The Study of Nasal Insulin in the Fight Against Forgetfulness (SNIFF)

• Sponsor: University of Southern California (Other)
• Overall Status: Completed
• CT.gov ID: NCT01767909
• Collaborator: National Institute on Aging (NIA) (NIH), Alzheimer's Therapeutic Research Institute (Other), Wake Forest University Health Sciences (Other)
• Enrollment: 240
• Locations: 25
• Arms: 2
• Actual Duration (Months): 59.1
• Patients Per Site: 9.6
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

An urgent need exists to find effective treatments for Alzheimer's disease (AD) that can arrest or reverse the disease at its earliest stages. The emotional and financial burden of AD to patients, family members, and society is enormous, and is predicted to grow exponentially as the median population age increases. Current FDA-approved therapies are modestly effective at best. This study will examine a novel therapeutic approach using intranasal insulin (INI) that has shown promise in short-term clinical trials. If successful, information gained from the study has the potential to move INI forward rapidly as a therapy for AD. The study will also provide evidence for the mechanisms through which INI may produce benefits by examining key cerebral spinal fluid (CSF) biomarkers and hippocampal/entorhinal atrophy. These results will have considerable clinical and scientific significance, and provide therapeutically-relevant knowledge about insulin's effects on AD pathophysiology. Growing evidence has shown that insulin carries out multiple functions in the brain, and that insulin dysregulation may contribute to AD pathogenesis.

This study will examine the effects of intranasally-administered insulin on cognition, entorhinal cortex and hippocampal atrophy, and cerebrospinal fluid (CSF) biomarkers in amnestic mild cognitive impairment (aMCI) or mild AD. It is hypothesized that after 12 months of treatment with INI compared to placebo, subjects will improve performance on a global measure of cognition, on a memory composite and on daily function. In addition to the examination of CSF biomarkers and hippocampal and entorhinal atrophy, the study aims to examine whether baseline AD biomarker profile, gender, or Apolipoprotein epsilon 4 (APOE-ε4) allele carriage predict treatment response.

In this study, 240 people with aMCI or AD will be given either INI or placebo for 12 months, following an open-label period of 6 months where all participants will be given active drug. The study uses insulin as a therapeutic agent and intranasal administration focusing on nose to brain transport as a mode of delivery.

Condition or Disease	Intervention/Treatment	Phase
Amnestic Mild Cognitive Impairment; Alzheimer's Disease	Drug: Insulin (Humulin® R U-100); Drug: Placebo	Phase 2/Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 240 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Therapeutic Effects of Intranasally-Administered Insulin in Adults With Amnestic Mild Cognitive Impairment (aMCI) or Mild Alzheimer's Disease (AD)
• Actual Study Start Date: Jan 8, 2014
• Actual Primary Completion Date: Dec 11, 2018
• Actual Study Completion Date: Dec 11, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Insulin (Humulin® R U-100) 120 subjects will take two daily doses of INI (20 IU bid for a total daily dose of 40 IU) approximately 30 minutes after breakfast and dinner for 12 months. A 6-month open label period will follow in which all participants will receive INI.	Drug: Insulin (Humulin® R U-100); 20 IU bid taken twice daily (approximately 30 minutes after breakfast and dinner) for a total of 40 IU daily, which will be administered intranasally. The device used to administer insulin releases a metered dose into a chamber covering the participant's nose. The insulin is then inhaled by breathing evenly over a specified period.
Placebo Comparator: Placebo 120 subjects will take two daily doses of placebo approximately 30 minutes after breakfast and dinner for 12 months. A 6-month open label period will follow in which all participants will receive INI.	Drug: Placebo; Placebo taken twice daily (approximately 30 minutes after breakfast and dinner), which will be administered intranasally. The device used to administer placebo releases a metered dose into a chamber covering the participant's nose. The placebo is then inhaled by breathing evenly over a specified period.

Outcome Measures

Primary Outcome Measures

1. Change in Global Measure of Cognition as Measured by the Alzheimer's Disease Assessment Scale-Cognitive 12 (ADAS-Cog12) [12 months (blinded phase) followed by 6 months (open label phase)]

   The ADAS-Cog is a psychometric instrument that evaluates memory, attention, reasoning, language, orientation, and praxis. The ADAS-Cog12 version was used in this study which includes Delayed Word Recall - a measure of episodic memory. Scores from the original portion of the test range from 0 (best) to 70 (worse) and then number of items not recalled ranging from 0-10 is added for a maximum score of 80. A positive change indicates cognitive worsening.

Secondary Outcome Measures

1. Change in Memory Composite as Measured by Story Recall (Immediate Paragraph Recall and Delayed Paragraph Recall) and Free and Cued Selective Reminding Test (FCSRT) [12 months (blinded phase) followed by 6 months (open label phase)]

   Memory Composite is composed from Story Recall (both Immediate Paragraph Recall and Delayed Paragraph Recall) and the Free and Cued Selective Reminding Test (FCSRT). Each of the three component scores were normalized by subtracting the baseline sample mean, and dividing by the baseline sample standard deviation, to form three separately standardized z-scores with mean 0 and standard deviation 1. The three Z-scores were summed to form the memory composite. No other standardization was performed on the sum. If any of Immediate Paragraph Recall, Delayed Paragraph Recall and FCSRT is missing, the memory composite is missing. Higher scores indicate better performance. In this study the scores ranged from about -4.74 to 9.15 at baseline, and about -5.10 to 9.43 across all visits over 12 months.

2. Change in Daily Functioning as Measured by the ADCS-MCI Activities of Daily Living (ADCS-ADL-MCI) [12 months (blinded phase) and 6 months (open label phase)]

   The Alzheimer's Disease Cooperative Study - Activities of Daily Living Scale (ADCS-ADL) is an activities of daily living questionnaire aimed at detecting functional decline in people with Mild Cognitive Impairment (MCI). In a structured interview format, informants are queried as to whether participants attempted each item in the inventory during the prior 4 weeks and their level of performance. The questions focus predominantly on instrumental activities of daily living scales (e.g. shopping, preparing meals, using household appliances, keeping appointments, reading). The total score can range from 0-54. A higher score indicates greater functional ability.

3. Change in Cognitive Deficit as Measured by Clinical Dementia Rating - Sum of Boxes (CDR-SB) [12 months (blinded phase) followed by 6 months (open label phase)]

   The Clinical Dementia Rating - Sum of Boxes (CDR-SB) is administered as a structured interview with the participant and study partner, where impairment is scored in each of categories: memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care. Impairment is scored on a scale in which none = 0, questionable = 0.5, mild = 1, moderate = 2 and severe = 3. The 6 individual category ratings, or "box scores", are added together to give the CDR-Sum of Boxes which ranges from 0-18 with higher scores indicated more impairment.

4. Change in Hippocampal and Entorhinal Atrophy as Measured by Magnetic Resonance Imaging (MRI) [Screen and Month 12]

   MRI will be used to assess the effect of treatment on rate of hippocampal and entorhinal atrophy, and conduct exploratory analyses of other brain regions. Volume change was normalized to the participant's own intracranial volume to account for each participant's brain size.

5. Change in CSF Biomarkers of AD [Baseline and Month 12]

   Quantify Abeta and Tau biomarkers in CSF

Eligibility Criteria

Criteria

• Ages Eligible for Study: 55 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Fluent in English or Spanish

• Diagnosis of aMCI by Petersen criteria or probable AD by National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria

• Mini Mental State Examination (MMSE) score at screening is greater than or equal to 20

• Clinical Dementia Rating is 0.5-1 at screening

• Logical Memory is less than or equal to 8 for 16 or more years of education, less than or equal to 4 for 8-15 years of education, less than or equal to 2 for 0-7 years of education. Scores measured at screening on Delayed Paragraph Recall (Paragraph A only) from the Wechsler Memory Scale-Revised

• Able to complete baseline assessments

• Modified Hachinski score of less than or equal to 4

• A study partner able to accompany the participant to most visits and answer questions about the participant

• The study partner must have direct contact with the participant more than 2 days per week (minimum of 10 hours per week) and provide supervision of drug administration as needed

• Stable medical condition for 3 months prior to screening visit

• Stable medications for 4 weeks prior to the screening and baseline visits

• Stable use of permitted medications

• At least six years of education or work history

• Clinical laboratory values must be within normal limits or, if abnormal, must be judged to be clinically insignificant by the investigator

• Visual and auditory acuity adequate for neuropsychological testing

Exclusion Criteria:

• A diagnosis of dementia other than probable AD

• Probable AD with Down syndrome

• History of clinically significant stroke

• Current evidence or history in past two years of epilepsy, focal brain lesion, head injury with loss of consciousness or Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM IV) criteria for any major psychiatric disorder including psychosis, major depression, bipolar disorder, alcohol or substance abuse

• Sensory impairment that would preclude the participant from participating in or cooperating with the protocol

• Diabetes (type 1 or type II) requiring pharmacologic treatment (including both insulin dependent and non-insulin dependent diabetes mellitus)

• Current or past use of insulin or any other anti-diabetic medication

• Evidence of any significant clinical disorder or laboratory finding that renders the participant unsuitable for receiving investigational drug including clinically significant or unstable hematologic, hepatic, cardiovascular, pulmonary, endocrine, metabolic, renal or other systemic disease or laboratory abnormality.

• Active neoplastic disease, history of cancer five years prior to screening (history of skin melanoma or stable prostate cancer are not excluded)

• History of seizure within the past five years

• Pregnancy or possible pregnancy

• Contraindications to Lumbar Puncture (LP) procedure: prior lumbosacral spine surgery, severe degenerative joint disease or deformity of the spine, platelets is less than 100,000 or history of bleeding disorder

• Use of anticoagulants warfarin (Coumadin) and dabigatran (Pradaxa) due to LP requirement

• Contraindications for MRI (claustrophobia, craniofacial metal implants of any kind, pacemakers)

• Residence in a skilled nursing facility at screening

• Use of an investigational agent within two months or screening visit

• Regular use of narcotics, anticonvulsants, medications with significant anticholinergic activity, antiparkinsonian medications or any other exclusionary medications

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Banner Alzheimer's Institute	Phoenix	Arizona	United States	85006
2	Barrow Neurology Clinics	Phoenix	Arizona	United States	85013
3	University of California, Irvine	Irvine	California	United States	92697
4	Yale University School of Medicine	New Haven	Connecticut	United States	06510
5	Georgetown University	Washington	District of Columbia	United States	20057
6	Howard University	Washington	District of Columbia	United States	20060
7	Mayo Clinic, Jacksonville	Jacksonville	Florida	United States	32224
8	Emory University	Atlanta	Georgia	United States	30322
9	Northwestern University	Chicago	Illinois	United States	60611
10	Rush University Medical Center	Chicago	Illinois	United States	60614
11	Indiana University	Indianapolis	Indiana	United States	46202
12	University of Kentucky	Lexington	Kentucky	United States	40504
13	Johns Hopkins University	Baltimore	Maryland	United States	21224
14	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
15	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
16	Mayo Clinic, Rochester	Rochester	Minnesota	United States	55905
17	Mount Sinai School of Medicine	New York	New York	United States	10029
18	University of Rochester Medical Center	Rochester	New York	United States	14620
19	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
20	Case Western Reserve University	Beachwood	Ohio	United States	44122
21	Tulsa Clinical Research	Tulsa	Oklahoma	United States	74104
22	Rhode Island Hospital	Providence	Rhode Island	United States	02903
23	Roper St. Francis Hospital	Charleston	South Carolina	United States	29401
24	Baylor College of Medicine	Houston	Texas	United States	77030
25	U of WA / VA Puget Sound Alzheimer's Disease Research Center	Seattle	Washington	United States	98108

Sponsors and Collaborators

• University of Southern California
• National Institute on Aging (NIA)
• Alzheimer's Therapeutic Research Institute
• Wake Forest University Health Sciences

Investigators

• Study Director: Suzanne Craft, PhD, Wake Forest University Health Sciences
• Study Director: Paul Aisen, MD, USC Alzheimer's Therapeutic Research Institute (ATRI)

Study Documents (Full-Text)

• Study Protocol - Dec 5, 2016
• Statistical Analysis Plan - Jun 22, 2018

More Information

Additional Information:

• Alzheimer's Disease Education and Referral (ADEAR) Center. The ADEAR Center is a service of the National Institute on Aging (NIA).
• Alzheimer's Therapeutic Research Institute (ATRI)

Publications

• Baker LD, Cross DJ, Minoshima S, Belongia D, Watson GS, Craft S. Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. Arch Neurol. 2011 Jan;68(1):51-7. doi: 10.1001/archneurol.2010.225. Epub 2010 Sep 13.
• Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, Arbuckle M, Callaghan M, Tsai E, Plymate SR, Green PS, Leverenz J, Cross D, Gerton B. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol. 2012 Jan;69(1):29-38. doi: 10.1001/archneurol.2011.233. Epub 2011 Sep 12.
• Craft S, Peskind E, Schwartz MW, Schellenberg GD, Raskind M, Porte D Jr. Cerebrospinal fluid and plasma insulin levels in Alzheimer's disease: relationship to severity of dementia and apolipoprotein E genotype. Neurology. 1998 Jan;50(1):164-8.
• Reger MA, Watson GS, Green PS, Wilkinson CW, Baker LD, Cholerton B, Fishel MA, Plymate SR, Breitner JC, DeGroodt W, Mehta P, Craft S. Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology. 2008 Feb 5;70(6):440-8. Epub 2007 Oct 17. Erratum in: Neurology. 2008 Sep 9;71(11):866.

• Responsible Party: Paul Aisen, Professor, University of Southern California
• ClinicalTrials.gov Identifier: NCT01767909
• Other Study ID Numbers: ADC-046-INI; RF1AG041845
• First Posted: Jan 15, 2013
• Last Update Posted: May 18, 2020
• Last Verified: May 1, 2020

• Keywords provided by Paul Aisen, Professor, University of Southern California: Intranasal insulin; Alzheimer's disease; Amnestic mild cognitive impairment; Dementia; Brain diseases; Memory problems; Mental disorders; Cognitive disorders
• Additional relevant MeSH terms: Alzheimer Disease; Cognitive Dysfunction; Insulin; Insulin, Globin Zinc

Study Results

Participant Flow

Arm/Group Title	Insulin (Humulin® R U-100)	Placebo
Arm/Group Description	20 IU BID intranasal insulin (Humulin® R U-100) twice daily for a total of 40 IU daily for 12 months, followed by a 6-month open label period.	50% of participants received placebo treatment twice daily for 12 months followed by a 6-month open label period where all participants received 20 IU BID intranasal insulin (Humulin® R U-100) twice daily (total of 40 IU daily).
Period Title: Overall Study
STARTED	121	119
COMPLETED	108	107
NOT COMPLETED	13	12

Baseline Characteristics

Arm/Group Title	Insulin (Humulin® R U-100)	Placebo	Total
Arm/Group Description	50% of participants received 20 IU BID intranasal insulin (Humulin® R U-100) twice daily for a total of 40 IU daily for 12 months, followed by a 6-month open label period.	50% of participants received placebo treatment twice daily for 12 months followed by a 6-month open label period where all participants received 20 IU BID intranasal insulin (Humulin® R U-100) twice daily (total of 40 IU daily).	Total of all reporting groups
Overall Participants	121	119	240
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	70.46 (7.38)	71.06 (6.79)	70.76 (7.09)
Sex: Female, Male (Count of Participants)
Female	59 48.8%	58 48.7%	117 48.8%
Male	62 51.2%	61 51.3%	123 51.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 4.1%	5 4.2%	10 4.2%
Not Hispanic or Latino	116 95.9%	113 95%	229 95.4%
Unknown or Not Reported	0 0%	1 0.8%	1 0.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 0.8%	4 3.4%	5 2.1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	3 2.5%	6 5%	9 3.8%
White	117 96.7%	108 90.8%	225 93.8%
More than one race	0 0%	1 0.8%	1 0.4%
Unknown or Not Reported	0 0%	0 0%	0 0%
Education (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	16.07 (2.64)	16.31 (2.92)	16.19 (2.78)
ApoE-e4 carrier status (Positive vs Negative) (Count of Participants)
Negative	42 34.7%	42 35.3%	84 35%
Positive	79 65.3%	77 64.7%	156 65%
Alzheimer's Disease Assessment Scale-Cognitive 12 (ADAS-Cog12) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	25.91 (8.28)	24.73 (7.56)	25.33 (7.94)
Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	3.59 (1.51)	3.35 (1.51)	3.47 (1.51)
Memory Composite (Story Recall and the Free and Cued Selective Reminding Test) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	-0.16 (2.47)	0.25 (2.59)	0.04 (2.53)

Outcome Measures

1. Primary Outcome

Title	Change in Global Measure of Cognition as Measured by the Alzheimer's Disease Assessment Scale-Cognitive 12 (ADAS-Cog12)
Description	The ADAS-Cog is a psychometric instrument that evaluates memory, attention, reasoning, language, orientation, and praxis. The ADAS-Cog12 version was used in this study which includes Delayed Word Recall - a measure of episodic memory. Scores from the original portion of the test range from 0 (best) to 70 (worse) and then number of items not recalled ranging from 0-10 is added for a maximum score of 80. A positive change indicates cognitive worsening.
Time Frame	12 months (blinded phase) followed by 6 months (open label phase)

Outcome Measure Data

Analysis Population Description

Modified intent-To-Treat [mITT] population: All randomized participants in Impel Device with ADAS-Cog12 observed at baseline and at least one follow-up.

Arm/Group Title	Insulin (Humulin® R U-100)	Placebo
Arm/Group Description	50% of participants received 20 IU BID intranasal insulin (Humulin® R U-100) twice daily for a total of 40 IU daily for 12 months, followed by a 6-month open label period.	50% of participants received placebo treatment twice daily for 12 months followed by a 6-month open label period where all participants received 20 IU BID intranasal insulin (Humulin® R U-100) twice daily (total of 40 IU daily).
Measure Participants	121	119
Blinded Phase (M12 change from Baseline)	3.893 (0.643)	3.867 (0.650)
Open Label Phase (M18 change from Baseline)	7.091 (0.937)	6.164 (0.942)

2. Secondary Outcome

Title	Change in Memory Composite as Measured by Story Recall (Immediate Paragraph Recall and Delayed Paragraph Recall) and Free and Cued Selective Reminding Test (FCSRT)
Description	Memory Composite is composed from Story Recall (both Immediate Paragraph Recall and Delayed Paragraph Recall) and the Free and Cued Selective Reminding Test (FCSRT). Each of the three component scores were normalized by subtracting the baseline sample mean, and dividing by the baseline sample standard deviation, to form three separately standardized z-scores with mean 0 and standard deviation 1. The three Z-scores were summed to form the memory composite. No other standardization was performed on the sum. If any of Immediate Paragraph Recall, Delayed Paragraph Recall and FCSRT is missing, the memory composite is missing. Higher scores indicate better performance. In this study the scores ranged from about -4.74 to 9.15 at baseline, and about -5.10 to 9.43 across all visits over 12 months.
Time Frame	12 months (blinded phase) followed by 6 months (open label phase)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Insulin (Humulin® R U-100)	Placebo
Arm/Group Description	50% of participants received 20 IU BID intranasal insulin (Humulin® R U-100) twice daily for a total of 40 IU daily for 12 months, followed by a 6-month open label period.	50% of participants received placebo treatment twice daily for 12 months followed by a 6-month open label period where all participants received 20 IU BID intranasal insulin (Humulin® R U-100) twice daily (total of 40 IU daily).
Measure Participants	121	119
Blinded Phase (M12 change from Baseline)	-0.496 (0.163)	-0.433 (0.162)
Open Label Phase (M18 change from Baseline)	-0.594 (0.183)	-0.802 (0.184)

3. Secondary Outcome

Title	Change in Daily Functioning as Measured by the ADCS-MCI Activities of Daily Living (ADCS-ADL-MCI)
Description	The Alzheimer's Disease Cooperative Study - Activities of Daily Living Scale (ADCS-ADL) is an activities of daily living questionnaire aimed at detecting functional decline in people with Mild Cognitive Impairment (MCI). In a structured interview format, informants are queried as to whether participants attempted each item in the inventory during the prior 4 weeks and their level of performance. The questions focus predominantly on instrumental activities of daily living scales (e.g. shopping, preparing meals, using household appliances, keeping appointments, reading). The total score can range from 0-54. A higher score indicates greater functional ability.
Time Frame	12 months (blinded phase) and 6 months (open label phase)

Outcome Measure Data

Analysis Population Description

Modified intent-To-Treat [mITT] population: All randomized participants in Impel Device with ADCS-ADL-MCI observed at baseline and at least one follow-up.

Arm/Group Title	Insulin (Humulin® R U-100)	Placebo
Arm/Group Description	50% of participants received 20 IU BID intranasal insulin (Humulin® R U-100) twice daily for a total of 40 IU daily for 12 months, followed by a 6-month open label period.	50% of participants received placebo treatment twice daily for 12 months followed by a 6-month open label period where all participants received 20 IU BID intranasal insulin (Humulin® R U-100) twice daily (total of 40 IU daily).
Measure Participants	121	119
Blinded Phase (M12 change from Baseline)	-3.63 (0.769)	-4.26 (0.779)
Open Label Phase (M18 change from baseline)	-7.35 (0.925)	-6.56 (0.934)

4. Secondary Outcome

Title	Change in Cognitive Deficit as Measured by Clinical Dementia Rating - Sum of Boxes (CDR-SB)
Description	The Clinical Dementia Rating - Sum of Boxes (CDR-SB) is administered as a structured interview with the participant and study partner, where impairment is scored in each of categories: memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care. Impairment is scored on a scale in which none = 0, questionable = 0.5, mild = 1, moderate = 2 and severe = 3. The 6 individual category ratings, or "box scores", are added together to give the CDR-Sum of Boxes which ranges from 0-18 with higher scores indicated more impairment.
Time Frame	12 months (blinded phase) followed by 6 months (open label phase)

Outcome Measure Data

Analysis Population Description

Modified intent-To-Treat [mITT] population: All randomized participants in Impel Device with CDR-SB observed at screening and at least one follow-up.

Arm/Group Title	Insulin (Humulin® R U-100)	Placebo
Arm/Group Description	50% of participants received 20 IU BID intranasal insulin (Humulin® R U-100) twice daily for a total of 40 IU daily for 12 months, followed by a 6-month open label period.	50% of participants received placebo treatment twice daily for 12 months followed by a 6-month open label period where all participants received 20 IU BID intranasal insulin (Humulin® R U-100) twice daily (total of 40 IU daily).
Measure Participants	121	119
Blinded Phase (M12 change from Baseline)	1.682 (0.195)	1.402 (0.196)
Open Label Phase (M18 change from Baseline)	2.361 (0.247)	2.122 (0.249)

5. Secondary Outcome

Title	Change in Hippocampal and Entorhinal Atrophy as Measured by Magnetic Resonance Imaging (MRI)
Description	MRI will be used to assess the effect of treatment on rate of hippocampal and entorhinal atrophy, and conduct exploratory analyses of other brain regions. Volume change was normalized to the participant's own intracranial volume to account for each participant's brain size.
Time Frame	Screen and Month 12

Outcome Measure Data

Analysis Population Description

Intent-To-Treat [ITT] population: All randomized participants in Impel Device. Follow-up visits include month 12 and early termination 1 (et1) visits. Percent change data is available for 3 subjects with et1 visit and 187 subjects with month 12 as follow-up.

Arm/Group Title	Insulin (Humulin® R U-100)	Placebo
Arm/Group Description	50% of participants received 20 IU BID intranasal insulin (Humulin® R U-100) twice daily for a total of 40 IU daily for 12 months, followed by a 6-month open label period.	50% of participants received placebo treatment twice daily for 12 months followed by a 6-month open label period where all participants received 20 IU BID intranasal insulin (Humulin® R U-100) twice daily (total of 40 IU daily).
Measure Participants	116	116
Normalized hippocampal volume change	-0.01 (0.02)	-0.02 (0.02)
Normalized entorhinal volume change	-0.01 (0.03)	-0.01 (0.03)
Normalized whole brain volume change	-1.35 (1.09)	-1.41 (1.18)

6. Secondary Outcome

Title	Change in CSF Biomarkers of AD
Description	Quantify Abeta and Tau biomarkers in CSF
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

CSF collection was optional; only a subset of participants underwent the LP procedure

Arm/Group Title	Insulin (Humulin® R U-100)	Placebo
Arm/Group Description	120 subjects will take two daily doses of INI (20 IU bid for a total daily dose of 40 IU) approximately 30 minutes after breakfast and dinner for 12 months. A 6-month open label period will follow in which all participants will receive INI. Insulin (Humulin® R U-100): 20 IU bid taken twice daily (approximately 30 minutes after breakfast and dinner) for a total of 40 IU daily, which will be administered intranasally. The device used to administer insulin releases a metered dose into a chamber covering the participant's nose. The insulin is then inhaled by breathing evenly over a specified period.	120 subjects will take two daily doses of placebo approximately 30 minutes after breakfast and dinner for 12 months. A 6-month open label period will follow in which all participants will receive INI. Placebo: Placebo taken twice daily (approximately 30 minutes after breakfast and dinner), which will be administered intranasally. The device used to administer placebo releases a metered dose into a chamber covering the participant's nose. The placebo is then inhaled by breathing evenly over a specified period.
Measure Participants	72	75
Abeta 40	-264.851 (1168.995)	-127.539 (1600.604)
Abeta 42	-15.552 (61.884)	-4.456 (82.156)
Total Tau	-4.717 (263.810)	1.937 (291.160)
p-Tau	-2.764 (18.729)	-0.567 (25.293)

Adverse Events

Time Frame	Adverse Event Table represents data collected over a period of 12 months (blinded phase).
Adverse Event Reporting Description	"Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.
Arm/Group Title	Insulin (Humulin® R U-100)		Placebo
Arm/Group Description	50% of participants received 20 IU BID intranasal insulin (Humulin® R U-100) twice daily for a total of 40 IU daily for 12 months, followed by a 6-month open label period.		50% of participants received placebo treatment twice daily for 12 months followed by a 6-month open label period where all participants received 20 IU BID intranasal insulin (Humulin® R U-100) twice daily (total of 40 IU daily).
All Cause Mortality
	Insulin (Humulin® R U-100)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/121 (0.8%)		0/119 (0%)
Serious Adverse Events
	Insulin (Humulin® R U-100)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/121 (14.9%)		10/119 (8.4%)
Blood and lymphatic system disorders
BLOOD AND LYMPHATIC SYSTEM DISORDERS	2/121 (1.7%)	2	0/119 (0%)	0
Cardiac disorders
CARDIAC DISORDERS	2/121 (1.7%)	2	3/119 (2.5%)	4
Gastrointestinal disorders
GASTROINTESTINAL DISORDERS	3/121 (2.5%)	3	1/119 (0.8%)	1
General disorders
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS	1/121 (0.8%)	3	2/119 (1.7%)	2
Hepatobiliary disorders
HEPATOBILIARY DISORDERS	1/121 (0.8%)	1	0/119 (0%)	0
Infections and infestations
INFECTIONS AND INFESTATIONS	1/121 (0.8%)	1	2/119 (1.7%)	2
Injury, poisoning and procedural complications
INJURY, POISONING AND PROCEDURAL COMPLICATIONS	1/121 (0.8%)	1	0/119 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS)	1/121 (0.8%)	1	1/119 (0.8%)	1
Nervous system disorders
NERVOUS SYSTEM DISORDERS	1/121 (0.8%)	1	2/119 (1.7%)	2
Psychiatric disorders
PSYCHIATRIC DISORDERS	1/121 (0.8%)	1	0/119 (0%)	0
Renal and urinary disorders
RENAL AND URINARY DISORDERS	2/121 (1.7%)	3	0/119 (0%)	0
Vascular disorders
VASCULAR DISORDERS	4/121 (3.3%)	7	1/119 (0.8%)	1
Other (Not Including Serious) Adverse Events
	Insulin (Humulin® R U-100)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	98/121 (81%)		91/119 (76.5%)
Blood and lymphatic system disorders
BLOOD AND LYMPHATIC SYSTEM DISORDERS	4/121 (3.3%)	4	2/119 (1.7%)	2
Cardiac disorders
CARDIAC DISORDERS	8/121 (6.6%)	9	6/119 (5%)	8
Endocrine disorders
ENDOCRINE DISORDERS	1/121 (0.8%)	1	0/119 (0%)	0
Eye disorders
EYE DISORDERS	5/121 (4.1%)	5	2/119 (1.7%)	2
Gastrointestinal disorders
GASTROINTESTINAL DISORDERS	21/121 (17.4%)	26	13/119 (10.9%)	17
General disorders
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS	11/121 (9.1%)	11	7/119 (5.9%)	8
Hepatobiliary disorders
HEPATOBILIARY DISORDERS	1/121 (0.8%)	1	0/119 (0%)	0
Immune system disorders
IMMUNE SYSTEM DISORDERS	2/121 (1.7%)	2	1/119 (0.8%)	1
Infections and infestations
INFECTIONS AND INFESTATIONS	32/121 (26.4%)	36	27/119 (22.7%)	32
Injury, poisoning and procedural complications
INJURY, POISONING AND PROCEDURAL COMPLICATIONS	20/121 (16.5%)	31	30/119 (25.2%)	36
Investigations
INVESTIGATIONS	6/121 (5%)	9	4/119 (3.4%)	4
Metabolism and nutrition disorders
METABOLISM AND NUTRITION DISORDERS	4/121 (3.3%)	6	4/119 (3.4%)	5
Musculoskeletal and connective tissue disorders
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS	17/121 (14%)	20	16/119 (13.4%)	19
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS)	9/121 (7.4%)	10	6/119 (5%)	6
Nervous system disorders
DEMENTIA AND AMNESTIC CONDITIONS	0/121 (0%)	0	1/119 (0.8%)	1
NERVOUS SYSTEM DISORDERS	19/121 (15.7%)	23	21/119 (17.6%)	25
Psychiatric disorders
PSYCHIATRIC DISORDERS	18/121 (14.9%)	20	20/119 (16.8%)	23
Renal and urinary disorders
RENAL AND URINARY DISORDERS	7/121 (5.8%)	8	3/119 (2.5%)	3
Respiratory, thoracic and mediastinal disorders
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS	20/121 (16.5%)	23	24/119 (20.2%)	28
Skin and subcutaneous tissue disorders
SKIN AND SUBCUTANEOUS TISSUE DISORDERS	10/121 (8.3%)	11	6/119 (5%)	6
Surgical and medical procedures
SURGICAL AND MEDICAL PROCEDURES	2/121 (1.7%)	3	1/119 (0.8%)	1
Vascular disorders
VASCULAR DISORDERS	15/121 (12.4%)	20	6/119 (5%)	7

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

PIs agree to provide a copy of the manuscript to Dr. Suzanne Craft, Project Director, Wake Forest School of Medicine, and the National Institutes of Health (NIH) must be cited as a funding agency.