Clinical trial NCT04115384
Conditions: Frontotemporal Dementia, Behavioral Variant
Keywords: intranasal insulin
Sponsor: HealthPartners Institute
Start date: 2019-09-09; Completion date: 2023-05-15
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This project will study intranasal (IN) insulin in Frontotemporal dementia (FTD) in 12 patients. Study Investigators aim to evaluate the feasibility of the EXAMINER cognitive battery as a cognitive outcome measure in FTD, the ability of the HealthPartners Center for Memory and Aging's ability to sufficiently recruit subjects with FTD, and the safety of IN regular insulin administered 20 IU twice per day in two specific variants of FTD (behavioral variant frontotemporal dementia (bv-FTD), semantic dementia (SD)) over a 4 week period.

Detailed description:
Frontotemporal dementia (FTD) with its multiple pathological manifestations, is a disease that results in progressive deterioration of social comportment, executive function, and language. Despite the debilitating nature of FTD and the relatively high prevalence in the younger patient population, available pharmacological interventions are limited to symptomatic treatments. There are no therapeutic agents that have been developed that specifically treat the progressive cognitive symptoms of FTD. This project will study IN insulin in FTD in 12 patients. Investigators aim to evaluate the feasibility of the EXAMINER cognitive battery as a cognitive outcome measure in FTD, the ability of the HealthPartners Center for Memory and Aging's Center's ability to sufficiently recruit subjects with FTD, and the safety of IN regular insulin administered 20 IU twice per day in two specific variants of FTD (behavioral variant frontotemporal dementia (bv-FTD), semantic dementia (SD)) over a 4 week period. Frontotemporal dementia (FTD) with its multiple pathological manifestations, is a disease that results in progressive deterioration of social comportment, executive function, and language. Despite the debilitating nature of FTD and the relatively high prevalence in the younger patient population, available pharmacological interventions are limited to symptomatic treatments. There are no therapeutic agents that have been developed that specifically treat the progressive cognitive symptoms of FTD.

Arms: arm 1: Regular insulin (Novolin-R) 20 IU/IN (0.1ml/10 units IN in each nostril) BID
Interventions: intervention 1: Novolin-R insulin
Intervention descriptions: intervention 1: Insulin (Novolin-R) 20 IU/IN (0.1ml/10 units IN in each nostril), twice per day, once in the morning and again in the evening (at least 8 hours between doses) for 4 weeks.

Protocol documents:
Prot_SAP_000.pdf: 
A Single Center Feasibility Study of Intranasal Insulin in Frontotemporal Dementia 
NIFT-D (Nasal Insulin in Frontotemporal dementia) 
 
 
 
Clinical Study Protocol 
US IND Number: 139885 
Serial Number: 0008 
Amendment 3.2 Date: August 27, 2019 
Amendment 3.1 Date: May 17 2019  
Amendment 3 Date: April 17, 2019 
Amendment 2 Date: Dec 14 2018 
Amendment 1 Date: Aug 01 2018 
Original Protocol Date: July 5 2018 
Sponsor 
Michael H Rosenbloom 
HealthPartners Center for Memory & Aging 
HealthPartners Neuroscience Center 
295 Phalen Blvd, 
St Paul, MN 55130 
 
 
 
 
 
 
This study will be conducted in compliance with the protocol, IND regulations and other applicable 
regulatory requirements. 
 
 
 
 
 
 
Confidential Information 
No use or disclosure of this document outside HealthPartners Center for Memory & Aging is permitted 
without prior written authorization from HealthPartners Center for Memory & Aging. 
 
 


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PROTOCOL SIGNATURE PAGE 
 
 
 
 
 
 
 
I have read this protocol and agree to adhere to the requirements. I will provide copies of this 
protocol and pertinent information to the study personnel under my supervision and my local ethics 
committee/institutional review board (EC/IRB). I will discuss this material with them and ensure they 
are fully informed regarding the study medication and the conduct of the study according to this 
protocol, applicable law, applicable regulatory requirements including 21 CFR parts, 50, 54, 56, 312 
and 812, general standards of good clinical practice and local EC/IRB requirements. 
 
 
 
 
 
 
 
 
 
_______________________________________                              
Principal Investigator 
 
 
 
____________________ 
Date  
 
 


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Table of Contents 
LIST OF TABLES .............................................................................................................................................. 7 
DEFINITIONS .................................................................................................................................................. 8 
PROTOCOL SUMMARY .................................................................................................................................. 9 
1 
INTRODUCTION ............................................................................................................................... 12 
1.1 
Background/Rationale ................................................................................................................ 12 
1.2 
Supporting Data .......................................................................................................................... 14 
2 
Summary of Device Description ...................................................................................................... 15 
2.1 
Intranasal device ......................................................................................................................... 15 
3 
Objectives........................................................................................................................................ 16 
3.1 
Primary Objective........................................................................................................................ 16 
3.2 
Secondary/Exploratory Objectives ............................................................................................. 16 
4 
Endpoint(s) ...................................................................................................................................... 16 
4.1 
Primary Endpoints ....................................................................................................................... 16 
4.2 
Secondary Endpoints .................................................................................................................. 16 
4.3 
Exploratory Endpoints ................................................................................................................. 16 
4.4 
Safety .......................................................................................................................................... 16 
5 
Study Design.................................................................................................................................... 17 
5.1 
Drug Administration Training ...................................................................................................... 17 
5.2 
Drug Administration with Aerosol Nasal Device ......................................................................... 17 
5.3 
Device Dose Loading and Administration ................................................................................... 18 
5.4 
Outcome Measures ..................................................................................................................... 19 
5.5 
Study Duration ............................................................................................................................ 19 
6 
Study Population ............................................................................................................................. 20 
6.1 
Eligibility Criteria ......................................................................................................................... 20 
6.1.1 
Inclusion Criteria ................................................................................................................. 20 
6.1.2 
Exclusion Criteria ................................................................................................................. 20 
7 
Study Assessments and Procedures................................................................................................ 21 
7.1 
Demographic and Baseline Assessments .................................................................................... 21 
7.1.1 
Visit 1: Screening (Week-2) ................................................................................................. 21 
7.1.2 
Visit 2: Baseline/Initial Treatment Visit (Week 0) ............................................................... 21 
7.1.3 
Phone Visit 1: Safety Check (Week 2) ................................................................................. 22 
7.1.4 
Visit 3: Final Treatment and Safety Visit (Week 4).............................................................. 22 


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7.1.5 
Phone Visit 2: Safety Check (Week 6) ................................................................................. 22 
7.2 
Early Withdrawal ......................................................................................................................... 22 
7.3 
Safety .......................................................................................................................................... 22 
7.3.1 
Physical Examination ........................................................................................................... 22 
7.3.2 
Neurological Examination ................................................................................................... 22 
7.3.3 
Vital Signs ............................................................................................................................ 22 
7.3.4 
Weight ................................................................................................................................. 23 
7.3.5 
ECG ...................................................................................................................................... 23 
7.3.6 
Laboratory Samples ............................................................................................................ 23 
7.4 
Neuropsychological Assessment ................................................................................................. 24 
7.4.1 
EXAMINER BATTERY ............................................................................................................ 24 
7.4.2 
Appetite and Eating Habit Questionnaire (APEHQ) ............................................................ 27 
7.4.3 
Columbia-Suicide Severity Scale 0 (C-SSRS) ........................................................................ 27 
8 
Investigational Product(s) ............................................................................................................... 27 
8.1 
Description of Investigational Product ....................................................................................... 27 
8.2 
Handling and Storage .................................................................................................................. 27 
8.3 
Packaging and Labeling ............................................................................................................... 28 
8.4 
Occupational Safety .................................................................................................................... 28 
9 
Concomitant Medications and Non-Drug Therapies ...................................................................... 28 
9.1 
Permitted Medications ............................................................................................................... 28 
9.2 
Prohibited Medications ............................................................................................................... 28 
10 
Subject Completion and Withdrawal .............................................................................................. 29 
10.1 
Subject Completion ..................................................................................................................... 29 
10.2 
Subject Withdrawal ..................................................................................................................... 29 
11 
Adverse Events (AE) and Serious Adverse Events (SAE) ................................................................. 29 
11.1 
Definition of AE ........................................................................................................................... 29 
11.2 
Definition of SAE ......................................................................................................................... 29 
11.2.1 
Clinical Laboratory Abnormalities & Other Abnormal Assessments as AEs & SAEs ........... 30 
11.2.2 
Time Period and Frequency of Detecting AEs and SAEs ..................................................... 30 
11.2.3 
Device Failures and Malfunctions ....................................................................................... 30 
12 
Data Analysis and Statistical Considerations .................................................................................. 30 
12.1 
Analysis Overview ....................................................................................................................... 30 
12.2 
Statistical Analysis of Primary Outcomes .................................................................................... 30 


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12.3 
Statistical Analysis of Exploratory Outcomes .............................................................................. 31 
12.4 
Statement of Precision ................................................................................................................ 31 
13 
Study Conduct Considerations ........................................................................................................ 31 
13.1 
Regulatory and Ethical Considerations, Including the Informed Consent Process ..................... 31 
13.2 
Data Safety Monitoring Board .................................................................................................... 32 
13.3 
Quality Assurance ....................................................................................................................... 32 
13.4 
Study Closure .............................................................................................................................. 32 
13.5 
Records Retention ....................................................................................................................... 32 
13.6 
Provision of Study Results and Information to Investigators ..................................................... 32 
13.7 
Data Management ...................................................................................................................... 32 
13.8 
Device Accountability .................................................................................................................. 32 
14 
References ...................................................................................................................................... 33 
 
 
 


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LIST OF TABLES 
 
Table 1: Schedule of Assessments .............................................................................................................. 24 
Table 2: Prohibited Medications ................................................................................................................. 28 
 
 


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DEFINITIONS 
 
Adverse event (AE)  
Any undesirable patient experience that may include 
but is not limited to an abnormal sign, symptom, 
illness, abnormal laboratory value, or other medical 
event. 
Appetite and Eating Habit 
Questionnaire (APEHQ) 
A set of questions examining changes in eating 
behaviors 
Columbia-Suicide Severity Rating Scale 
(C-SSRS) 
A scale designed to quantify the severity of suicidal 
ideation and behavior. 
Data Safety Monitoring Board (DSMB) 
An independent group assigned to review safety data 
to monitor for incidence of trends that would warrant 
termination of the trial. 
ExecutiveAbilities: Measures and 
Instruments for Neurobehavioral 
Evaluation and Research (EXAMINER) 
A set of cognitive tests that assess working memory, 
inhibition, set-shifting, fluency, planning, insight, and 
social cognition/behavior.    
Frontotemporal Dementia (FTD) 
A type of dementia resulting due to a degenerative 
process in the frontal and temporal lobes, refers to a 
continuum of disorders 
Intranasal (IN) 
A method of drug delivery that is particularly applicable 
to delivering centrally acting medications into the 
central nervous system. 
Mini Mental State Exam (MMSE) 
A 30 point cognitive screening tool that assesses 
orientation, working memory, short term memory, 
visuospatial construction, and language. 
Montreal Cognitive Assessment 
(MOCA) 
A 30 point screening instrument for cognitive 
impairment that has a 90% sensitivity for MCI and 
100% sensitivity for AD. 
Serious adverse events (SAE) 
Any symptom, sign, illness or experience that develops 
during the study and results in a life-threatening 
situation, hospitalization, significant disability, and 
other events determined by the investigator to be 
significant. 
FTD Types 
- Behavioral variant frontotemporal 
dementia (bv-FTD) 
- Semantic Dementia (SD) 
- Progressive non-fluent aphasia (PNFA) 
- Amyotrophic lateral sclerosis (ALS) 
- Progressive supranuclear palsy (PSP) 
- Corticobasal degeneration 
Different types of frontotemporal dementia 
 
 


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PROTOCOL SUMMARY 
 
PROTOCOL TITLE 
Nasal Insulin in Frontotemporal Dementia (NIFT-D) 
 
SHORT TITLE  
IN Insulin in FTD 
STUDY PHASE 
Phase II 
STUDY OBJECTIVES AND PURPOSE  
Primary Objectives:  
• 
Evaluate the feasibility of using the EXAMINER battery as a cognitive outcome measure in 
frontotemporal dementia (FTD) 
• 
Evaluate the HealthPartners Center for Memory & Aging’s recruitment capacity for FTD 
subjects  
• 
Assess the safety and tolerability of intranasal (IN) insulin in FTD subjects  
Exploratory Objectives:  
• 
Evaluate the effect of IN insulin on executive function and behavior in FTD 
• 
Evaluate the effect of IN insulin on eating behavior in FTD 
STUDY DESIGN  
Study Type 
Feasibility 
Control Type 
None 
Study Indication Type 
Treatment 
Blinding Schema 
N/A 
Device 
Aerosol nasal Device 
Study Design 
Prospective, non-randomized, no placebo controlled 
Planned Duration of 
Subject Participation 
9 weeks 
Planned Duration of 
Treatment 
4 weeks  
PRIMARY ENDPOINTS 
• 
Number of subjects completing the EXAMINER battery  
• 
Number of subjects enrolled 
• 
Total number of AEs and SAEs 
 


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SECONDARY  ENDPOINTS 
• 
Reasons for subjects failing to complete EXAMINER battery 
• 
Number of subjects completing the study 
• 
Number of screen failures 
• 
Reasons for screen failure  
• 
Number of unique subjects with an AE/SAE  
EXPLORATORY ENDPOINTS  
• 
Pre-post change in executive function and behavior (EXAMINER Battery) 
• 
Pre-post change in Appetite and Eating Habits Questionnaire (APEHQ) 
INVESTIGATIONAL PRODUCTS, DOSE AND MODE OF ADMINISTRATION 
Investigational Product 
Regular insulin (Novolin-R) 20 IU/IN (0.1ml/10 units IN in each nostril) BID  
SUBJECT SELECTION 
Targeted Accrual 
12 subjects.  We estimate a need to consent 20 subjects in order to reach 
this goal. 
INCLUSION CRITERIA 
1. Male or female subject meeting international consensus criteria for probable behavioral 
variant frontotemporal dementia or criteria for semantic dementia (Gorno-Tempini et al., 
2011; Rascovsky et al., 2011)  
2. Subject has a MMSE score ≥18.  
3. Subject is > 40 and <90 years of age. 
4. Female subjects are post-menopausal or have a negative pregnancy test  
5. The subject must be proficient in speaking, reading and understanding English in order to 
comply with procedural testing of cognitive function, memory and physiology. 
6. Subject has a dedicated family member /caregiver, who will be able to attend all visits and 
report on subject’s status. 
7. Subject and family member/caregiver have both provided fully informed written consent 
prior to participation.  In the event that subject is legally unable to provide informed written 
consent due to deterioration in cognitive abilities, fully informed written consent must be 
provided by a legally authorized representative. 
8. Subject must have undergone a brain CT or MRI as part of receiving FTD diagnosis 
EXCLUSION CRITERIA 
1. Subject has medical history and/or clinically determined evidence of other CNS disorders 
including, but not limited to brain tumor, active subdural hematoma, seizure disorder, 
multiple sclerosis, Alzheimer’s disease, vascular dementia, corticobasal syndrome, 
progressive supranuclear palsy, Parkinson’s disease, multiple system atrophy, Lewy body 
dementia, normal pressure hydrocephalus, Huntington’s disease, or Jakob-Creutzfeldt 
disease presenting as dementia. 
2. Subject has medical history and/or clinically determined disorders: current B12 deficiency, 
chronic sinusitis, untreated thyroid disease, or significant head trauma. 


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3. Subject has history of any of the following: moderate to severe pulmonary disease, poorly 
controlled congestive heart failure, significant cardiovascular and/or cerebrovascular events 
within previous 6 months, condition known to affect absorption, distribution, metabolism, 
or excretion of drugs such as any hepatic, renal or gastrointestinal disease or any other 
clinically relevant abnormality that inclusion would pose a safety risk to the subject as 
determined by investigator. 
4. Subject has had previous nasal and/or oto-pharyngeal surgery and severe deviated septum 
and/or other anomalies.  
5. Subject has a history of any psychiatric illness that would pose a safety risk to the subject as 
determined by investigator.   
6. Subject is currently taking any medications (anticholinergics, antihistamines, 
benzodiazepines, barbiturates, or insulin) that are clinically contraindicated as determined 
by investigator.  
7. Subject has undergone a recent change (<1 month) in their SSRI or anti-depressant 
medication. 
8. Subject has current or recent drug or alcohol abuse or dependence as defined by DSM-IV TR. 
9. Screening laboratory results that are medically relevant, in which inclusion would pose a 
safety risk to the subject as determined by investigator. 
10. The subject has participated in a clinical trial investigation within 1 month of this study. 
11. The subject has an insulin allergy. 
 
 
 


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1 INTRODUCTION 
1.1 Background/Rationale 
Frontotemporal dementia (FTD) with its multiple pathological manifestations, is a disease that results in 
progressive deterioration of social comportment, executive function, and language.  FTD refers to a 
continuum of disorders that includes behavioral variant frontotemporal dementia (bv-FTD), semantic 
dementia (SD), progressive non-fluent aphasia (PNFA), amyotrophic lateral sclerosis (ALS), progressive 
supranuclear palsy (PSP), and corticobasal degeneration and is responsible for 12% of the cases of young 
onset dementia and represents the second most common cause of dementia in this population. In 
addition to the various clinical syndromes, FTD is associated with various neuropathological findings that 
include tar DNA binding protein-43 (TDP-43), tau, and fused in sarcoma (FUS). (Harvey et al., 2003).    
Despite the debilitating nature of FTD and the relatively high prevalence in the younger patient 
population, available pharmacological interventions are limited to symptomatic treatments such as 
selective serotonin reuptake inhibitors (SSRIs) and neuroleptics that are geared toward behavioral 
management.   Drugs approved by Food and Drug Administration (FDA) for AD have been found to 
ineffective in FTD as in the case of memantine (Boxer et al., 2013) or detrimental to behavioral 
symptoms as in the case of cholinesterase inhibitors (Mendez et al., 2007).  Thus, there are no 
therapeutic agents that have been developed that specifically treat the progressive cognitive symptoms 
of FTD.   
bv-FTD is the most common FTD clinical syndrome, representing 50-70% of cases within the U.S. and 
Europe (Bang et al., 2015), and leading to progressive dysfunction of neural networks responsible for 
social behavior, emotional regulation, theory of mind, and decision-making (Rosenbloom et al., 2012; 
Seelaar et al., 2011). The five major clinical features associated with bv-FTD are characterized by 1) early 
behavioral disinhibition; 2) early apathy or inertia; 3) early loss of sympathy or empathy; 4) early 
perseverative, stereotyped, or compulsive/ritualistic behavior; and 5) hyperorality and dietary changes 
(Rascovsky et al., 2011).  bv-FTD has a variety of underlying pathologies that include tau 36-50% of the 
time, TDP-43 50% of the time, and FUS 10% of the time (Bang et al., 2015).   
Semantic dementia (SD) or the semantic variant of primary progressive aphasia (sv-PPA) leads to 
progressive, focal atrophy of the anterior temporal lobe and amygdala.  The clinical presentation varies 
based on the lateralization of neurodegeneration: left anterior temporal atrophy, which is the most 
common disease manifestation, results in a fluent aphasia consisting of deficits that involves language 
deficits whereas the right anterior temporal atrophy leads to behavioral changes (Bang et al., 2015). 
Common language manifestations include impaired object knowledge, surface dyslexia, and impaired 
single word comprehension (Bang et al., 2015).  Although sv-PPA is most commonly associated with 
language dysfunction, patient with right anterior temporal atrophy manifest symptoms of social 
disinhibition, depression and aggressive behavior (Chan et al., 2009). sv-PPA is almost exclusively 
associated with TDP-43 neuropathology (Bang Lancet 2015).    
The non-fluent variant of primary progressive aphasia (nfv-PPA) is the third most common clinical 
syndrome under the FTD umbrella and results from dominant hemispheric atrophy involving the insular 
cortex.  Patients present with telegraphic, agrammatical speech, apraxia of speech and difficulty with 
comprehending complex sentences; there is relative sparing of object knowledge and single word 


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comprehension (Gorno-Tempini et al., 2011).  Associated neuropathology includes tau (36-50%)>TDP43 
(50%)>FUS (10%) (Bang Lancet 2015/Neumann Brain 2009).   
For the purposes of this study, we are including subjects carrying the diagnosis of bv-FTD and sv-PPA 
while excluding nfv-PPA subjects as behavioral symptoms are less common in this FTD subtype. 
Intranasal (IN) delivery offers a non-invasive route to deliver large molecules such as insulin directly to 
the brain while minimizing systemic exposure. Peptides, proteins, vaccines, drug treatments and ions of 
various sizes are able to pass along the olfactory and trigeminal nerves and are deposited directly into 
the CNS without having to pass through the blood brain barrier (BBB), which may degrade or limit the 
amount arriving at the target (Born et al., 2002; Derad et al., 1998; Dhanda et al., 2005; Garmise et al., 
2007; Kern et al., 1997; Perras et al., 1999; Thorne et al., 1995; Thorne et al., 2004). CSF insulin levels in 
healthy adults have been detected as early as 10 minutes following IN delivery while not measurably 
increasing systemic blood-glucose levels (Born et al., 2002; Kern et al., 1999). Similar observations of the 
safety of IN insulin have been made in memory impaired adults (Reger et al., 2006; Reger et al., 2008). 
Originally thought to exist solely in the periphery, insulin has since been determined to be instrumental 
in the overall health and function of the CNS (Zhao and Alkon, 2001).  Central insulin and insulin 
receptors (IRs) have been established as differing from that of the systemically occurring counter parts 
that specifically regulate glucose utilization. In rodents, insulin receptors and insulin-sensitive glucose 
transporters are selectively co-localized in brain areas responsible for memory, thus providing a 
platform for insulin signaling whereby selective increases in cerebral glucose utilization could modulate 
memory (Craft and Watson, 2004; Watson and Craft, 2003). Consistent with evidence of insulin 
functioning as a neuromodulator for memory-related function is the high-density of IRs in the 
hippocampus and cerebral cortex, brain regions integral to the formation, retention and recall of 
information (Singh et al., 1997; Zhao and Alkon, 2001). Systems with impaired insulin signaling pathways 
have demonstrated inhibition of acetylcholine biosynthesis and subsequently have incurred debilitating 
effects on neuronal plasticity (Rivera et al., 2005; Stockhorst et al., 2004). 
Increased insulin resistance and glucose intolerance has been observed in a multitude of 
neurodegenerative processes including Alzheimer’s disease (Craft and Watson, 2004), Parkinson’s 
disease (Sandyk, 1993), and Huntington’s disease (Petersén and Björkqvist, 2006).  Likewise, multiple 
investigations suggest a similar disturbance in frontotemporal dementia (FTD). Beyond the potential 
impact on cognitive and behavioral symptoms, IN insulin’s role in FTD appears particularly relevant upon 
consideration of the high frequency of abnormal feeding behaviors and metabolic syndrome in this 
population. Approximately 60% of bv-FTD patients demonstrate hyperorality, binge-eating, and 
increased carbohydrate consumption upon clinical presentation (Piguet et al., 2009).   Patients with bv-
FTD consume more calories and have a greater predilection for sucrose-containing food products 
compared to AD (Ahmed et al., 2016a). This clinical characteristic is predominant enough such that it is 
one of the five major clinical features associated with bv-FTD and has been included in the international 
consensus criteria.   In addition, changes in food consumption have also been observed in semantic 
dementia (SD).   Brain regions linked to these eating disturbances have been identified in the 
frontoinsular cortex and anteromedial temporal brain areas (Whitwell et al., 2007; Woolley et al., 2007).   
Both bv-FTD and SD patients manifest systemic metabolic abnormalities that include increased 
triglyceride levels, insulin resistance, and reduced HDL levels relative to controls, suggesting the 
presence of a metabolic syndrome (Ahmed et al., 2014b).   In addition, both conditions have elevated 


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body mass indices (BMI) compared to controls and bv-FTD patients have a higher prevalence of diabetes 
(Ahmed et al., 2016b).  However, whether the metabolic syndrome is a contributing factor or the end 
product of a neurodegenerative process remains to be determined. 
We proposed a pilot study of IN insulin in FTD, more specific bv-FTD and SD.  The majority of clinical 
trials of dementia employ outcome measures that focus on memory and have greater relevance to 
Alzheimer’s disease.  For instance, the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-
cog) is a battery that is heavily-weighted toward cognitive tasks affected in Alzheimer’s disease, but 
would be unsuitable to measure change in FTD.  For this reason, we will be utilizing the EXAMINER 
cognitive battery (https://memory.ucsf.edu/examiner) which was developed at the University of 
California, San Francisco to reliably and validly assess domains of executive function—the primary 
cognitive modality impacted in FTD.  In addition, the battery includes outcomes with respect to social 
cognition.  EXAMINER has the following attributes: modular (separate modules testing various elements 
of executive function), modifiable (any standard battery can be adapted to a range of experimental and 
clinical situations), efficient (relatively short administration time), applicable to a broad range of 
individuals from different age and ethnic groups, and reliable.   
We aim to evaluate the feasibility of the EXAMINER cognitive battery as a cognitive outcome measure in 
FTD, the ability of our Center’s ability to sufficiently recruit subjects with FTD, and the safety of IN 
regular insulin administered 20 IU BID in bv-FTD and SD over a 4 week period. Prior studies performed in 
the AD population have demonstrated favorable effects of this regimen in the MCI/AD population (Craft 
et al., 2012).  
In addition, the clinical trial will investigate exploratory outcomes related to the effect of IN insulin on 
executive performance as measured by the EXAMINER battery and feeding behavior as measured by 
Change in Appetite and Eating Habits Questionnaire (APEHQ).  
1.2 Supporting Data 
Preclinical studies have suggested that insulin signaling deficits play a major role in the development of 
neurodegenerative diseases such as AD.  Early in the course of AD reduced glucose utilization and 
deficient energy metabolism develop, thus indicating a role for IN insulin in the progression of this 
neurodegenerative disease (Steen et al., 2005).  Although brain deposition of beta-amyloid (Aβ) plaques 
and neurofibrillary tangles (NFTs) are both critical pathological signatures of AD, they are also 
modulated by CNS insulin activity. As AD progresses, the presence of soluble Aβ aggregates further 
induces tau hyperphosphorylation as well as decreases the number of synaptic insulin receptors (IRs) 
(Craft and Watson, 2004). The down-regulation of dendritic surface IRs from accumulating Aβ 
compromises synaptic function in brain regions associated with memory and cognitive function, leading 
to the disruption in the insulin-signaling pathway that is characteristic of AD (Zhao et al., 2008).  Insulin 
further inhibits neurofibrillary tangle production by maintaining a phosphorylation equilibrium between 
kinase and phosphatase activity (Craft, 2006; Hong and Lee, 1997; Planel et al., 2007; Wang et al., 2007). 
Such evidence of signaling deficits in AD have resulted in the theory of this condition representing a 
“type 3 diabetes” of the brain (Steen et al., 2005). 
Clinical investigations of intranasal insulin in AD have demonstrated therapeutic effects impacting 
memory, attention and cognition without significantly altering serum insulin or glucose levels. A clinical 
trial consisting of 26 memory impaired subjects (13 with AD and 13 with mild cognitive impairment) and 


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35 normal controls showed that a single dose IN insulin 20 IU or 40 IU resulted in improvements on two 
declarative memory tasks compared to placebo within 15 minutes of drug administration (Reger et al., 
2006). IN insulin administered at 20 IU resulted in greater story recall whereas doses at 40 IU more 
favorably improved word list recall. There was no impact on IN insulin on serum glucose or insulin levels. 
Another study of 24 early AD/mild cognitive impairment subjects showed that 20 IU BID of intranasal 
insulin resulted in sustained benefit in over a 21 day period (Reger et al., 2008). Furthermore, IN insulin 
induced favorable changes in the serum Aβ 40/42 ratio while having no impact on systemic glucose or 
insulin levels. Most recently, Craft and colleagues have demonstrated improved delayed memory and 
preserved caregiver-rated functional ability as represented by the ADAS-Cog and ADCS-ADL, respectively 
in MCI/AD patients treated with regular insulin 10 and 20 IU bid during a four month treatment trial 
(Craft et al., 2012). These changes in memory and function were associated with favorable changes in 
CSF tau and tau-Ab42 ratio. Additionally, IN insulin minimized progression in terms of loss of cerebral 
hypometabolism as measured by FDG-PET.  
There have been no clinical investigations to our knowledge of IN insulin in FTD.  Relative to other 
neurodegenerative processes, FTD is a more complex disorder to treat based on the multitude of 
underlying neuropathologies that include TDP-43, tau, and FUS proteins.   However, there are multiple 
factors suggesting a role for insulin in modifying this disease process.  Tau phosphorylation through the 
activity of the GSK-3B enzyme is a critical step in the formation of tau-based inclusions.  Insulin has been 
shown to inhibit the enzyme GSK-3B, resulting in decreased tau phosphorylation and aggregation. Up to 
50% of FTD pathology is associated with CNS tau deposition, and so this mechanism of action may 
benefit a substantial portion of individuals carrying the diagnosis (Baborie et al., 2011; Josephs et al., 
2011; Sieben et al., 2012).  In addition, evidence has suggested that intercellular spread of tau 
aggregates through a conformational change that resembles a prion-like mechanism may be responsible 
for the propagation of neurodegeneration in affected individuals (Holmes and Diamond, 2014).  
Targeted inhibitors of GSK-3B have already been tested in clinical trials for progressive supranuclear 
palsy, a neurodegenerative tauopathy that falls within the spectrum of FTD disorders (Tolosa et al., 
2014).  Finally, patients with FTD demonstrate regional FDG-PET involving the frontotemporal lobes, 
thus suggesting the possibility of abnormal regional glucose metabolism in this disorder (Foster et al., 
2007). 
2 Summary of Device Description 
2.1 Intranasal device 
The delivery of drugs to the CNS remains a development challenge mainly due to the impenetrable 
nature of the BBB. Device innovative approach enables broad, consistent drug delivery (either liquids or 
powders) to the upper area of the nasal cavity, which improves the absorption of the active ingredients 
when compared to commercial nasal delivery devices.  Currently available nasal devices such as 
droppers, sprays, or pumps that deliver aerosol mainly to the lower and mid turbinate of the nasal cavity 
and only minor amounts, about 5% to the upper turbinate of the nasal cavity (Djupesland and Skretting, 
2012). Device company has conducted animal studies using an aerosol nasal device with the same 
technology that is designed for humans. To address the different nasal cavity size and structure, 
adaptations were used for the device to fit each animal model.  


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The Aerosol nasal device is an aerosol nasal delivery platform that uses pressurized delivery through the 
discharge of compressed air, resulting in an aerosol that delivers the drug in a narrow plume geometry, 
which targets the olfactory epithelium in the upper nasal cavity. From the olfactory epithelium, 
therapeutics rapidly reach the central nervous system, traveling extracellularly along the olfactory 
nerves.  The device is not currently commercially available, but numerous studies have demonstrated its 
ability to intranasally deliver radiolabeled and therapeutic compounds to the brain.  
3 Objectives 
3.1 Primary Objective 
• 
Evaluate the feasibility of using the EXAMINER battery as a cognitive outcome measure in 
frontotemporal dementia (FTD) 
• 
Evaluate the HealthPartners Center for Memory & Aging’s recruitment capacity for FTD subjects  
Assess the safety and tolerability of intranasal (IN) insulin in FTD subjects  
 
3.2 Secondary/Exploratory Objectives 
• 
Evaluate the effect of IN insulin on executive function and behavior in FTD 
• 
Evaluate the effect of IN insulin on eating behavior in FTD 
 
4 Endpoint(s) 
4.1 Primary Endpoints 
• 
Number of subjects completing the EXAMINER battery  
• 
Number of subjects enrolled 
• 
Total number of AEs and SAEs 
  
4.2 Secondary Endpoints 
• 
Reasons for subjects failing to complete EXAMINER battery 
• 
Number of subjects completing the study 
• 
Number of screen failures 
• 
Reasons for screen failure  
• 
Number of unique subjects with an AE/SAE 
 
4.3 Exploratory Endpoints 
• 
Pre-post change in executive function and behavior (EXAMINER Battery) 
• 
Pre-post change in Appetite and Eating Habits Questionnaire (APEHQ) 
 
4.4 Safety 
• 
Incidence and severity of serious adverse events (SAEs) and adverse events (AEs) 
• 
Frequency of change in clinically-significant vital signs, physical exam or neurological exam 
• 
Plasma glucose level <70mg/dl 
 


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5 Study Design 
This study is a single center trial of intranasal (IN) regular insulin in subjects with probable behavioral 
variant FTD (bv-FTD) and semantic variant PPA (sv-PPA) and is designed to assess –  
1) Evaluate the feasibility of using the EXAMINER battery as a cognitive outcome measure in 
frontotemporal dementia (FTD),  
2) Evaluate the HealthPartners Center for Memory & Aging’s recruitment capacity for FTD subjects 
and  
3) Assess the safety and tolerability of intranasal (IN) insulin in FTD subjects.  
 
After written informed consent has been obtained from the subject and family member/caregiver, 
subjects will be screened to assess study eligibility based on study inclusion/exclusion criteria. Subjects 
who are eligible at the end of the screening visit (Visit 1) will be scheduled for a baseline to take place 2 
weeks later (Visit 2). During the baseline visit, subjects will be administered the EXAMINER battery and 
APEHQ questionnaire.  A final safety/assessment visit will take place four weeks after visit 2 (Visit 3) at 
which time the EXAMINER battery and APEHQ questionnaire will be re-administered.  There will be two 
phone visits (one between visit 2 and 3 and another after visit 3) to address study drug compliance and 
AEs/SAEs. 
5.1 Drug Administration Training 
All subjects and study partners will receive extensive training at each visit regarding home 
administration of IN insulin using the aerosol nasal device during visits 1 and 2 (screening and baseline, 
respectively).   Subjects will be required to administer the dose twice daily, once in the morning and 
again in the evening (at least 8 hours between doses).   Subjects will have the opportunity to 
immediately do a retrial administration if they are unsuccessful in releasing the study drug intranasally.  
If the aerosol nasal device is discharged prior to insertion into the nose, then a retrial admission would 
be indicated.  However, if the device is discharged following nasal insertion, then a retrial would not be 
permitted.   The steps to ensure that subjects maintain compliance with the study protocol over 4 weeks 
include administering the following: 
• 
In-clinic training sessions: screening and baseline visits 
• 
Phone call to assess drug compliance from study coordinator 2 weeks after baseline visit. 
 
In addition to drug administration training, subjects will be given a daily Drug Diary to record the time 
and date of each self-administered dose, drug vial number and any comments for study staff. 
Instructions and training for the Drug Diary will be given to all subjects and study partners at the same 
times as the drug administration training. 
 
5.2 Drug Administration with Aerosol Nasal Device 
Each dosing administration will require the following items:  a) 2 Devices each with a nose piece cover; 
b) Device holder; c) 10 ml vial of Regular Insulin (Novolin R); d) 2 Insulin syringes; e) alcohol wipe; f) 
needle clipper and/or sharps container. 
During the baseline/initial treatment visit the subject/study partner will administer the study drug in 
front of study personnel to ensure adherence to study protocol for drug administration. To ensure 
safety and medication compliance, subjects will be followed-up with a routine phone call 2 weeks after 


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baseline (safety and drug compliance) and final treatment visit (safety). Non-insulin dependent diabetic 
subjects will monitor their fingerstick glucose as part of routine schedule as determined by their primary 
clinician/endocrinologist. 
Devices will be shipped to the clinical study site. One device with a nose piece cover will be supplied for 
each dose to be administered in the study. A kit containing the necessary items will be distributed to 
each subject and replaced as necessary. This will include several extra devices in case there are issues 
with any devices. Each device is to be loaded with a 10 unit dose of regular insulin to be used 
immediately with up to a maximum of 10 minutes prior to IN administration. The Nose Piece and 
Secondary Drug Container (temporary) are the only components of the device that will come into 
contact with regular insulin and subject’s nasal cavity.  
5.3 Device Dose Loading and Administration 
 
1. The care partner will prepare device. 
 
 
 
 
 
 
 
 
 
 
a. Remove the syringe, device and study drug. Open the device covers and place devices in 
device holder (Figure 5). Carefully remove the cap from the syringe needle.  
The care partner will switch to a new study drug vial every two weeks during the dosing 
period. Study drug vials will be prepared by staff before subject and care partner receive 
them. Subjects will receive two vials of medication at the first dosing visit. 
 
2. The care partner will load the drug formulation into the devices.  
 
a. Remove the cap from the top of the vial.   
 
b. Wipe the top of the vial with an alcohol wipe. 
 
c. Load the 0.1 ml desired regular insulin dose volume from the vial using the Insulin 
syringe. 
i. Immediately (within 10 minutes) before taking dose, load the devices with study 
drug.  
ii. Pull Syringe plunger to 0.1 ml 
iii. Insert syringe needle into the vial top, and push air into the vial 
iv. Turn the medication vial upside-down and slowly pull the syringe plunger down, 
withdrawing the study drug until 0.3ml line is visible just above the plunger. Tap 
the syringe to move any air bubbles to the top 
Remove Cap from 
S
d D
Wipe Top of the Vial with Alcohol 
Pull the Syringe Plunger Down 
Wipe the top of the Vial with an Alcohol Wipe 


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v. Slowly push the plunger up to the 0.1ml line to push any air bubbles back into 
the vial.  There should be a fluid level at the 0.1 ml line. 
vi. Turn the medication vial upright and gently pull the syringe out without moving 
the plunger. 
 
d. Insert the syringe with the needle carefully into the top of the device. 
 
e. Slowly depress the syringe plunger, ensuring that no dose leaks. After the plunger is fully 
depressed, remove the syringe with the needle carefully from the device and leave the 
device in the device holder. 
f. Dispose of the syringe and the needle by using a needle clipper and or in a sharps 
container.  
g. Repeat these steps, using another syringe for the second device. 
 
3. Subject will blow their nose prior to administering the first dose. 
4. Subject will turn the device upside down and flick the nose piece to allow the drug to 
concentrate at its edge as shown in the figure. This helps the subject to see if the drug is loaded 
prior to administration.  
5. The research staff will provide guidance to the subject on placement for nasal administration for 
the first dosing.  
a. Place the nose piece of the device comfortably in the nose as shown in the figure below.  
b. After the initial placement, the examiner will make slight adjustments to orient the nose 
piece in the proper direction. 
 
6. Press the activation button to administer the drug in the nasal cavity. 
 
7. Steps 3-5 will be repeated for the other nostril using the second prepared device. 
 
5.4  Outcome Measures 
Neuropsychological and behavioral batteries will be performed at baseline and visit 3 (see section 7.4 
for additional details).   
5.5 Study Duration 
Study participation will last approximately 9 weeks, consisting of a screening visit, baseline visit, follow-
up assessment visit and two phone call visits.   Subjects will receive treatment for a period of 4 weeks.  
Subjects who discontinue treatment will continue follow-up measures as possible. 
Nose Piece Placement 
in the Nose 
Nose Piece  


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6 Study Population 
6.1 Eligibility Criteria 
6.1.1 Inclusion Criteria 
1. Male or female subjects meeting international consensus criteria for probable behavioral 
variant frontotemporal dementia or criteria for semantic dementia (Gorno-Tempini et al., 
2011; Rascovsky et al., 2011)  
2. Subject has a MMSE score ≥18.  
3. Subject is > 40 and <90 years of age. 
4. Female subjects are post-menopausal or have a negative pregnancy test  
5. The subject must be proficient in speaking, reading and understanding English in order to 
comply with procedural testing of cognitive function, memory and physiology. 
6. Subject has a dedicated family member /caregiver, who will be able to attend all visits and 
report on subject’s status. 
7. Subject and family member/caregiver have both provided fully informed written consent prior 
to participation.  In the event that subject is legally unable to provide informed written 
consent due to deterioration in cognitive abilities, fully informed written consent must be 
provided by a legally authorized representative. 
8. Subject must have undergone a brain CT or MRI as part of  receiving their FTD diagnosis 
 
6.1.2 
Exclusion Criteria 
A subject will not be included for consideration in this study if any of the following criteria are met: 
1. Subject has medical history and/or clinically determined evidence of other CNS disorders 
including, but not limited to brain tumor, active subdural hematoma, seizure disorder, multiple 
sclerosis, Alzheimer’s disease, vascular dementia, corticobasal syndrome, progressive 
supranuclear palsy, Parkinson’s disease, multiple system atrophy, Lewy body dementia, normal 
pressure hydrocephalus, Huntington’s disease, or Jakob-Creutzfeldt disease presenting as 
dementia. 
2. Subject has medical history and/or clinically determined disorders: current B12 deficiency, 
chronic sinusitis, untreated thyroid disease, or significant head trauma. 
3. Subject has history of any of the following: moderate to severe pulmonary disease, poorly 
controlled congestive heart failure, significant cardiovascular and/or cerebrovascular events 
within previous 6 months, condition known to affect absorption, distribution, metabolism, or 
excretion of drugs such as any hepatic, renal or gastrointestinal disease or any other clinically 
relevant abnormality that inclusion would pose a safety risk to the subject as determined by 
investigator. 
4. Subject has had previous nasal and/or oto-pharyngeal surgery and severe deviated septum 
and/or other anomalies.  
5. Subject has history of any psychiatric illness that would pose a safety risk to the subject as 
determined by investigator.   
6. Subject is currently taking any medications (anticholinergics, antihistamines, benzodiazepines, 
barbiturates, or insulin) that are clinically contraindicated as determined by investigator.  
7. Subject has undergone a recent change (<1 month) in their SSRI or anti-depressant medication. 
8. Subject has current or recent drug or alcohol abuse or dependence as defined by DSM-IV TR. 
9. Screening laboratory results that are medically relevant, in which inclusion would pose a safety 
risk to the subject as determined by investigator. 


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10. The subject has participated in a clinical trial investigation within 1 month of this study. 
11. The subject has an insulin allergy. 
7 Study Assessments and Procedures 
A summary of study events and procedures is outlined in the Study Visit Table.  Demographic, Screening, 
and Baseline Assessments are described in Sections 7.1.1-7.1.2, the Treatment Phase is outlined in 
Sections 7.1.2-7.1.4, and the safety monitoring are detailed in Section 7.1.5; details of 
neuropsychological assessments are outlined in Section 7.4.  Note that all visits are fasting unless 
otherwise noted. 
7.1 Demographic and Baseline Assessments 
7.1.1 Visit 1: Screening (Week-2) 
The following procedures will be performed at this visit: 
• 
Obtain written informed consent from study partner and subject (or subject’s legally authorized 
representative) prior to any study related procedures. 
• 
Review Inclusion/Exclusion Criteria. 
• 
Review medical history, as it pertains to inclusion/exclusion criteria, such as research diagnosis, 
disease severity, and course of FTD 
• 
Obtain subject’s demographic information (date of birth, gender, race, education, etc.). 
• 
Obtain details of medications taken over the course of the last 30 days. 
• 
Complete physical exam, including neurological exam.  Collect vital signs, height and weight 
prior to ECG and blood draw. 
• 
Administer MMSE 
• 
Obtain laboratory studies 
• 
Perform a standard 12-lead ECG. 
• 
Serum pregnancy test in women of child bearing potential 
• 
Study Drug administration training; Hypoglycemia rescue training 
• 
Visit 2 will be scheduled within 2 weeks (± 5 days). 
 
7.1.2 Visit 2: Baseline/Initial Treatment Visit (Week 0) 
The following procedures will be performed at this visit: 
• 
Review Inclusion/Exclusion Criteria. 
• 
Collect vital signs and weight.  
• 
Collect concomitant medication information and record AEs/SAEs. 
• 
Neuropsychological testing with EXAMINER 
• 
Administer APEHQ 
• 
Administer C-SSRS 
• 
Study Drug administration training (following testing with EXAMINER).  
• 
Hypoglycemia rescue training.  
• 
First dose of intranasal insulin administered 
• 
Finger glucose stick at baseline prior to first dose, and at 15 and 30 min after first dose 
• 
Phone visit will be scheduled in 2 weeks (± 3 days). 
• 
Visit 3 will be scheduled in 4 weeks (± 5 days). 
 


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7.1.3 Phone Visit 1: Safety Check (Week 2) 
• 
Study staff phone call to address IN insulin compliance and AEs/SAEs 
• 
Reminder to take the last dose the night before visit 3. 
 
7.1.4 Visit 3: Final Treatment and Safety Visit (Week 4) 
The following procedures will be performed at this visit: 
• 
Collect vital signs and weight.  
• 
Collect concomitant medication information and record AEs/SAEs. 
• 
Review/collect AE/SAE information 
• 
Physical and neurological examination 
• 
Neuropsychological testing with EXAMINER 
• 
Administer APEHQ 
• 
Administer C-SSRS 
• 
Obtain laboratory studies  
• 
Phone visit will be scheduled in 2 weeks (± 3 days). 
 
7.1.5 Phone Visit 2: Safety Check (Week 6) 
• 
Study staff phone call to address AEs/SAEs 
 
7.2 Early Withdrawal 
If subject withdraws from the study after the screening visit, but before visit 2, no further evaluations 
are necessary.  If subject withdraws from the study after visit 2, all safety assessments will be performed 
(see section 7.3). 
7.3 Safety 
For all safety assessments described below, any clinically significant change will be recorded as 
an AE or SAE. 
7.3.1 Physical Examination 
Complete physical examination will be performed at visits, 1 and 3, or if the subject withdraws or is 
withdrawn from the study early.  Any abnormalities noted at Visit 1, will be documented as part of the 
subject’s medical history. 
7.3.2 Neurological Examination 
Neurological examination will be performed at visits 1, 3 or if the subject withdraws early.  Any 
abnormalities noted at Visit 1, will be documented as part of the subject’s medical history.   
7.3.3 Vital Signs 
Vital signs will be recorded at all visits.  For within subject consistency, brachial artery pressure will be 
obtained in the routine fashion.  
Blood pressure and heart rate to be measured after subject has been sitting quietly for a minimum of 5 
minutes.  Diastolic blood pressure will be measured at the disappearance of Korotkoff sounds. Vitals sign 
will be monitored by clinical staff during each visit of the study.  


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A blood glucose ˂ 70 mg/dL will be considered clinically significant.  Subjects will be given training 
regarding hypoglycemic rescue therapy and contacting 911 in severe cases.  Any episodes will be 
reported to the study coordinator and research team.  The likelihood of peripheral hypoglycemia is 
relatively low based on numerous clinical trials performed in the AD and healthy aging population 
showing no effects of IN insulin on peripheral glucose. 
Vital signs will be taken prior to ECG and blood draw. 
7.3.4 Weight 
Body weight will be measured at all visits. 
7.3.5 ECG 
A standard 12-lead ECG will be performed on subjects at visit 1. 
7.3.6 Laboratory Samples 
All subjects will be required to fast for a minimum of 12 hours prior to collection of blood sampling. 
See Table 1 for a specific list of laboratory assessments. 
 
 


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Table 1: Schedule of Assessments 
Assessment/ Procedure  
Visit 1: 
Screen  
Visit 2: 
Baseline/Initial 
Treatment 
Phone Visit 
1: 
Safety 
Check  
Visit 3:  
Final 
Treatment / 
Safety  
Phone 
Visit 2: 
Safety 
Check  
Early 
Withdrawal  
 
 
 
 
 
 
 
Schedule - Week and Windows 
- 2  
0  
2  
4  
6  
 
 
± 5 days 
± 3 days 
± 5 days 
± 3 days 
 
Informed consent  
X 
 
 
 
 
 
Review of inclusion/exclusion 
criteria  
X 
X 
 
 
 
 
Medical History, demographic  
X 
 
 
 
 
 
Physical/neurological exam  
X 
 
 
X 
 
X 
Vital signs 
X 
X 
 
X 
 
X 
Height 
X 
 
 
 
 
 
Weight  
X 
X 
 
X 
 
X 
12-lead ECG 
X 
 
 
 
 
 
Basic Metabolic Panel ( Na, K, 
CO2, CL, BUN, Creatinine, Glucose 
and Ca) 
X 
 
 
X 
 
X 
Insulin Level  
X 
 
 
X 
 
 
HbA1c  
X 
 
 
 
 
 
Thyroid Stimulating Hormone 
(TSH) 
X 
 
 
 
 
 
Vitamin B12  
X 
 
 
 
 
 
Pregnancy Test (in females)  
X 
 
 
 
 
 
EXAMINER BATTERY 
 
X 
 
X 
 
 
MMSE 
X 
 
 
 
 
 
APEHQ 
 
X 
 
X 
 
 
C-SSRS 
 
X 
 
X 
 
X 
Study Drug administration training  X 
X 
 
 
 
 
Hypoglycemia rescue training  
X 
X 
 
 
 
 
Glucose finger sticks (baseline 
before 1st dose; 15 & 30 minutes 
after 1st dose) 
 
X 
 
 
 
 
Concomitant mediations  
 
X 
 
X 
 
 
IN INSULIN compliance 
 
 
X 
 
 
 
Adverse events  
 
X 
X 
X 
X 
X 
 
7.4 Neuropsychological Assessment 
See Table 1 for a specific list of neuropsychological assessments 
 
7.4.1 EXAMINER BATTERY 
The EXAMINER battery was developed at the University of California, San Francisco Memory and Aging 
Center as a means of validly assessing domains of executive function in an assortment of ages and 
disorders to capture real-life social and executive deficits in subjects with frontal lobe disorders 
(http://www.memory.ucsf.edu).  The battery consists of subtests in a variety of domains that include 
working memory, inhibition, set-shifting, fluency, planning, insight, and social cognition/behavior.    


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7.4.1.1 
Working Memory Subtests: 
7.4.1.1.1 Dot Counting:   
The dot counting task measures verbal working memory. The examinee is asked to look at a screen with 
a mixed array of green circles, blue circles and blue squares. The examinee is asked to count all of the 
blue circles on the screen one at a time, out loud and remember the final total. Once the examinee 
finishes counting the blue circles on one screen, the examiner switches the display to a different mixed 
array of green circles, blue circles and blue squares. The examinee is instructed to count the blue circles 
in the new display. The number of different displays presented to the examinee in each trial increases 
from two to seven over six experimental trials. After counting the blue circles on all of the displays 
presented within a trial, the examinee is asked to recall the total number of blue circles that were 
counted in each of the different displays in the order in which they were presented. Partial credit is 
given based on how many totals the examinee can recall correctly from each trial. 
7.4.1.1.2 N-Back 
The n-back paradigm is a widely used measure of working memory that requires flexible updating 
capabilities. EXAMINER includes a spatial 1-back and 2-back task to assess spatial working memory. The 
1-back requires maintaining and updating 1 location at a time, whereas the more difficult 2-back 
requires maintaining and updating 2 locations. 
 
7.4.1.2 
Inhibition 
7.4.1.2.1 Flanker 
A row of five arrows is presented in the center of the screen. The examinee is required to indicate 
whether the centrally presented arrow is pointing either to the left or right by pressing the left or right 
arrow key. The examinee is presented with two different conditions during the task, incongruent and 
congruent. In the congruent trials, the non-target arrows point in the same direction as the target arrow 
and in the incongruent trials they point in the opposite direction. Examinees should respond as quickly 
and accurately as possible. 
 
7.4.1.2.2 Continuous Performance Task 
The continuous performance task is a classic response inhibition task, which requires subjects to 
respond to a certain type of stimulus and withhold a response to another. 
 
7.4.1.2.3 Anti-saccades  
The subjects look at a fixation point in the center of a computer screen and move their eyes upon 
presentation of a laterally presented stimulus. In the first block (pro-saccade), subjects are instructed to 
move their eyes in the direction of the presented stimulus. In the second and third blocks (anti-saccade), 
subjects are instructed to move their eyes in the opposite direction of the presented stimulus. 
 
7.4.1.2.4 Dysexecutive Errors 
An underlying assumption in developing the EXAMINER battery is that executive related deficits can 
manifest as impulsive errors, failure to shift set, perseverative behavior, and stimulus-boundedness, 
even when achievement scores on tests are unremarkable. Accordingly, we generated a composite error 
score using false responses and rule violations on a variety of EXAMINER tasks, including: CPT, verbal 
fluency tasks, Flanker, and Set Shifting.  
 


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7.4.1.3 
Set-Shifting 
Subjects are required to match a stimulus on the top of the screen to one of two stimuli in the lower 
corners of the screen. In task-homogeneous blocks, subjects perform either Task A (e.g., classifying 
shapes) or Task B (e.g., classifying colors). In task-heterogeneous blocks, subjects alternate between the 
two tasks pseudo-randomly. The combination of task-homogeneous and task-heterogeneous blocks 
allows measurement of general switch costs (latency differences between heterogeneous and 
homogeneous blocks) and specific switch costs (differences between switch and non-switch trials within 
the heterogeneous block). 
 
7.4.1.4 
Fluency 
7.4.1.4.1 Phonemic Fluency 
For the phonemic fluency task, examinees are instructed to name as many words as they can that begin 
with a particular letter of the alphabet as quickly as they can. Sixty seconds are allowed for each letter. 
7.4.1.4.2 Categorical Fluency 
For the category fluency task, examinees are asked to generate as many items that they can think of 
that belong to a particular category as quickly as possible. Sixty seconds are allowed for each category. 
7.4.1.5 
Planning 
7.4.1.5.1 Unstructured Task 
This task was modeled after the 6-elements test (Shallice and Burgess, 1991). Subjects are presented 
with three booklets, each containing five pages of simple puzzles (4 per page).The puzzles were designed 
to be cognitively simple (e.g., connect the dots; trace the design) but average completion times range 
from 4 to 60 seconds. Each puzzle has a designated point value, and subjects are given 6 minutes to earn 
as many points as possible. Irrespective of actual point value, puzzles can have a high cost-benefit ratio 
(i.e., the time required to complete the puzzle makes it less desirable) or a low cost-benefit ratio (i.e., 
the time required to complete the puzzle makes it more desirable). In addition, the proportion of low 
cost-benefit items decreases as subjects proceed through a booklet. Subjects need to plan ahead, avoid 
items that are strategically poor choices, and be cognizant of when a particular booklet offers 
diminishing returns. 
7.4.1.6 
Insight 
Examinees are asked to rate themselves on their performance immediately after completing the well-
normed verbal fluency tasks. They are instructed to assess their own performance relative to a 
hypothetical sample of 100 people of a similar age and level of education. 
7.4.1.7 
Social Cognition and Behavior 
7.4.1.7.1 Social Norms Questionnaire 
This task measures subjects’ crystallized knowledge of social norms in a linguistically and cognitively 
simple manner. This yes-no questionnaire is designed to determine the degree to which subjects 
actually understand and can accurately identify implicit but widely accepted social boundaries in the 
dominant U.S. culture. The Social Norms Questionnaire includes both socially inappropriate behaviors 
(e.g., “Cut in line if you are in a hurry,” “Pick your nose in public,”) and generally acceptable behaviors 
(e.g., “Tell a coworker your age”). The subject must decide whether the behavior is socially appropriate 
or not if it were hypothetically enacted with an acquaintance or coworker. 


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7.4.1.7.2 Behavioral Rating Scale 
This rating scale is completed by the examiner after completion of the testing. Examiners restrict their 
ratings to behaviors that they have observed directly, but include all observed behaviors, regardless of 
the context. Thus, although behaviors during the actual assessment will likely provide the bulk of data, 
examiners should also note behaviors exhibited in all other situations, such as the waiting room and 
walking to and from the exam room. There are nine behavioral domains to rate, including agitation, 
stimulus-boundedness, perseverations, decreased initiation, motor stereotypies, distractibility, degree 
of social/emotional engagement, impulsivity, and social appropriateness. 
7.4.2 Appetite and Eating Habit Questionnaire (APEHQ) 
The APEHQ consists of 34 questions that examine changes in eating behaviors in the following domains: 
swallowing, appetite, eating habits (stereotypic eating behavior and table manners), food preference 
(including sweet preference and other food fads), and other oral behaviors (eg, food cramming, 
increased smoking). Caregivers are asked to rate the frequency (0 = never, 1 = less than weekly, 
2 = about once a week, 3 = several times a week, 4 = daily or continuously) and severity (0 = N/A [not 
applicable], 1 = mild, 2 = moderate, and 3 = marked) for each behavior. A composite score of frequency × 
severity is calculated for each question, and an overall score derived for each domain (Ahmed et al., 
2014a). 
7.4.3 Columbia-Suicide Severity Scale 0 (C-SSRS) 
The Columbia–Suicide Severity Rating Scale (C-SSRS) was designed to quantify the severity of suicidal 
ideation and behavior (Posner K, 2011).  In this study, suicidal ideation and behavior will be 
prospectively assessed using the C-SSRS. The C-SSRS will be administered by trained raters at specified 
time points, as indicated in table 1 as well as when clinically indicated. Any subjects demonstrating 
evidence of suicidality will prompt immediate consultation with the site’s on-call psychiatrist for 
assistance with decision-making and potential referral to behavioral health services.  
8 Investigational Product(s) 
8.1 Description of Investigational Product 
The Center for Memory & Aging will utilize the following investigational products: 
• 
Intranasal delivery route 
• 
Regular insulin [(Novolin-R); see section15.3]  
• 
Aerosol nasal device(Sections 2, 5.2, 5.3, 15.2 and Investigator’s brochure- 15.1) 
 
8.2 Handling and Storage 
The study drug (insulin) will be given to subject/care partner after training for administration at visit 2. 
Subjects will be instructed to keep study drug at room temperature according to label 
recommendations. 
The study drug will be kept at study site per label recommendations and institutional Standard 
Operational Policy.  To ensure that a stable temperature and/or conditions are maintained, site staff will 
verify and document refrigerator/room temperature at a minimum of three times per week or 
monitored continuously if automated systems such as temp trak are used.  A log will be securely stored 


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at the HealthPartners Center for Memory & Aging. Study staff will be responsible for safeguarding and 
maintaining the master log. 
8.3 Packaging and Labeling 
All study drug will be labeled according to the following specifications: 
• 
Protocol identifier/IRB  study number 
• 
Quantity statement 
• 
Subject ID # 
• 
“For Clinical Trial Use Only” 
• 
Study contact # 651-495-6262 
 
8.4 Occupational Safety 
No known significant safety risks exist to site personnel in direct or indirect contact with the study drug. 
9 Concomitant Medications and Non-Drug Therapies 
9.1 Permitted Medications 
Any medication not listed in list of Prohibited Medications (Table 2) will be permitted during this study.  
A record will be kept by site staff detailing doses and indication of any concomitant medications used by 
subjects. 
9.2 Prohibited Medications 
Subjects taking prohibited medications at time of screening will not be allowed to participate in study, 
unless such treatment is discontinued at least 30 days prior to screening. These medications include 
anticholinergics, and centrally acting antihistamines (e.g. Benadryl), opiates, benzodiazepines, 
barbiturates, muscle relaxants, and insulin. Randomized subjects taking a prohibited medication 
(episodic or PRN) will be considered for study participation on an individual basis. 
Table 2: Prohibited Medications 
Anticholinergics 
Antihistamines (centrally-acting) 
Barbiturates 
Benzodiazepines 
Insulin 
Muscle relaxants 
Opioids 
 


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10 Subject Completion and Withdrawal 
10.1 Subject Completion 
Subjects completing all 5 study visits (including the 2 phone visits) will be considered to have completed 
study. 
10.2 Subject Withdrawal 
Subject may withdraw from study at any time for any reason without penalty or be terminated from the 
study by the clinical investigator (see provisions for termination by study team.) Investigational team will 
document the reason(s) for withdrawal.  In the event a subject chooses to withdraw from study before 
Visit 3, the safety procedures described in Section 7.3 will be performed ideally within 3 days following 
subject’s decision to withdraw.  For all subjects who withdraw, all final safety assessments will be 
collected regardless of time elapsed since previous visit.  In addition to the termination visit, subjects 
who withdraw early will be contacted within 7 days by study staff via telephone to assess development 
of new and/or ongoing AEs and concomitant medications.  Efforts will be made to recruit subjects to 
replace any withdrawals at any point so as to maintain an n=12. 
Subject’s participation may be terminated at the discretion of the investigator.  Individuals may be 
withdrawn for the following reasons: 
• 
Clinically significant adverse events 
• 
Lost to follow-up 
• 
Protocol violations 
• 
Inability to tolerate study medication 
• 
Other 
 
11 Adverse Events (AE) and Serious Adverse Events (SAE) 
11.1 Definition of AE 
An adverse event is any symptom, sign, illness or experience which develops or worsens in severity 
during the course of the study. Intercurrent illnesses or injuries should be regarded as adverse events. 
Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 
• 
Results in study withdrawal 
• 
Is associated with clinical signs or symptoms 
• 
Leads to treatment or to further diagnostic tests 
• 
Is considered by the investigator to be of clinical significance 
 
11.2 Definition of SAE 
Adverse events are classified as either serious or non-serious. A serious adverse event is any event that 
results in: 
• 
Death 
• 
Life-threatening situation 
• 
Hospitalization or prolongation of hospitalization 
• 
Disability or incapacitation 


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• 
Other events determined by investigator to be medically significant in which subject’s well-being 
is jeopardized (e.g. events that have high likelihood of escalating to the point of meeting criteria 
outlined above) 
11.2.1 Clinical Laboratory Abnormalities & Other Abnormal Assessments as AEs & SAEs 
Any new abnormal, vital, examination, or laboratory finding judged clinically significant by the 
investigator will be documented as an AE or SAE, if meeting the definitions for such.  Abnormal lab 
findings or other abnormal assessments associated with the disease under study will not be considered 
AEs or SAEs unless more severe than expected, as judged by the investigator. 
11.2.2 Time Period and Frequency of Detecting AEs and SAEs 
Upon consenting, a subject is considered to be a subject in the study, and until that person either 
withdraws or completes study, AEs and SAEs will be recorded.  The investigational team will promptly 
report any AE/SAE as required per federal guidelines. 
11.2.3 Device Failures and Malfunctions  
Device Quality Control. All failures, performance issues and malfunctions of the device as reported by 
the participants will be reported to Device company. 
12 Data Analysis and Statistical Considerations 
12.1 Analysis Overview 
The study population will be summarized descriptively by demographics and baseline clinical values. 
Clinical values will include scores from all components of the EXAMINER battery as well as other 
neuropsychological assessment scores, vital signs, and laboratory values. We will examine the 
distribution of our exploratory endpoints (the EXAMINER battery and APEHQ scores) using graphs and 
measures of normality to ensure we have planned the appropriate analyses.  
Main analyses of these scores will only include subjects with non-missing data. Reason for missing data 
will be reported as often as possible to better inform future studies. Sensitivity analyses will be 
conducted to compare baseline values of tests between subjects who were able to complete the study 
and those who withdrew early. Neither methods of imputation nor adjustment for multiple comparisons 
will be utilized as they were deemed too conservative for this feasibility study. All statistical analyses will 
be conducted in SAS Version 9.4 using a 0.05 level of significance unless otherwise stated.  
12.2 Statistical Analysis of Primary Outcomes 
To evaluate the feasibility of using the EXAMINER battery as a cognitive outcome measure in the FTD 
population, we will report the number and percentage of our sample who were able to complete the 
battery. We will also document any reasons for incomplete data. We will then describe any factors that 
affect implementation ease or difficulty including battery components that were more challenging for 
subjects with advanced FTD. Finally, we will discuss the speed and efficiency of administering the tool.  
The Center for Memory & Aging’s recruitment capacity will be assessed by reporting the number and 
percentage of subjects who were: 1. contacted for participation, 2. screened, 3. screened positive, 4. 
able to complete the study. We will also report the average number of visits attended by our sample 
and any reason for screen failure or early withdrawal.  


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The number of unique subjects who experienced an adverse event or serious adverse event as well as 
the total number of each will be reported. A brief written description of these events will be provided. 
Suicidality, as assessed by the C-SSRS, will be included as an adverse event.  
12.3 Statistical Analysis of Exploratory Outcomes 
Four summarizing scores are calculated and output using the EXAMINER battery: 1. Executive Composite 
Score, 2. Fluency Factor Score, 3. Cognitive Control Factor Score, and 4. Working Memory Factor Score. 
Five domains are assessed by the APEHQ: 1. swallowing, 2. appetite, 3. eating habits, 4. food 
preferences, and 5. other oral behaviors. For each of these scores, we will report the mean and standard 
deviation from both time points as well as calculate the pre-post change among subjects who completed 
the two assessments. We will utilize these values to better inform future studies about possible effect 
sizes and do not anticipate seeing a significant change. Therefore, no inferential statistics will be 
performed; we will simply describe any trends we might see.  
To account for missing data, UCSF is developing a formula for a global executive score called an Item 
Response Theory (IRT) derived score, which our researchers will also calculate. Currently, this score 
formula is not yet finalized by UCSF, however, it will not require any additional information or testing by 
patients; we plan to include this calculation in our final analyses. 
Insulin levels and basic metabolic panel values (Na, K, CO2, Cl, BUN, Creatinine, Glucose and Ca) will be 
summarized at each time point using means and standard deviations. Changes will be discussed 
descriptively.  
As a sensitivity analysis, we will also descriptively compare baseline EXAMINER scores, APEHQ scores, 
and laboratory values between subjects who completed the study and those who withdrew early or 
were unable to complete the final battery.  
12.4 Statement of Precision 
The main purposes of this study are to assess the feasibility of using the EXAMINER battery as a 
cognitive outcome assessment tool and evaluate the Center for Memory & Aging’s ability to recruit 
within the FTD population. We will consider it to be feasible if at least 80% of our sample is able to 
complete the battery and we are able to recruit 12 subject within our enrollment period. With a sample 
size of 12, we will be able to estimate an EXAMINER battery completion rate of 80% to within a 95% 
confidence interval of ±22.6%. We do not except to see significant changes in the exploratory outcomes 
(EXAMINER, APEHQ, and laboratory values) and, therefore, have not included a power calculation for 
these outcomes.  
 
13 Study Conduct Considerations 
13.1 Regulatory and Ethical Considerations, Including the Informed Consent 
Process 
The study will be conducted in accordance with GCP.  Subject privacy requirements will also be observed 
as well as the fundamental concepts of the Declaration of Helsinki (e.g. IRB approval of the study, 


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obtaining informed consent from all subjects, and meeting reporting requirements).  The clinical trial 
will be registered on the clinicaltrials.gov website.  
13.2 Data Safety Monitoring Board 
The DSMB will be an independent group who are not participating in the trial and have no direct 
affiliation with HealthPartners Center for Memory & Aging. They will serve as an advisory panel to 
HealthPartners Center for Memory & Aging. The DSMB will be comprised of a neurologist, statistician, 
and intranasal insulin researcher. An un-blinded study liaison will participate in open sessions of the 
DSMB and serve as a liaison to the study team.  A DSMB Charter will be established prior to initiation of 
the study. The DSMB responsibilities include but are not limited to the following: 
• 
Stopping the study if the rate of SAE’s raises safety concerns.  The details will be specified in the 
DSMB charter.  
 
The DSMB will convene following the study completion of 6 subjects or earlier in the case of SAEs.  
During the course of the trial, the DSMB will review accumulating safety data to monitor for incidence of 
trends that would warrant termination of the trial. The frequency of the DSMB meetings, 
responsibilities, membership, and procedures will be documented in the DSMB charter. 
13.3 Quality Assurance 
In the event of a regulatory agency audit or inspection, site will allow the auditor/inspector access to all 
records documented and facilities utilized in conducting the study.  Site will also make accommodations 
(e.g. time, schedule) to discuss findings, concerns, and questions with auditor/inspector. 
13.4 Study Closure 
Upon completion of all subject visits, data entry and analysis, investigator will inform local IRB of study 
closure. 
13.5 Records Retention 
All site records will be maintained and stored in a safe and secure location for a minimum of 15 years 
post study completion. 
13.6 Provision of Study Results and Information to Investigators 
Study results will be made available by the study statistician once analysis is complete.   
13.7 Data Management 
Data collection/reporting tools will be developed internally (i.e. CRFs and source documents).  Data 
collected and stored electronically will remain confidential and secure (e.g. secured server, encrypted 
data, password protected file) 
13.8 Device Accountability 
A Device Tracking Log will be maintained at the investigational site. Aerosol nasals will be recorded on 
the log upon delivery to the investigational site and will be stored in a secured area. The Device Tracking 
Log will be updated as each device is delivered, dispensed, returned and the reason for the return.  
Serial numbers, expiration date and model number of devices delivered to the site will also be recorded. 


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