct, for which we previously used Verbal Fluency Category and FAS. These new variables are highly correlated 
with standard measures, but computerized systems allow for more accurate and higher-quality data collection. The 
Executive function composite score will be a sum of z scores from Paired Associates Learning (PAL, total errors) and 
Spatial Working Memory (SWM, total errors and strategy to complete tasks; lower score better). Verbal memory 
composite score will be calculated from z scores of verbal immediate free recall, immediate and delayed Verbal 
Recognition Memory (VRM; higher score better). The primary variables will be collected at baseline, during 4 intervention 
and 4 post-treatment visits (V2-baseline, V2 intervention 1, V4, V6, V8, V9-replaced by phone interview, V10, V11 and 
V12) (Table 3). Primary cognitive outcomes will be converted to scaled z-scores and summed to create composite 
cognitive measures. Primary efficacy measures will be compared between DM-INI and DM-Placebo and between 
Control-INI and Control placebo groups at baseline, on-treatment and post-treatment. The end-of-treatment 4 (V8) is the 
primary time point of interest in the assessment of the efficacy of the INI treatment at the end of intervention (Tables 2 
and 3). Functional measures (GDS and WHODAS) will be also collected at these time points. 
 
Linear mixed-effects models will be to estimate the effects of INI in the DM and Control groups. 
The INI efficacy for each of the  variables listed above are the differences D1, D2, D1-D2 where D1=DM_INI-
DM_PLACEBO, and D2=CONTROL_INI-CONTROL_PLACEBO. We will estimate D1 and D2 two different ways: first, 
at each of the 8 time points; second, the D1 or D2 differences at baseline, on-treatment and post-treatment.  Statistically, 
we will use a 2-tailed test and will test for the hypotheses that D1 ≠ 0, D2 ≠ 0, D1-D2 ≠ 0. To estimate D1, D2, and D1-
D2, we will use linear mixed-effects models (LMM),(64) 1 for each of the outcome variable. The dependent variable will 
be the outcome variable, the independent variable will be 4-level indicator variable (TREATMENT_ARM), 3-level 
indicator variable TIMEG, and the interaction TREATMENT_ARM*TIMEG. The randomization scheme would balance 
the background variables or baseline data, so that adjusting for these potential measured confounders may not be 
necessary; however, we will make sure that their distributions among the treatment arms are indeed similar. We will 
review the potential confounders such as baseline differences in cognition, years of education, and potential effects of 
age, sex, and race and use normative values for cognitive tests that account for these variables. Because the 
measurements for each subject are longitudinal and repeated, the within-subject data are correlated, we will use either 
an autoregressive model with lag such as AR(1) or compound symmetry to model the within-subject correlation. We will 
use the Akaike information criterion (AIC) computed from the maximized restricted log likelihood value to select the 
appropriate variance-covariance structure for the LMMs. We will use linear contrasts formed from the estimates of the 
main effects TREATMENT_ARM and TREATMENT_ARM*TIMEG to estimate quantities D1, D2, D1-D2, and 95% 
confidence intervals at each of the 8 time points.  
 
Power analyses 
We computed the required sample size based on the expected estimated mean difference at the end of treatment 
between the DM-Placebo and DM-INI group for CANTAB cognitive variables SWM errors, SWM strategy, VRM free 
recall. We set type-I error rate at 0.05, power of 0.80 or above, effect size of 15% improvement due to INI, and 
obtained n=120 for the DM group (60 DM-INI; 60 DM-Placebo) and n=90 for the Control group (45 Control-INI; 45 
Control-Placebo) yielding 210 patients with data at the end of the treatment period.  
 
 


15 
 
Analysis for Aim 2a:  Identify a clinical phenotype predictive of a positive response to INI therapy based on 
demographics, glycemic control measures, endothelial function, and genetic markers (ApoE4).  For Aim 2a, we 
define a positive response to INI therapy as D1=DM_INI-DM_PLACEBO for PAL (Total errors (adjusted) and SWM 
-Between errors and Strategy ≥1.5 at end-of-treatment 4 (V8) or at any time from week 24 to week 48 (V9*-V12). 
For V9 only GDS and WHODAS, glucose FS will be available The outcome is a binary variable (INI_RESPONSE) 
with a value of 1 for positive response or 0 otherwise. We have potential phenotype variables predictive of 
INI_RESPONSE: 3 demographic characteristics (AGE, SEX, ADIPOSITY), 5 glycemic control measures 
(FASTING_GLUCOSE, INSULIN, HbA1c, HOMA2_INSULIN_ RESISTANCE, DM_DURATION), endothelial 
function (ENDOTHELIAL), genetic markers (APOE4). These potential predictive variables will be used in a 
generalized linear model (GLM) with log link and binary error. The Akaike information criterion (AIC) will be used to 
select the optimum model predictive of INI_RESPONSE. We will first carry out a univariable GLM model and will 
retain those predictors that have a p-value of ≤0.20. We will then perform an all-subset model selection procedure 
by generating all possible main-effects models. For example, if 5 variables meet the univariable model criterion of 
having p-value ≤0.20, then there will be 25-1 = 31 possible main-effects models. Each of these will yield an estimate 
of AIC value. We will rank these models by ascending order of AIC estimates and will examine the first 5 models 
with the smallest AIC estimates. We will consider models whose AIC estimates are within 1% of each other to be 
equivalent statistically, and will also take into account the clinical significance and relevance of the chosen model. 
We will compute and report the estimated area under the receiver-operating-characteristic curve (aROC) by 
obtaining the model’s c-statistic. This is a check of the discriminatory value of the predictors. Models will be 
calibrated using the Hosmer-Lemeshow statistic that will allow us to estimate the predicted probability of positive 
response to INI for any patient with a given set of predictors’ values, and it will indicate the magnitude of 
association of the predictors in relation to the likelihood of a positive response to INI.  
 
Power analyses revised (9.11.2017) for reduced sample size of 120 DM and 90 Controls 
As determined in Aim 1, we will have a sample size of 210 subjects. With an estimated attrition rate of 20%, we will 
have 168 subjects by the end of the study. We estimate that 30% will have a positive response (INI_RESPONSE=1). 
We plan to split the sample of 168 into a validation set and a testing set. With N = 84 for testing, and an expected 
response rate of up to 30%, we will have 25 positive outcomes (INI_RESPONSE=1). We need about 5 outcomes per 
predictor in the selected multivariable GLM model. Thus, a sample size of 84 with 25 expected positive outcomes 
would be sufficient for the estimation. We will validate the model using the validation set of 84 subjects. In both the 
test and validation model, we expect to have a c-statistic of at least 0.70.  
 
 
 Aim 2b: We will determine different types of longitudinal trajectories that allow prediction of escalating dose-effects 
and maximum response to INI therapy. It is likely that trajectories based on the profile of baseline and 7 assessments 
for each of the 5 cognition outcomes, functional outcomes, and gait speed will form a finite number of distinct groups. 
For WHODAS and GDS we will have 8 assessments. Some subjects may experience the INI benefit earlier (e.g., at 
week 8 or earlier), while others may experience it later (up to week 24), and others may not respond to the INI (thus, 
a flat or declining line through follow-up time). Therefore, we will estimate the number and shape of the trajectories, 
using a mixture modeling technique of the longitudinal data for each subject. We will plot the data for each subject 
over time to understand the shape of the observed trajectories and how the individual trajectories cluster. We will 
assume that the number of clusters ranges from 1 to 6, but we expect the optimal estimate of the number of clusters 
is 3 or 4. The marginal density of a subject having the outcome variable cognition/memory/gait speed measurement 
at a particular time point is modeled as a function of the product of 2 densities: the probability of the outcome belonging 
to a particular trajectory, and the probability of observing such a measurement belonging to a particular trajectory. 
The first probability is modeled using a generalized logistic model since the outcome is categorical (from 1 to 6 
categories/types of trajectories), and the second probability is a polynomial linear regression of the outcome 
variable as a function of time (linear, quadratic, cubic). To select the optimal number of trajectories, we will compare 
the Bayesian information criterion value from the 6 models (corresponding to 1 to 6 types of trajectories). The 
algorithm and the SAS macro for this type of modeling has been published (65). 
 


16 
 
Power analyses includes reduced sample size of 120 DM and 90 Controls. We will use data from all subjects for 
this analysis. Given that we will have up to 6 data points per subject, estimating up to the cubic function for the 
trajectories would be acceptable with our sample size of 210 subjects. 
 
Aim 2c: To determine the INI effects on regional vasodilation and functional connectivity.  
Regional perfusion and vasoreactivity (vasodilation, vasoconstriction responses) will be quantified using Formula [1] 
in anterior circulation (e.g., the MCA territory and insular cortex) by 3D-PCASL MRI. Resting state brain activity and 
functional connectivity will be measured using fMRI fractional amplitude of low frequency fluctuations (fALFF) 
measured by BOLD MRI. MRI outcome variables (MCA_PERFUSION, VASODILATATION_RESPONSE, fALFF) will 
be obtained at baseline (before treatment initiation) and at the end of intervention (during or within 10 days before 
V8). For each subject, perfusion images will be registered to the corresponding high-resolution anatomical images 
and aligned to baseline (V2 pre-INI). The anatomical images in each subject will be normalized to the standard brain 
T1 template using statistical parametric mapping (SPM version 8, http://www.fil.ion.ucl.ac.uk/spm/, Wellcome 
Department of Imaging Neuroscience, London, England) toolbox. The alignment parameters will transform the 
perfusion maps to the space of the baseline perfusion image, the registration parameters will transform those images 
to the space of high-resolution anatomical images, and the normalization parameters will further transfer those 
images to the space of standard brain template. In this way, the perfusion maps from all subjects will be co-localized 
with the standard brain template. These maps will be smoothed by using an isotropic Gaussian kernel filter of 8-mm 
full width at half maximum to meet the assumption of the Gaussian field theory for SPM analysis.  
 
Low-frequency (0.01–0.08 Hz) fluctuations in resting-state BOLD signals are considered to reflect intrinsic neural 
activity in humans (66),(67). Recent studies proposed a reliable measure of intrinsic neural activity using Falff 
(68)(69). fALFF has proven to be sensitive to detect change in physiological and pathophysiological states of brain(68, 
70). An fALFF map will be calculated based on the power spectrum of each voxel’s time series, i.e., from the power 
in the low frequency range (0.01-0.08 Hz) and the power of the whole frequency range (0-0.25 Hz). BOLD image 
processing and statistical analysis will be carried out using SPM8 toolbox. BOLD image volumes will be aligned to 
the first BOLD image volume for the baseline and 4 week intervention of each subject. A created mean BOLD image 
from the alignment will be co-registered to the T1 structural image in the same session, and the co-registration 
parameters will be used to transform the fALFF map from the original BOLD space to T1 space. The T1 structural 
image will be normalized to the standard brain Montreal Neurological Institute T1 template, and the resulting 
normalization parameters will be used to further transform the fALFF map to the standard space. The normalized 
fALFF maps will be smoothed with isotropic Gaussian kernel filter of 6-mm full width at half maximum. The BOLD 
data will be high-pass filtered with a cut-off of 128 s (0.008 Hz) to remove low frequency noise. We will use same 
LLM approach as in Aim 1 to calculate differences between TREATMENT_ARM*TIME to compare INI treatment to 
placebo using SPM8. Only the clusters exceeding the whole-brain false discovery rate (FDR) of p < 0.05 will be 
reported as significant clusters. Regional analysis will be performed on the clusters to rule out the effects from 
potential confounders, such as age, sex, and race. Region-based analysis will be also performed in anatomical 
regions of specific interest, e.g., insular cortex and MCA territory, regressing out the above potential confounders. 
We have reported (24, 25) that acute positive cognitive response to INI therapy depends on vasodilation in the MCA 
territory (R2 =0.58, p=0.0098). We will also use our LMM approach described in Aim 2a.  
 
Power analyses revised use sample size of 120 DM and 90 Controls. We have based our power estimate on our 
data (24, 25) that showed an increase in perfusion on INI in right insular cortex in the DM group as compared to 
placebo (44.5±12.28 vs.37.7±11.8, p=0.028; paired t -test). With 60 subjects we will have a power 0.81 to detect a 
difference between insulin and placebo at this observed level of mean difference of 6.8, and SD of 13. 
 
 
Aim 3a: To determine the long-term safety of intranasal insulin vs. placebo. 
For this Aim we have 5 continuous safety outcomes: FASTING_GLUCOSE, Hb1AC, HOMA-2 INSULIN 
RESISTANCE, NUMBER_HYPO_EPISODES, BLOOD_PRESSURE. We will evaluate the D1 and D2 for these 
outcomes at each of the on-treatment and post-treatment 8 visits (V2, V4, V6, V8,V10, V11 and V12; V9 will have 


17 
 
only AEs, and glucose using FS) using the LMM and interaction term (as described in Aim 1). We will track the weekly 
glucose and AE monitoring logs. Based on our data with no AEs and studies with infrequent mild AEs, we do not 
expect significant differences from placebo.  
 
Aim 3b: Safety substudy. In the first 20 DM patients treated with subcutaneous insulin, we will conduct measure FS 
glucose five times per day for one week  during pre-treatment and one  week after V2 on INI or placebo treatment. 
We will calculate the number of symptomatic and asymptomatic hypoglycemic episodes (defined as glucose 
<70mg/dL on plasma glucose or finger stick measurement) and compare them using LMM before and after the first  
week of treatment to assess the overall glycemic trends and variability, and to assess the time-dependencies between 
INI administration, glucose control medications administration, meals and activities.  
 
Power analysis 3 a, b: For 5 safety outcomes, we expect that the 95% confidence interval of D1 and D2 will include 
zero, indicating no differences between INI and PLACEBO for both the DM and control groups.  
 
MISSING DATA  
Subjects and data will be included as described above in the Statistical section. Since this is a longitudinal study of 
48 weeks with data collected as frequently as weekly, and every 3 weeks (safety), and at 8 different time points for 
Labs, Cognitive tests, Functional tests, and Gait, we expect to have missing data that could occur for both the 
outcome (dependent) and exposure (independent) variables resulting from patients dropping out due to AEs or other 
reasons. We expect the key independent variable of TREATMENT and TIME used in Aims 1a, 1b, 2b, 2c, and 3a, 
3b to have no missing data. Potentially we may have minimal missing data in model covariates in Aim 2a (< 5%). 
Any missing data of these covariates for Aim 2a would cause the entire observation for that patient to be dropped 
from the analysis; therefore, we will make sure that these variable distributions are monitored carefully during 
collection. Other aims have continuous outcomes and their distributions are assumed to be random. The 
documentation of any exclusions of data will be stored with the remaining trial documentation.  LMMs that will be 
used for the analysis are designed to handle missing data in dependent variables. Therefore, a missing data point 
would not cause estimation issues since the distribution of the data (or its transformation using, for example, log 
function) is assumed to be normally distributed, and the missing data point for the dependent variable is implicitly 
imputed by the LMM model. However, even if LMM could impute the missing data points, when more than 70% of a 
participant’s data points are missing, that subject’s data may not be used in the LMM. We will attempt to use the 
multiple imputation technique via the Markov-Chain-Monte-Carlo algorithm in sensitivity analyses only to check for 
the effect of missing data on model inference.  
Interim Analysis Not planned. 
 
 
SUBJECT SELECTION 
 
We anticipate that we will screen 800 subjects by phone and enroll 360 subjects (ICF signed) in order to meet our 
enrollment goals of 210 subjects complete V8 treatment upon the trial’s completion; with 60 subjects in each of the 
four study groups (DM-INI, DM-placebo, control-INI, control-placebo). 
 
Randomization and matching  
A computer-generated random allocation sequence (blocks of 2,4,8 and 12) will be used for  randomization into 4 
groups. Our RCT design includes a non-DM group with cardiovascular risk factors, e.g., age, hypertension, obesity, 
and insulin resistance. In this RCT we expect the distribution of patient-specific confounding variables to be similar 
across groups, and we will adjust for differences in the analyses. We expect that we will have to randomize 360 
subjects (signed ICF) subjects (200 DM and 160 controls) in order to meet our goal to complete treatment (V8) with 
210 individuals (60 DM-INI, 60 DM placebo and 45 controls INI and 45 controls placebo).We expect that similar 
distribution of age, sex, education, and co-morbidities between the groups will be achieved through randomization. 
We will use frequency quota sampling at 25% increments to ensure that distribution of these variables is indeed 
similar.  


18 
 
 
Inclusion criteria: 1) Men and women aged 50-85 yr old; 2) able to walk for 6 min  3) DM group: diagnosis and 
treatment for type 2 DM with non-insulin oral or injectable agents or insulin; 4) non-DM group with similar age range 
as the DM group, non-diabetic fasting plasma glucose (<126 mg/dL) and HbA1c (<6.5%)(71). We’ll aim for race 
and gender. Subjects capable of providing informed consent 
 
Exclusion criteria: 1) Insulin-treated type 2 DM; 2) Type 1 DM; 3) intolerance to insulin; 4) history of severe 
hypoglycemia (Severe hypoglycemia is an event requiring assistance of another person to actively administer 
carbohydrates, glucagon, or take other corrective actions. Plasma glucose concentrations may not be available during 
an event, but neurological recovery following the return of plasma glucose to normal is considered sufficient evidence 
that the event was induced by a low plasma glucose concentration (72); 5) participants will be asked to keep a detailed 
diary about hypoglycemic episodes or other AEs that will be reviewed every 3-4 weeks. ADA clinical practice 
guidelines will be used for identification and documentation of hypoglycemic episodes as follows (symptomatic or 
asymptomatic hypoglycemia documented on plasma or finger stick measurements (glucose < 70 mg/dL) (72).     
After enrollment, participants who have more than one asymptomatic and/or symptomatic episode of hypoglycemia 
(glucose < 70 mg/dL) through the entire duration of the study documented on plasma glucose or finger stick will be 
excluded. 6) Acute medical condition that required either hospitalization or surgery within the past 6 months (e.g., 
severe hypoglycemia, malignancies, myocardial infarction, stroke); 7) liver or renal failure or transplant; 8) dementia. 
We will use age- and education-adjusted norms to screen for the presence of clinically significant dementia, but will 
include individuals who have MCI. Therefore we will adopt relatively liberal criteria by excluding only individuals with 
MMSE scores ≤20; 9) current recreational drug or alcohol abuse;) 10) serious systemic disease that would interfere 
with conduction of clinical trial (mild forms of neurological conditions e.g. PD, autonomic neuropathy etc. would 
be allowed); 11) MRI substudy: claustrophobia and implants incompatible with 3 Tesla MRI. 12) Safety substudy: 
Insulin-treated type 2 diabetics with a C-peptide of <0.8 ng/mL and fasting blood glucose >150 mg/dL will be excluded 
even without history of hypoglycemia during finger stick measurements. 
 
Withdrawal Criteria: 1) The subject may withdraw at will at any time; 2) pregnancy or intention of becoming 
pregnant; 3) non-compliance or inability to follow the details of the protocol; 4) hypoglycemic episodes; 5) serious 
adverse events; 6) medication(s)/treatment(s) not permitted during the trial. 
 
We anticipate that we will screen 800 subjects by phone and enroll 360 subjects (ICF signed) in order to meet our 
enrollment goals of 210 subjects complete V8 treatment upon the trial’s completion; with 60 subjects in each of the 
four study groups (DM-INI, DM-placebo, control-INI, control-placebo). 
 
Randomization and matching  
A computer-generated random allocation sequence (blocks of 2,4,8 and 12) will be used for  randomization into 4 
groups. Our RCT design includes a non-DM group with cardiovascular risk factors, e.g., age, hypertension, obesity, 
and insulin resistance. In this RCT we expect the distribution of patient-specific confounding variables to be similar 
across groups, and we will adjust for differences in the analyses. We expect that we will have to randomize 360 
subjects (signed ICF) subjects (200 DM and 160 controls) in order to meet our goal to complete treatment (V8) with 
210 individuals (60 DM-INI, 60 DM placebo and 45 controls INI and 45 controls placebo).We expect that similar 
distribution of age, sex, education, and co-morbidities between the groups will be achieved through randomization. 
We will use frequency quota sampling at 25% increments to ensure that distribution of these variables is indeed 
similar.  
 
Subject Replacement:  We will also implement frequency quota sampling to ensure similar distribution of 
demographic and other potentially confounding variables during recruitment at 25% sample increments. Therefore, 
the subject’s replacement will follow distribution of these variables within each group. We plan for a similar 
distribution of men and women in the study population. All women in the study will be required to be post-
menopausal or practice adequate birth control. All efforts will be made to assure that the study population includes 
a sample of minorities that is representative of the racial distribution of the population in Massachusetts. A special 


19 
 
effort to recruit Latinos and African Americans will be made so as to reflect the high nationwide distribution of stroke 
in these populations. Cost and sample size will prohibit us from studying each racial group separately. 
 
POSSIBLE BENEFITS 
Our previous experience, the noninvasive nature of the proposed studies, the general acceptance by practicing 
physicians of the procedures to be used, and the close supervision and monitoring of subjects, all minimize the 
potential risks. Based on previous research with this and similar protocols, we judge the risks associated with this 
study to be minimal. Individual subjects may benefit from the proposed study by learning more about their 
cardiovascular health and diabetes control that would not have been routinely indicated. 
 
Importance of the knowledge to be gained 
This translational study will address an important area—the long-term effects of intranasal insulin on cognition in 
older diabetic people—that has not been studied, and may provide a novel therapeutic target for prevention and 
treatment of cognitive decline and dementia. This prospective study will provide data about long-term effects of insulin 
on cognition in a larger population of older diabetic and control subjects. Identification of a clinical phenotype of people 
who would be more likely to respond positively to INI therapy would allow introduce new benefits to a larger population 
at an earlier disease stage, before cognitive decline manifests clinically. Therefore, INI could be a promising method 
for the treatment of disorders that involve abnormal insulin signaling within cognitive and reward networks, such as 
obesity, Alzheimer’s disease, and type 2 DM. If successful, knowledge gained from this study may be used for a 
design of large-scale trials.  
 
 


20 
 
 
 
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ICF_000.pdf: 
[CCI] Committee on Clinical Investigations 
 
Page 1 of 22 
 
Informed Consent – Part D 
CCI Form: 3-2013 
PI Revision Date: 3/18/2019  
 Version 20 
 
 
 
 
INFORMED CONSENT FORM TO TAKE PART IN A RESEARCH STUDY 
 
SUBJECT’S NAME: 
TITLE OF RESEARCH PROTOCOL:  Memory Advancement by Intranasal Insulin in Type 2 Diabetes 
(MemAID) 
PRINCIPAL INVESTIGATOR:  Vera Novak, PhD 
PROTOCOL NUMBER:  2015P000064 
 
INTRODUCTION: 
You are invited to take part in a research study about the effects of insulin on memory, daily 
functionality and walking speed in people with diabetes. You are being asked to take part in this study 
because you have type 2 diabetes mellitus, or because you are a non-diabetic volunteer. Please read 
this consent form carefully and ask the investigators or study staff to explain any words or information 
that you do not clearly understand.  
 Your participation is voluntary; 
 A research study includes only people who choose to take part; 
 You may or may not benefit from participating in the study. However, your participation 
may help others in the future as a result of knowledge gained from the research; 
 You may leave the study at any time; 
 If you choose not to take part, or if you leave the study, your decision will in no way harm 
your relationship with any member of the research team or any other individuals at Beth 
Israel Deaconess Medical Center. 
Once you read this consent form and understand what your participation in this study will involve, you 
will be asked to sign this form if you wish to take part. You will be given a signed copy of this form to 
keep for your records. 
 
DISCLOSURE OF SPECIAL INTERESTS OF BIDMC AND INVESTIGATORS 
This study is being conducted by Vera Novak, Ph.D. and is funded by the National Institutes of Health 
(NIH). The sponsor agency in this study National Institute of Diabetes and Digestive and Kidney 
Diseases (NIDDK), is paying Beth Israel Deaconess Medical Center (BIDMC) and the Principal 
Investigator, Dr. Vera Novak, to perform this research. BIDMC or Dr. Novak does not have any 
 
**FOR CCI USE ONLY** 
Approved by the Beth Israel Deaconess Medical Center Committee on 
Clinical Investigations:  
 
 
Consent Approval Date:   
03/25/2019 
 
 
 
 
Protocol Number:  
2015P000064 
 
   
 
 
 
COMMITTEE ON CLINICAL INVESTIGATIONS 
APPROVAL EXPIRATION DATE 
 
12/09/2019


  [CCI] Committee on Clinical Investigations 
Page 2 of 22 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: MEMORY ADVANCEMENT BY 
INTRANASAL INSULIN IN TYPE 2 DIABETES (MEMAID) 
PRINCIPAL INVESTIGATOR'S NAME: VERA NOVAK, PHD 
PROTOCOL #: 2015 P000064 
 
 
 
 
Informed Consent – Part D 
CCI Form: 3-2013  
PI Revision Date: 3/18/2019 
Version 20 
 
 
additional interests in this research project or in the funding agency. BIDMC has also received 
supplemental in kind contribution for safety substudy from Medtronic, Inc. and of Novolin® R insulin 
from Novo Nordisk, Inc. One of our co-investigators, Dr. Mantzoros is a paid consultant for Novo 
Nordisk, Inc. Harvard Medical School (HMS) participates in neuropsychological training. The Brigham 
and Women’s Hospital (BWH) participates as the second study site.  
 
WHOM TO CONTACT IF YOU HAVE QUESTIONS OR PROBLEMS 
If you have any questions, concerns or complaints about this research or experience any problems, 
you should contact Dr. Vera Novak at 617-632-8680. In case of medical emergency, you should 
contact the investigators (pager 617-632 7243x ID 34257) and the study clinicians (Dr. Lioutas, Dr. 
Peter Novak, Dr. Buss or Dr. Mateo) will be contacted. For BIDMC-scheduling call 617-632-8883 or 
617-632-8859. Dr. Peter Novak is the Principal Investigator and the study clinician for the BWH 
participants (617-983-7580 or for emergencies call 617-540-8541), for BWH-scheduling call:  617-
632-8884.  
 
PURPOSE 
Type 2 diabetes mellitus accelerates brain aging, alters cerebral blood flow regulation and increases 
the risk for dementia and Alzheimer's disease. Previous studies have shown that insulin sprayed into 
the nose may improve memory in older non-diabetic adults and in people with mild problems of 
reasoning and memory when used once daily over up to a one month period. These studies have 
shown that insulin sprayed into the nose is safe and not associated with major side effects and did not 
affect sugar levels in the blood.  
 
The purpose of this study is to find the long-term effects of daily administration of 40 International Units 
(IU) of Novolin® R insulin administered as intranasal spray as compared to placebo (sterile saline) on 
cognition and memory in people with type 2 diabetes mellitus, and non-diabetic controls over 24 weeks 
of treatment and 24 weeks of follow-up. The insulin or placebo (sterile saline) will be sprayed into the 
nose once daily. We are interested to see whether intranasal insulin can improve memory and 
cognition and blood flow in the brain in the diabetic group as compared to placebo and to the non-
diabetic group over a long-term period. We will use a ViaNase device (nasal spray device), 
manufactured by Kurve Technology, Inc. to effectively deliver the insulin/placebo into the nose. This 
device is listed by the Food and Drug Administration [FDA] as a noninvasive device.  
 
The use of intranasal insulin to improve cognition and blood flow in the brain is investigational. The use 
of insulin for improvement of blood flow and memory is still being tested in research studies. The Food 
and Drug Administration [FDA] has not approved insulin use for such purposes. This investigational 
agent, insulin, has been approved by the FDA for use in other diseases or conditions, but we do not 
yet know if it is useful or safe as a treatment for cognitive decline and impairment of blood flow. In 
addition, we hope to learn what kinds of side effects will be caused by insulin sprayed into the nose, 
 
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SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: MEMORY ADVANCEMENT BY 
INTRANASAL INSULIN IN TYPE 2 DIABETES (MEMAID) 
PRINCIPAL INVESTIGATOR'S NAME: VERA NOVAK, PHD 
PROTOCOL #: 2015 P000064 
 
 
 
 
Informed Consent – Part D 
CCI Form: 3-2013  
PI Revision Date: 3/18/2019 
Version 20 
 
 
and how severe those side effects will be. This means that you may experience the side effects listed 
in the Risks section of this consent form.  
 
STUDY PARTICIPANTS 
You have been asked to be in the study because you have type 2 diabetes or as a non-diabetic 
volunteer, and you meet other criteria for this study. We anticipate that we will screen 800 subjects by 
phone and enroll 360 subjects (sign consent form) in order to meet our enrollment goal to complete 
treatment in 210 subjects upon the trial’s completion: 120 diabetics (60 in DM-INI, 60 DM-placebo) 
and 90 non-diabetics (45 control-INI, 45 control-placebo)  across all study sites. Approximately 600 
people will take part in this study at BIDMC and 200 will take part at BWH.  
 
Procedures that will be done at the Beth Israel Deaconess Medical Center:  
BIDMC participants will complete all visits at the BIDMC Clinical Research Center. BIDMC 
participants may complete the study at BWH if needed. 
Procedures that will be done at the Brigham and Women’s Hospital:  
Participants enrolled at the BWH will complete all visits at the BWH Center for Clinical 
Investigations. Laboratory samples collected from the BWH site will be stored at the BIDMC Clinical 
Research Center (CRC) laboratory. BWH diabetics may participate in MRI substudy at BIDMC. 
 
DESCRIPTION OF STUDY DETAILS 
If you agree to be in this study, you will be asked to read and sign this consent form. According to 
Good Clinical Practices, all procedures will be explained to you and all of your questions will be 
answered. You can opt out from participating in the study at any time. After you sign the consent form, 
the following things will happen as outlined below and in the Table 1: 
 
The MemAID study will require 24 weeks of treatment and 24 weeks of long-term follow-up, and it 
includes 12 visits (V1-V12). There is one screening visit (V1). There are eight assessment visits: V2-
baseline assessment, V2-intervention 1-beginning of treatment, V4- intervention 2, V6- intervention 3, 
V8-intervention 4-end of treatment; V9-treatment 5 is a “virtual visit” and only short phone call 
assessment, V10-post-treatment 6, V11- post-treatment 7, V12-post-treatment 8. There are three 
short follow-up visits during the treatment period V3, V5, V7. You may be allowed to skip some 
assessment visits (V4, V6, V10 and V11) and some follow-up visits (V5 or V7) for significant reasons. 
If you choose to skip a visit during the treatment period, your medications will be mailed to you and 
you will be asked to bring all medications vials and study materials (home calendar of device usage) 
for your next visit. You will be asked to continue using the device daily and call investigators if you 
have any questions or device problems. However, not more than 8 weeks may elapse between in-
person visits during treatment period. Meals will be provided for all assessment visits and as needed. 
Transportation assistance will be provided, as needed.  
 
 
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SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: MEMORY ADVANCEMENT BY 
INTRANASAL INSULIN IN TYPE 2 DIABETES (MEMAID) 
PRINCIPAL INVESTIGATOR'S NAME: VERA NOVAK, PHD 
PROTOCOL #: 2015 P000064 
 
 
 
 
Informed Consent – Part D 
CCI Form: 3-2013  
PI Revision Date: 3/18/2019 
Version 20 
 
 
Magnetic Resonance Imaging (MRI) substudy: In 40 diabetic participants, MRI will be done at the 
BIDMC Center for Magnetic Resonance Imaging at baseline and before the end of treatment. 
You may choose not to participate in the MRI substudy and still participate in the MemAID.  
 
Health management: Your primary care provider will manage your health/diabetes during the 
course of the study. We will send pertinent medical information (e.g. medical history, medication list, 
laboratory results, ECG etc.) to your primary care provider. We may request additional information 
regarding your health status and/or medication list.  
 
Data and samples: Laboratory samples collected from the study will be stored at the BIDMC 
Clinical Research Center (CRC) laboratory and at the MemAID study freezers at the Department of 
Neurology at the BIDMC. The information about data from all study participants will be stored 
centrally at the BIDMC and the secured Science Trax Servers. 
 
Criteria for participation for the two study groups: 
Participants will be between the ages of 50 to 85 years, men and women of any race. They should be 
able to walk for 6 minutes. Diabetic group will include participants  with type 2 diabetes mellitus who 
are being treated with oral or injectable agents. Control group will be similar in age as diabetic group, 
with a normal fasting glucose (<126 mg/dl) and HbA1c (<6.5%). 
 
You cannot participate in this study if you have any of the following conditions: 
1. 
Type 2 diabetes treated with subcutaneous insulin 
2. 
Type 1 diabetes mellitus  
3. 
Intolerance to insulin   
4. 
History of severe low blood sugar. After enrollment, participants who have more than one 
asymptomatic and/or symptomatic episode of hypoglycemia (glucose < 54 mg/dL) through the 
entire duration of the study during home measurements using finger stick or on plasma glucose 
measurements will be excluded. 
5. 
Acute medical condition that required either hospitalization or surgery within the past 6 months 
(e.g. severe hypoglycemia, malignancies, myocardial infarction, stroke). 
6. 
Liver or renal failure or transplant. 
7. 
Dementia (MMSE scores ≤20).   
8. 
Current recreational drug or alcohol abuse.  
9. 
Serious systemic diseases that would interfere with conduction of clinical trial. 
10. 
MRI substudy: claustrophobia, implants and body proportions incompatible with 3 Tesla MRI.  
11. 
All women in the study are required to be post-menopausal or practice adequate birth control. 
 
 
 
 
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Page 5 of 22 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: MEMORY ADVANCEMENT BY 
INTRANASAL INSULIN IN TYPE 2 DIABETES (MEMAID) 
PRINCIPAL INVESTIGATOR'S NAME: VERA NOVAK, PHD 
PROTOCOL #: 2015 P000064 
 
 
 
 
Informed Consent – Part D 
CCI Form: 3-2013  
PI Revision Date: 3/18/2019 
Version 20 
 
 
If you qualify to take part in this research study, you will undergo the following procedures:  
Table 1: Research Procedures and Study Timeline  
Weeks 
Visits 
Procedures 
 
 
 
 
 
Week 0 
Visit 1 
Screening 
 
 
 
120 mins 
 Consent form explanation, medical history and medication review 
 Vital signs and ECG 
 Blood Draw 
 Physical Examination 
 Mini-Mental State Examination 
 Meal 
MRI substudy (only): MRI safety checklist; head circumference and 
shoulder width measurements.  
MRI Substudy 
90 mins  
Selected subjects will have a magnetic resonance imaging (MRI) 
scan within 2 weeks before Visit 2. 
ENROLLMENT, RANDOMIZATION -BASELINE, START OF TREATMENT 
 
 
 
 
 
 
 
Week1 
 
Visit 2 
Baseline 
 
 
 
 
 
 
Intervention 1  
 
 
240 min 
Baseline Assessment 
 Vital signs, height, weight and hip-waist ratio, blood draw  
 Medical history and medications update 
 Appetite scale 
 Meal  
 Cognitive and walking test (6 min normal and 6 min dual-task walk. 
Intervention Assessment 1 
 Teaching session: Review of study procedures, glucometer and 
finger stick training, intranasal insulin device training. 
 
First intranasal insulin/placebo administration 
 
Blood draw  
 
Cognitive and walking test (6min normal and 6 min dual-task walk) 
 
Meal 
Study team will call participant one week after Visit 2 to follow-up. 
 
 
Week 4 
 
Visit 3 
Follow-up 1 
 
45 min 
 Vital signs 
 Medical history and medication review 
 Cleaning of the nosepiece and device 
 Medication refill & new calendars 
 Adverse events monitoring and compliance checks 
 
Week 8 
 
Visit 4 
Intervention 2 
 
 Vital signs, height, weight and hip-waist ratio, blood draw  
 Medical history and medications update 
 Appetite scale 
 Intranasal insulin/placebo administration 
 
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Page 6 of 22 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: MEMORY ADVANCEMENT BY 
INTRANASAL INSULIN IN TYPE 2 DIABETES (MEMAID) 
PRINCIPAL INVESTIGATOR'S NAME: VERA NOVAK, PHD 
PROTOCOL #: 2015 P000064 
 
 
 
 
Informed Consent – Part D 
CCI Form: 3-2013  
PI Revision Date: 3/18/2019 
Version 20 
 
 
 
180 min 
 Meal 
 Cognitive and walking test (6min normal and 6 min dual-task walk) 
 Medication refill & new calendars 
 Adverse events monitoring and compliance checks 
 
Week 12 
Visit 5  
Follow-up 2 
45 min 
Follow-up procedures are the same as Visit 3. 
 
Week 16 
Visit 6  
Intervention 3 
180 min 
Assessment procedures and fasting blood draws are the same as Visit 4. 
 
Week 20 
Visit 7 
Follow-up 3  
45 min 
Follow-up procedures are the same as Visit 3 and 5. 
 
Week 24 
Visit 8 
Intervention 4 
180 min 
Assessment procedures and fasting blood draws are the same as Visits 4 
and 6. Final review of study documentation. 
MRI Substudy: Second MRI. Additional 60 mins duration.  
END OF TREATMENT- START OF LONG TERM FOLLOW-UP 
 
 
Week 25 
 
 
Visit 9 
Phone Interview 
Post-treatment 5 
 
20 min 
Post-treatment Assessment 5 
Phone Call (Mail these forms on a prepaid envelope given in Visit 8) 
 Medical history and medication review 
 Functional assessment forms (GDS, WHODAS) 
 Glucose finger sticks value 
Week 32 
 
Week 40 
 
Week 48 
Visit 10 
Post-treatment 6 
Visit 11 
Post-treatment7 
Visit 12 
Post-treatment 8 
180 min 
 Vital signs and blood draw 
 Dietitian assessment   
 Meal  
 Cognitive and walking test (6min normal and 6 min dual-task walk) 
 Adverse events monitoring  
STUDY COMPLETION 
 
INTERIM VISIT: You may also be asked to come on a separate visit if the study procedures cannot 
be completed during any of the study visits for any reason. For example, if you are not able to come 
fasting for your first visit or other study visits, we will ask you to come back for an extra visit; or any 
scheduling issues for physical exam, MRI studies, walk test, cognitive tests or other reasons. In case 
of an emergency some functional assessments might be completed over the phone. 
 
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Page 7 of 22 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: MEMORY ADVANCEMENT BY 
INTRANASAL INSULIN IN TYPE 2 DIABETES (MEMAID) 
PRINCIPAL INVESTIGATOR'S NAME: VERA NOVAK, PHD 
PROTOCOL #: 2015 P000064 
 
 
 
 
Informed Consent – Part D 
CCI Form: 3-2013  
PI Revision Date: 3/18/2019 
Version 20 
 
 
VISIT 1: SCREEENING (Week 0)  
This visit will take about 120 minutes. You will be asked to read and sign this informed consent. 
Screening procedures will be used to determine if you are eligible to participate in this study. Medical 
history and medications will be assessed. You must bring all your medications in their original bottles.  
Visit procedures: vital signs, ECG, height, weight, waist and hip circumference (HCW).  
Mini-mental state examination (MMSE): You will complete a short task evaluating your mental status.  
Laboratory tests: You have to come after about 8 hours of fasting. Three teaspoons of blood, 
approximately 15 ml, will be drawn and about 5 teaspoons of urine will be collected for routine 
laboratory tests of kidney function. Routine blood testing includes an evaluation of blood sugar, lipids, 
and blood cell counts and C-peptide for insulin-treated diabetic subjects. You may be asked to come 
for an additional visit for the blood test in case you cannot come fasting.  
Physical and neurological exam will be done by a study physician or a Clinical Research Center 
physician. Toronto neuropathy scale will be completed. You may have to come for an interim visit, if 
there is a scheduling conflict, or the physician needs to further evaluate your health status. 
 
MRI substudy: If you have diabetes and want to be in the MRI substudy, you will be asked to 
complete the MRI safety checklist. Your shoulder width and head circumference will be measured. 
You cannot have MRI if you have any metal implants or devices not compatible with 3 Tesla MRI.  
 
Medications: Bring all your medications with you in the original bottles for each visit. 
 
Fasting blood draws & and holding blood sugar control medications: Visits V1, V2, V4, V6, V8, 
V10, V11, V12) require that you’ll come after about 8 hours of fasting. You will be given a meal after 
blood draw is completed.  
 
Control group: If you are a control and you are not taking any sugar control medications, you will take 
your medications as prescribed.  
 
Diabetic group: If you have diabetes and you take sugar lowering medications, fasting may increase 
the risk of low blood sugar (hypoglycemia).  If you take your sugar control medications in the morning, 
you will be asked to hold your morning dose of sugar control medications before the visits that require 
you to come fasting (V1, V2, V4, V6, V8, V10, V11, V12). Bring your medications with you to each visit, 
and you will take them after the fasting blood draw. Meals will be provided after blood draws.  
If you cannot come fasting for these visits (e.g. scheduling or other reasons), you will take all your 
medications including sugar control medications as usual. You will be asked to come early morning 
another day (within few days before or after the visit) for an interim visit for fasting blood draws.   
 
COMMITTEE ON CLINICAL INVESTIGATIONS 
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SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: MEMORY ADVANCEMENT BY 
INTRANASAL INSULIN IN TYPE 2 DIABETES (MEMAID) 
PRINCIPAL INVESTIGATOR'S NAME: VERA NOVAK, PHD 
PROTOCOL #: 2015 P000064 
 
 
 
 
Informed Consent – Part D 
CCI Form: 3-2013  
PI Revision Date: 3/18/2019 
Version 20 
 
 
Glucose monitoring and symptoms of low blood sugar (hypoglycemia):  
Glucose levels will be monitored during the study. You will continue your usual daily activities and 
treatments. You will have to measure fasting glucose with a finger stick once a week and keep a 
detailed diary of low blood sugar level episodes and physical activities. If you experience symptoms 
of hypoglycemia, such as being shaky, sweaty, dizzy, anxious, irritable, confused, very hungry and 
nauseated, very sleepy – not at bed time or loss of consciousness), you will also be asked to take a 
finger stick to make sure your blood glucose is within normal limits. You cannot participate in the 
study if you have a history of severe symptoms due to low blood sugar or low glucose levels during 
home monitoring. If your glucose levels are low or you experience symptoms such as shaking, 
sweating, headache, or confusion etc., an emergency protocol will be initiated. 
 
You need to complete Visit 2 within the 3 months after the screening Visit 1. It is important to keep 
your appointments on time or within 2 weeks of the original scheduled visit (Visits 4, 6, 8, 10, 11, 
12). Please contact the study team immediately if you need to reschedule any of your visits. You will 
be asked to come to BIDMC Research Center or to BWH Clinical Research Center (BWH 
participants) for these visits. 
 
VISIT 2 (Week 1): BASELINE AND INTERVENTION 1- BEGINNING OF TREATMENT:  
This visit will take about four hours. You have to come after about eight hours of fasting. Bring all 
your medications in original bottles. You will receive meals and snacks, and you can take breaks. 
 
Visit procedures: vital signs, physical and neurological exam by study physician (if not done before), 
medical history review, medication review, HWC and VAS for appetite feelings. A blood draw to 
measure: fasting glucose, insulin and metabolic panels, and endothelial and DNA (ApoE4) markers.  
A whole blood sample for ApoE4 makers can be also taken at other visits if not done at V2. 
 
Baseline Assessment: You will be asked to complete a neuropsychological assessment, 6-min 
normal walking and performance of a dual task (6-min walking while counting backwards), 30-
second balance test with eyes open, 30-second balance test with eyes closed, functional measures 
and depression scale.  Neuropsychological testing will be done using a computer system 
(Cambridge Cognition computerized system CANTAB), and will include testing of word memory and 
visuospatial learning, recognition and memory and depression and functional measures.  
 
Teaching session: The study team will review procedures and you will receive instructions on how 
to administer the study drug using the ViaNase device, how to measure glucose using a study 
glucometer and a finger stick, and how to fill out home calendars. The study glucometer will be 
provided.  
 
 
 
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SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: MEMORY ADVANCEMENT BY 
INTRANASAL INSULIN IN TYPE 2 DIABETES (MEMAID) 
PRINCIPAL INVESTIGATOR'S NAME: VERA NOVAK, PHD 
PROTOCOL #: 2015 P000064 
 
 
 
 
Informed Consent – Part D 
CCI Form: 3-2013  
PI Revision Date: 3/18/2019 
Version 20 
 
 
 
Intervention Assessment 1 TREATMENT BEGINS:  
You will take the first dose of insulin/placebo yourself under supervision of the study staff. You will 
spray insulin/placebo twice into each nostril, alternating the nostrils, which will take about one 
minute. The following procedures will be repeated again after the nasal spray: blood draws for 
glucose and insulin, neuropsychological, depression, functional assessments, normal walk, walk 
with a counting backwards, balance test with eyes open and with eyes closed. 
You will use intranasal insulin/placebo at home once daily for a maximum of 168 days. 
You will use insulin/placebo daily in the morning before breakfast and write down the time of nasal 
spray on the home calendar. Once a week you will measure your fasting glucose using a finger 
stick. A week after V2 the study team will give you a call to check compliance and assess any 
problems with device usage and other study procedures.  
 
MRI substudy: A subset of 40 diabetic participants will also complete a MRI scan at baseline (within 
two weeks days before V2) and at the end of intervention (during or within two weeks days before 
V8.). You cannot participate in this substudy if you have metal implants or pacemakers, or exceed 
body proportions parameters. You will be asked to lie down on an imaging table that will slide into 
the magnetic field. An MRI imaging coil, which is made from special wires that are covered in plastic, 
will be placed around your head. Foam pads will be placed around your head to limit head 
movement during the scan. During the scan, you will be asked to lie still on your back for up to 80 
minutes and stay still when the images will be acquired which takes from 2-15 minutes. You will hear 
a loud knocking or hammering noise while the MRI is taking pictures, but the process itself will be 
painless. You will be given disposable earplugs to use to help make the noise less noticeable. 
During the procedure, you will be in constant contact with the MRI technician through an intercom. If 
at any time during the scan you feel too uncomfortable to continue, no matter what the reason, the 
procedure will be immediately stopped and you will be removed from the magnet (MRI scanner). 
 
Carbon dioxide re-breathing and hyperventilation: You will be asked to breathe a mixture of air 
and carbon dioxide to increase your carbon dioxide level above normal. Then you will be asked to 
breathe faster.  
 
Genetic testing:  This study will obtain blood samplessamples( V2 or other visit) from participants to 
measure apolipoprotein E4 (ApoE4), a genetic marker which researchers have found to increase the 
risk of developing Alzheimer’s disease. There are no clear-cut tests to diagnose Alzheimer disease 
during life. Some doctors may use the ApoE4 test with other clinical information to help in the 
diagnosis of Alzheimer disease in adults who have dementia. In this study we are doing the test for 
research only. This study is not designed to diagnose Alzheimer’s disease and we will not provide the 
results of The ApoE4 testing to you or your primary care provider. The blood samples will be stored 
and we will do all testing at the end of the study. If you have questions about Alzheimer’s disease we 
 
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Page 10 of 22 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: MEMORY ADVANCEMENT BY 
INTRANASAL INSULIN IN TYPE 2 DIABETES (MEMAID) 
PRINCIPAL INVESTIGATOR'S NAME: VERA NOVAK, PHD 
PROTOCOL #: 2015 P000064 
 
 
 
 
Informed Consent – Part D 
CCI Form: 3-2013  
PI Revision Date: 3/18/2019 
Version 20 
 
 
will encourage you to talk with your primary healthcare provider. 
Are you interested in having ApoE4 measured?    YES           NO         
 
VISIT 3 (Week 4): FOLLOW-UP 1 
This visit will take about 45 minutes. Visit will include: vital signs measurement, glucose 
measurement using a finger-stick, drug inventory and refill, compliance checks, adverse events 
monitoring, device testing and further re-training on device usage.  
 
VISIT 4 (Week 8): INTERVENTION ASSESSMENT 2 
This visit will take about three hours. Visit will include: vital signs measurement, medical history, 
medication review, fasting glucose, insulin and metabolic panels, endothelial markers, HWC, visual 
analog scales (VAS) for appetite feelings; drug inventory and refill, compliance checks, and adverse 
events monitoring.  
You will be asked to complete a neuropsychological assessment, 6-min normal walk and 
performance of a dual task (a 6-min walk while counting backwards), 30-second balance test with 
eyes open, 30-second balance test with eyes closed, functional measures and depression scale. 
 
VISIT 5 (Week 12): FOLLOW-UP 2 
This visit will take about 45 minutes. The visit will include: vital signs glucose measurement using a 
finger-stick, drug inventory and refill, compliance checks, adverse events monitoring.  
 
VISIT 6 (Week 16): INTERVENTION ASSESSMENT 3 
This visit will take about three hours. Visit will include: vital signs measurement, medical history, 
fasting glucose, insulin and metabolic panels, HWC, VAS for appetite feelings; drug inventory and 
refill, compliance checks, and adverse events monitoring. 
You will be asked to complete a neuropsychological assessment, 6-min normal walk and 
performance of a dual task (6-min walk while counting backwards), 30-second balance test with 
eyes open, 30-second balance test with eyes closed, functional measures and depression scale. 
 
VISIT 7 (Week 20): FOLLOW-UP 3 
These visits will take about 45 minutes. Visits will include: vital signs, glucose measure using a 
finger-stick, drug inventory and refill, compliance checks, adverse events monitoring.  
 
VISIT 8 (Week 24): INTERVENTION ASSESSMENT 4 – END OF TREATMENT  
This is the most important assessment visit that needs to be completed. This visit will take about 
three hours. This the end-of treatment visit and the last day that you will take the nasal spray. Visit 
procedures: vital signs, medical history, fasting glucose, insulin and metabolic panels, endothelial 
markers, urine creatinine and microalbumin, HWC, VAS for appetite feelings; drug inventory, 
compliance checks, and adverse events monitoring. 
 
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  [CCI] Committee on Clinical Investigations 
Page 11 of 22 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: MEMORY ADVANCEMENT BY 
INTRANASAL INSULIN IN TYPE 2 DIABETES (MEMAID) 
PRINCIPAL INVESTIGATOR'S NAME: VERA NOVAK, PHD 
PROTOCOL #: 2015 P000064 
 
 
 
 
Informed Consent – Part D 
CCI Form: 3-2013  
PI Revision Date: 3/18/2019 
Version 20 
 
 
You will be ask to complete a neuropsychological assessment, 6-min normal walk and performance 
of a dual task (6-min walk while counting backwards), 30-second balance test with eyes open, 30-
second balance test with eyes closed, functional measures and depression scale. 
 
If you participate in MRI substudy, you will also complete an MRI scan at this visit (or within 10 days 
before this visit). 
 
VISITS 9-12: POST-TREATMENT ASSESSMENTS 5-8 - LONG-TERM FOLLOW-UP 
PHONE CALL “Visit 9” (Week 25): This assessment will be done over the phone and it will take 
about 30 minutes. The phone interview will include: medical history review, medication review, 
functional and depression scales, glucose measurement using a finger stick, VAS for appetite 
feelings. You will be asked to fill out the forms prior to the interview and mail the forms and 
glucometer to the investigators.  
 
Visit 10, 11, 12 (Week 32, 40 and 48)-END OF STUDY 
These visits will take place at weeks 25, 32, 40, and 48, and will last about 3 hours each at the 
Clinical Research Center. Visits procedures: fasting blood draws for glucose, insulin and 
fructosamine, and at V12 also urine creatinine and microalbumin and endothelial function markers; 
medical history review, HWC, VAS for appetite feelings, vital signs measurement, glucose measure 
using a finger-stick, neuropsychological assessment, 6-min normal walk and performance of a dual 
task (6-min walking while counting backwards), functional measures and depression scale.  
 
RISKS AND DISCOMFORTS 
As a result of your participation in this study, you are at risk for side effects listed in this section.  
You should discuss these with the investigator and with your regular doctor if you choose. 
 
 Intranasal insulin or placebo:  You may spend time and experience side effects taking a drug 
that may not provide you with any health-related benefits. 
 Hypoglycemia symptoms: being shaky, sweaty, dizzy, anxious, irritable, confused, very sleepy 
– not at bed time or loss of consciousness 
 Risk of hypoglycemia: Previous studies reported that intranasal insulin has minimal effects on 
peripheral glucose levels. You will be asked to monitor your blood sugar at home and those 
with hypoglycemic events during monitoring will be excluded. Fasting blood glucose will be 
sampled before the visits and monitored during the study to minimize the risk of 
hypoglycemia. Appropriate clinical measures will be administered if hypoglycemia is detected. 
These studies reported that blood sugar levels were not affected by insulin administration at the 
dose that will be administered into the nose in one session and over a one month period. 
 Several study visits require that you come fasting. Sugar control medications including insulin 
may increase the risk for hypoglycemia if you are fasting. Therefore, you may be asked to hold 
 
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  [CCI] Committee on Clinical Investigations 
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SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: MEMORY ADVANCEMENT BY 
INTRANASAL INSULIN IN TYPE 2 DIABETES (MEMAID) 
PRINCIPAL INVESTIGATOR'S NAME: VERA NOVAK, PHD 
PROTOCOL #: 2015 P000064 
 
 
 
 
Informed Consent – Part D 
CCI Form: 3-2013  
PI Revision Date: 3/18/2019 
Version 20 
 
 
your sugar control medications before those visits and you will take your usual prescribed dose 
after the fasting blood draw is completed. You will be provided a meal after a fasting blood 
draw. 
 
The studies have also shown that intranasal insulin administrations is safe and is not associated with 
major side - effects.  
 
The insulin administered into the nose may cause some, all or none of the side-effects listed below: 
 You will be instructed not to inhale insulin. 
 Side effects reported were mild. More common side effects may include: lightheadedness or 
dizziness, headache, nose bleed, mild nose irritation or running nose, sneezing (to insulin or 
placebo), weakness, upper respiratory tract infection/flu like symptoms, fall, rash, other 
unspecific effects, or allergic reaction to other ingredients in insulin/placebo. 
 Less common effects were headache and low glucose level.  
 Other possible adverse effects may include: allergic reaction, local allergic reaction to insulin or 
other substances in insulin/placebo preparation, skin thickens at administration site, swelling, 
vision changes, low potassium in blood. 
 
Since the combination of insulin and its delivery is so new, there may also be other side effects that we 
cannot predict, because of our very limited experience with this combination of insulin and nasal 
delivery. Participants will be evaluated by the study physicians and treatment will be stopped if 
medically indicated.  
 
Glucose monitoring using a finger sticks: You will be required to measure fasting glucose once a 
week using a finger sticks, and may experience discomfort, pain and rarely, infection at the site. 
Insulin-treated diabetics will measure glucose using finger stick five times per day for two weeks.  
Weight and body mass: INI may be potentially associated with reduced food intake. Therefore, body 
weight, waist and hip circumference will be monitored during study visits. 
Visual Analogue Scale (VAS): You will be required to complete a scale regarding your appetite 
feelings; the use of VAS may cause minimal risk, including mental stress or exhaustion. Rest will be 
given if necessary, and testing will be stopped upon your request.  
Blood drawing: There are risks and discomforts when drawing blood from a vein. These include the 
possibility of pain or bruising at the site of the blood draw; occasional lightheadedness; and rarely, 
infection at the site of the blood draw.  
Cognitive Tests: Some tests may cause frustration or anxiety. If you are feeling overwhelmed, the 
administrator will stop testing. 
Walking tests: The proposed walking tests will be conducted at preferred speed and for relatively 
short duration (six minutes). Physical activity associated with these tests is therefore low to 
moderate intensity, and potential risks include strains, sprains, muscle soreness, and light-
 
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  [CCI] Committee on Clinical Investigations 
Page 13 of 22 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: MEMORY ADVANCEMENT BY 
INTRANASAL INSULIN IN TYPE 2 DIABETES (MEMAID) 
PRINCIPAL INVESTIGATOR'S NAME: VERA NOVAK, PHD 
PROTOCOL #: 2015 P000064 
 
 
 
 
Informed Consent – Part D 
CCI Form: 3-2013  
PI Revision Date: 3/18/2019 
Version 20 
 
 
headedness. In rare instances, more serious side effects such as an injurious fall may occur. 
Walking:  Gait speed will be measured during a 6-minute walk at participant’s preferred speed in an 
unobstructed hallway with a cognitive challenge (a dual task counting backwards subtracting seven).  
Balance: Balance will be measured during two 30-second trials. You will stand still first with eyes 
open and then with eyes closed. The research assistant will accompany participants to minimize the 
risk of falling during walk and balance tests using Mobility Lab System (APDM, Inc. Portland OR). 
Other adverse effects: Unknown adverse effects may occur, and therefore we will ask you to keep 
detailed diaries of all potential adverse events. 
 
MRI sub-study: Magnetic Resonance Imaging at 3Tesla is a method of taking pictures of the brain 
and of the blood flow in the brain, using a large magnet and radio signals. It allows examination of 
your brain without exposing you to X-rays. All studies performed under this protocol will not exceed 
the FDA guidelines for magnetic resonance in any way. Therefore, the risks assumed by you are the 
same as in any noninvasive protocol involving whole body MRI. Patients with metal implants and 
pacemakers and those who do not meet body proportion requirements are excluded from the study, 
because of physical risks related to imaging subjects with such devices. You must tell the 
investigators about any operations you have had and any metal you may have in your body, so it 
can be decided if it is safe for you to proceed with the scan. We will also require that all people 
involved with the study remove all metal from their clothing and all metal objects from their pockets. 
No metal objects will be allowed into the magnet room at any time. During the MRI session, the 
scanner will generate loud beeping and clicking noises. The expected discomforts during MRI are 
dizziness, claustrophobia (fear of small places), and annoying beeping and clicking sounds 
generated by the scanner. You will be given earplugs to minimize discomfort from the noise. You will 
be in constant two-way contact with the technologist and may ask that the scan be stopped because 
of noise or for any other reason. If you feel the need to be removed from the MRI scanner at any 
time, the scan will be stopped immediately. Hyperventilation and CO2 breathing will be used to test 
vasodilatation and vasoconstriction reserves. 
Hyperventilation: Hyperventilation is a standard clinical procedure that may be associated with a 
transient dizziness and tingling in the fingers due to decline of CO2, but symptoms disappear after 
the end of hyperventilation.  
CO2 rebreathing may be associated with discomfort from the cannula or mask, shortness of breath 
and potential risk of panic attacks. You may need a medical evaluation at that time. If you tell us that 
you wish to be removed from the scanner, we will end the study. 
 
EARLY TERMINATION  
Your participation in the trial can be terminated at any time for non-compliance or inability to follow 
study procedures and/or serious adverse events. 
 
 
 
COMMITTEE ON CLINICAL INVESTIGATIONS 
APPROVAL EXPIRATION DATE 
 
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  [CCI] Committee on Clinical Investigations 
Page 14 of 22 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: MEMORY ADVANCEMENT BY 
INTRANASAL INSULIN IN TYPE 2 DIABETES (MEMAID) 
PRINCIPAL INVESTIGATOR'S NAME: VERA NOVAK, PHD 
PROTOCOL #: 2015 P000064 
 
 
 
 
Informed Consent – Part D 
CCI Form: 3-2013  
PI Revision Date: 3/18/2019 
Version 20 
 
 
LOSS OF CONFIDENTIALITY 
There is the potential for loss of confidentiality by participating in this study.  Every effort will be 
made to protect the confidentiality of your identifiable information. However, if your participation 
becomes known, it could create a problem or hardship for you depending upon the type of 
information disclosed.  
 
PSYCHOLOGICAL STRESS 
Some of the questions we will ask you as part of this study may make you feel uncomfortable. You 
may refuse to answer any of the questions and you may take a break at any time during the study. 
You may stop your participation in the study at any time. 
 
CERTIFICATE OF CONFIDENTIALITY  
The National Institutes of Health has issued a Certificate of Confidentiality for this research. This 
adds special protection for the research information and specimens that may identify you. The 
researchers may not disclose information or specimens that may identify you, even under a court 
order or subpoena, unless you give permission.  However, a Certificate of Confidentiality does not 
prevent researchers from disclosing your information or specimens if required by law (such as to 
report child abuse, communicable diseases or harm to self or others); if you have consented to the 
disclosure (such as for your medical treatment); or for use in other research as allowed by law. In 
addition, the Certificate cannot be used to refuse a request if a governmental agency sponsoring the 
project wants to audit the research.  By signing this form, you are giving your consent to the 
disclosure of your information or specimens for any purpose you have agreed to in this informed 
document and for any purpose permitted without additional authorization in the BIDMC Notice of 
Privacy Practices.  Any research information that is placed in your medical record would not be 
covered under this Certificate.   The Certificate does not stop you from voluntarily releasing 
information about yourself or your involvement in this research. If others obtain your written consent 
to receive research information or specimens, then the researchers are permitted, but not 
necessarily required, to disclose that information.   
 
CONFIDENTIALITY 
Information learned from your participation in this study and from your medical records may be 
reviewed and photocopied by the Food and Drug Administration (FDA) and/or other federal and 
state regulatory agencies, the National Institutes of Health, accreditation agencies, the Committee 
on Clinical Investigations, the Human Subjects Protection Office and others involved in research 
administration of the Beth Israel Deaconess Medical Center with protection of confidentiality so far 
as permitted by applicable law.  Information resulting from this study and from your medical records 
may be used for research purposes and may be published; however, you will not be identified by 
name in such publications. 
 
 
COMMITTEE ON CLINICAL INVESTIGATIONS 
APPROVAL EXPIRATION DATE 
 
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  [CCI] Committee on Clinical Investigations 
Page 15 of 22 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: MEMORY ADVANCEMENT BY 
INTRANASAL INSULIN IN TYPE 2 DIABETES (MEMAID) 
PRINCIPAL INVESTIGATOR'S NAME: VERA NOVAK, PHD 
PROTOCOL #: 2015 P000064 
 
 
 
 
Informed Consent – Part D 
CCI Form: 3-2013  
PI Revision Date: 3/18/2019 
Version 20 
 
 
POSSIBLE BENEFITS 
Although there may not be any direct benefit to you from participating in this research study, your 
participation may contribute to a better understanding of diabetes and its complications in the brain 
and the effects of insulin on blood flow regulation and cognition, which may help future patients. 
intranasal insulin has been previously shown in prior studies to improve memory. However, this 
result cannot be guaranteed. The investigators do not expect to cure your disease or condition with 
the study treatments. 
 
OTHER AVAILABLE OPTIONS 
Taking part in this study is voluntary. You may choose not to participate in this study. This is study 
may provide information that may lead to future novel applications of intranasal insulin for blood flow 
impairment in diabetes. You may choose to participate in clinical studies treating diabetes. 
Information about these studies is available on National Institutes of Health and American Diabetes 
Association Web Sites. Though the MRI images obtained will be helpful for research, they cannot be 
used in place of a standard clinical MRI. Though genetic testing for ApoE4 will be obtained, it is not 
for diagnosis, and these tests cannot be used in place of standard clinical evaluations for diagnosis 
of cognitive impairment or dementia. If for any reason, you desire a clinical evaluation of your brain, 
your memory or mental status, you will have to arrange it separately in consultation with your 
physician. 
 
We recommend that you discuss these and other options with the investigator and your regular 
doctor so that you can make a well-informed decision about participating in this study. Instead of 
being in this study, you have the following options: 
 
 There is no therapy to treat mild memory impairment in diabetics at this time. You will, 
however, be provided with care to help you feel more comfortable. It is important to note that 
it is possible to get treatment for cognitive impairment at this institution or other locations 
even if you do not take part in the study.  
 
This research study is not meant to diagnose or treat medical problems not stated in this informed 
consent form. Participation in this research study does not take the place of routine physical 
examinations or visits to your regular doctor. 
 
We recommend that you discuss these and other options with the investigator and your regular 
doctor so that you can make a well-informed decision about participating in this study. 
 
IF YOU DECIDE NOT TO TAKE PART IN THE STUDY 
Participation in this study is voluntary.  You have the right to decide not to take part in this study.  If 
you choose to participate, you have the right to leave the study at any time. Your decision to not 
 
COMMITTEE ON CLINICAL INVESTIGATIONS 
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  [CCI] Committee on Clinical Investigations 
Page 16 of 22 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: MEMORY ADVANCEMENT BY 
INTRANASAL INSULIN IN TYPE 2 DIABETES (MEMAID) 
PRINCIPAL INVESTIGATOR'S NAME: VERA NOVAK, PHD 
PROTOCOL #: 2015 P000064 
 
 
 
 
Informed Consent – Part D 
CCI Form: 3-2013  
PI Revision Date: 3/18/2019 
Version 20 
 
 
participate will not result in any penalties or loss of benefits to you. The investigators will tell you 
about new information that may affect your willingness to stay in this study.  
If you decide not to participate in the study or decide to leave the study early, your decision will not 
affect your relationship with the research team or any other individual at Beth Israel Deaconess 
Medical Center.   
 
INVESTIGATORS RIGHT TO STOP THE STUDY 
The investigators have the right to end your participation in this study if they determine that you no 
longer qualify to take part, or if it would be dangerous for you to continue, or if you do not follow 
study procedures as directed by the investigators.  Beth Israel Deaconess Medical Center or the 
funding source may stop the study at any time. 
 
COSTS AND/OR PAYMENTS TO YOU 
 
COSTS COVERED BY STUDY 
You will not be charged for laboratory tests, MRI and other tests that are part of this research study. 
However, you and your insurance company will be charged for other tests, procedures or 
medications of this study that are considered standard treatment for your medical condition- for 
example cost of medications or other medical procedures that you will need to treat your medical 
conditions while participating in this study.  
 
PAYMENTS TO YOU: 
The total payment for this study remains the same but payment schedule has changed. Therefore, 
you will receive the same total amount (up to $1000) upon completion of all study procedures:  
 
1. Visit 1 (Screening): $20 
2. Visit 2 (Baseline/Interv1): $150 
3. Visits 3-5, 7: (Follow - up visits): $50 per visit  
5. Visits 4, 6, 8, 10, 11, 12 (Functional assessments): $110 per visit  
6. Visit 9 (phone interview): $20 
7. Interim visit: $20 for completion 
8. MRI substudy: $50 each scan ($100 total) 
9. If you skip V4,V5,V6, V7 and use the study medication as prescribed, and bring the vials and 
home glucose calendar to your next visit, you will be compensated with $50 for the skipped visit. 
 
Parking vouchers and MBTA tickets, other transportation (Uber, Lyft, etc.) will also be either 
provided or reimbursed. Lyft concierge service can be used upon request and approval. Taxi fare 
will be paid for but only in special circumstances. 
 
 
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  [CCI] Committee on Clinical Investigations 
Page 17 of 22 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: MEMORY ADVANCEMENT BY 
INTRANASAL INSULIN IN TYPE 2 DIABETES (MEMAID) 
PRINCIPAL INVESTIGATOR'S NAME: VERA NOVAK, PHD 
PROTOCOL #: 2015 P000064 
 
 
 
 
Informed Consent – Part D 
CCI Form: 3-2013  
PI Revision Date: 3/18/2019 
Version 20 
 
 
It may take up to eight weeks for you to receive payment by check. 
Any payments made to you may be taxable income. This does not include any payments you may 
receive to reimburse (pay you back) you for certain expenses like parking fees or travel.  We are 
required to obtain your name and social security number for preparation and submission of Internal 
Revenue Service (IRS) Form 1099-Misc. You may receive an Internal Revenue Service Form 1099 
from BIDMC if you receive more than $600 in one calendar year for taking part in one or more 
research studies at BIDMC. Questions about your own tax status should be referred to your 
personal tax advisor. 
 
COST OF RESEARCH RELATED INJURY: 
If you are injured as a direct result of your participation in this study, you should contact the 
Investigator at the number provided under the section “Who to Call if You Have Questions” in this 
form.  You will be offered the necessary care to treat your injury. We reserve the right to bill your 
insurance company or the sponsor (NIH), if appropriate, for the care you get for the injury. We will 
try to get these costs paid for, but you may be responsible for some of them. You may be 
responsible for all co-payments and deductibles required under your insurance. At this time there is 
no plan to reimburse you for items such as lost wages or lost time from work.  By signing this 
consent form you have not given up any legal rights. 
 
OTHER IMPORTANT INFORMATION  
A description of this clinical trial is available on www.ClinicalTrials.gov  (NCT0421556) as required 
by U.S. law.  This Web site will not include information that can identify you.  At most, the Web site 
will include a summary of the results.  You can search this Web site at any time. 
 
USE OF YOUR TISSUE FOR COMMERCIAL DEVELOPMENT 
As part of this research program, samples of your tissue and information about your medical history 
may be provided to other researchers and/or outside collaborators without identifying you by name. 
They may use your tissue and information in other scientific research, product testing or commercial 
development. It is unknown whether a product will ultimately be developed from any such work that 
may be performed.  In signing this consent form, you are acknowledging and voluntarily consenting to 
the possibility that your tissue may be used for commercial purposes.  You also understand and agree 
that tissue obtained from you in this research may be used to establish a cell line that could be 
patented and licensed.  Beth Israel Medical Deaconess Medical Center has no program to 
compensate you in the event product testing or commercial development takes place. 
 
AUTHORIZATION FOR USE AND DISCLOSURE OF YOUR PROTECTED HEALTH 
INFORMATION 
As part of this study, we will be collecting, using and sharing with others information about you.  
Please review this section carefully as it contains information about the federal privacy rules and the 
 
COMMITTEE ON CLINICAL INVESTIGATIONS 
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  [CCI] Committee on Clinical Investigations 
Page 18 of 22 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: MEMORY ADVANCEMENT BY 
INTRANASAL INSULIN IN TYPE 2 DIABETES (MEMAID) 
PRINCIPAL INVESTIGATOR'S NAME: VERA NOVAK, PHD 
PROTOCOL #: 2015 P000064 
 
 
 
 
Informed Consent – Part D 
CCI Form: 3-2013  
PI Revision Date: 3/18/2019 
Version 20 
 
 
use and disclosure of your information.   
 
PROTECTED HEALTH INFORMATION [PHI] 
By signing this informed consent document, you are allowing the investigators and other authorized 
personnel to use [internally at BIDMC and BWH] and disclose [to people and organizations outside 
the BIDMC and BWH workforce identified in this consent] health information about you.  This may 
include information about you that already exists (for example: your medical records and other 
sources of health information, demographic information, the results of any laboratory tests, as well 
as any new information generated as part of this study.  This is your Protected Health Information. 
 
PEOPLE/GROUPS AT BIDMC WHO WILL SHARE AND USE YOUR PROTECTED HEALTH INFORMATION 
Your Protected Health Information may be shared with and used by investigators listed on this 
consent form as well as the supporting research team [i.e. research assistants and coordinators, 
statisticians, data managers, laboratory personnel, pharmacy personnel, administrative assistants]. 
Your Protected Health Information may also be shared with the members and staff of the Committee 
on Clinical Investigations of Beth Israel Deaconess Medical Center and Brigham and Women’s 
Hospital, which is responsible for reviewing studies for the protection of the research subjects.  
 
PEOPLE/GROUPS OUTSIDE OF BIDMC WITH WHOM YOUR PROTECTED HEALTH INFORMATION WILL BE 
SHARED 
We will take care to maintain confidentiality and privacy about you and your Protected Health 
Information.  We may share your Protected Health Information with the following groups so that they 
may carry out their duties related to this study: 
 The funding source of this study National Institutes of Health and their clinical research 
organizations.  
 Laboratories not affiliated with BIDMC that are involved in conducting tests related to the 
research 
 Statisticians and other data monitors not affiliated with BIDMC 
 The members and staff of any other IRBs (beyond the BIDMC Committee on Clinical 
Investigations) that oversee the research  
 Centralized data collectors  
 Your health insurance company 
 The Food and Drug Administration [FDA], the Department of Health and Human Services 
[DHHS], the National Institute of Health [NIH], the Office for Human Research Protections 
[OHRP], and other federal and state agencies that may have jurisdiction over the research 
 Data and Safety Monitoring boards that oversee this study (if applicable) 
 
Those who receive your Protected Health Information during the course of the research may not be 
required by the federal privacy regulations to protect it, and they may make further disclosures to 
 
COMMITTEE ON CLINICAL INVESTIGATIONS 
APPROVAL EXPIRATION DATE 
 
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  [CCI] Committee on Clinical Investigations 
Page 19 of 22 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: MEMORY ADVANCEMENT BY 
INTRANASAL INSULIN IN TYPE 2 DIABETES (MEMAID) 
PRINCIPAL INVESTIGATOR'S NAME: VERA NOVAK, PHD 
PROTOCOL #: 2015 P000064 
 
 
 
 
Informed Consent – Part D 
CCI Form: 3-2013  
PI Revision Date: 3/18/2019 
Version 20 
 
 
others and use your information without being subject to penalties under those laws.   
 
WHY WE ARE USING AND SHARING YOUR PROTECTED HEALTH INFORMATION 
The main reason for using and sharing your Protected Health Information is to conduct and oversee 
the research as described in this Informed Consent Document.  We also shall use and share your 
Protected Health Information to ensure that the research meets legal, institutional and accreditation 
requirements and to conduct public health activities. 
 
NO EXPIRATION DATE – RIGHT TO WITHDRAW AUTHORIZATION 
Your authorization for the use and disclosure of your Protected Health Information in this Study shall 
never expire.  However, you may withdraw your authorization for the use and disclosure of your 
Protected Health Information at any time provided you notify the Principal Investigator in writing. If 
you would like to take back your authorization so that your Protected Health Information can no 
longer be used in this study, please send a letter notifying the Principal Investigator of your 
withdrawal of your authorization Vera Novak, Ph.D. at Division of Neurology Beth Israel Deaconess 
Medical Center, 185 Pilgrim Road Palmer Bldg. 127, Boston MA 02215. Please be aware that the 
investigators in this study will not be required to destroy or retrieve any of your Protected Health 
Information that has already been used or disclosed before the Principal Investigator receives your 
letter, and they are permitted to continue to use and disclose your previously collected information 
as necessary to complete the research. 
 
REFUSAL TO SIGN 
Your clinical treatment may not be conditioned upon whether you sign the Authorization for 
Research. However, if you choose not to sign this informed consent document and authorization for 
the use and disclosure of your Protected Health Information, you will not be allowed to take part in 
the research study. 
 
RIGHT TO ACCESS AND COPY YOUR PHI 
If you wish to review or copy your Protected Health Information as it is made part of your medical 
record, you may do so after the completion or termination of the study by sending a letter to the 
Principal Investigator requesting a copy of your Protected Health Information. You may not be 
allowed to inspect or copy your Protected Health Information until this study is completed or 
terminated. 
 
ADDITIONAL CONTACT FOR QUESTIONS OR CONCERNS 
You may contact the Human Subjects Protection Office at (617) 975-8500 in the event that you 
would like to obtain information or to offer input about the research study or Dr. Peter Novak [617] 
424-4101 for BWH participants. This office is independent of the investigator or investigator’s 
 
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  [CCI] Committee on Clinical Investigations 
Page 20 of 22 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: MEMORY ADVANCEMENT BY 
INTRANASAL INSULIN IN TYPE 2 DIABETES (MEMAID) 
PRINCIPAL INVESTIGATOR'S NAME: VERA NOVAK, PHD 
PROTOCOL #: 2015 P000064 
 
 
 
 
Informed Consent – Part D 
CCI Form: 3-2013  
PI Revision Date: 3/18/2019 
Version 20 
 
 
research staff and can also assist with questions relating to your rights as a participant in research, 
which may include questions, concerns or complaints about your participation in the study. 
 
THE FOLLOWING PARAGRAPHS CONTAIN SOME STANDARD INFORMATION WHICH 
GENERALLY APPLIES TO INDIVIDUALS PARTICIPATING IN A RESEARCH STUDY. 
 
CONSENT FORM FOR CLINICAL RESEARCH 
I have read the previous page[s] of the consent form and the investigator has explained the details of the 
study.  I understand that I am free to ask additional questions. 
 
If I wish additional information regarding this research and my rights as a research subject, or if I believe I 
have been harmed by this study, I may contact the Human Subjects Protection Office (HSPO). 
 
I am aware that this is a research project and that unforeseen side effects may occur. 
 
I understand that the Beth Israel Deaconess Medical Center has no formal program for compensating 
patients for medical injuries arising from this research.  Medical treatment will be provided for injuries at the 
usual charge to me or to my insurer unless payment is otherwise provided for in this consent form. 
 
I understand that participation in this study is voluntary and I may refuse to participate or may discontinue 
participation at any time without penalty, loss of benefits, or prejudice to the quality of care which I will 
receive. 
 
I acknowledge that no guarantees have been made to me regarding the results of the treatment involved in 
this study, and I consent to participate in the study and have been given a copy of this form. 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
Signature of Subject or Legally Authorized Representative  
 
 
 Date 
 
 
(Parent if the subject is a minor) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relationship of Legally Authorized Representative to Subject   
 
The subject has been given the opportunity to read this consent form and to ask questions before signing, and 
has been given a copy. 
 
___________________________________________________________ 
SIGNATURE OF INVESTIGATOR/Co-Investigator   
DATE 
 
 
__________________________________________________________ 
PRINT INVESTIGATOR’S/Co-Investigator’s  
NAME  
 
COMMITTEE ON CLINICAL INVESTIGATIONS 
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  [CCI] Committee on Clinical Investigations 
Page 21 of 22 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: MEMORY ADVANCEMENT BY 
INTRANASAL INSULIN IN TYPE 2 DIABETES (MEMAID) 
PRINCIPAL INVESTIGATOR'S NAME: VERA NOVAK, PHD 
PROTOCOL #: 2015 P000064 
 
 
 
 
Informed Consent – Part D 
CCI Form: 3-2013  
PI Revision Date: 3/18/2019 
Version 20 
 
 
 
HE FOLLOWING SECTIONS ARE NOT NEEDED FOR ALL STUDIES AND SHOULD BE 
UTILIZED AS INDICATED: 
 
If the subject is able to speak and understand English but is not able to read or write  
 
I was present during the entire oral presentation of the informed consent and witnessed the subject’s agreement to 
participate in the study. 
 
Signature of Witness:  
 
Printed Name of Witness:  
 
Date:   
 
 
If the subject is able to understand English but is not physically able to read or write or see 
 
I was present during the entire oral presentation of the informed consent and witnessed the subject’s agreement to 
participate in the study. 
 
Signature of Witness:  
 
Printed Name of Witness:  
 
Date:   
 
 
If the subject is not English speaking and signed the translated Short Form in lieu of the English consent 
document 
 
As someone who understands both English and the language spoken by the subject, I interpreted, in the subject’s 
language, the researcher’s presentation of the English consent form.  The subject was given the opportunity to ask 
questions.  
 
Signature of Interpreter:  
 
 
Printed name of Interpreter:  
 
 
Date:  
 
 
 
 
 
 
COMMITTEE ON CLINICAL INVESTIGATIONS 
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  [CCI] Committee on Clinical Investigations 
Page 22 of 22 
 
SUBJECT'S NAME: 
TITLE OF RESEARCH PROTOCOL: MEMORY ADVANCEMENT BY 
INTRANASAL INSULIN IN TYPE 2 DIABETES (MEMAID) 
PRINCIPAL INVESTIGATOR'S NAME: VERA NOVAK, PHD 
PROTOCOL #: 2015 P000064 
 
 
 
 
Informed Consent – Part D 
CCI Form: 3-2013  
PI Revision Date: 3/18/2019 
Version 20 
 
 
 
 
COMMITTEE ON CLINICAL INVESTIGATIONS 
APPROVAL EXPIRATION DATE 
 
12/09/2019