Trial Outcomes & Findings for The Study of Nasal Insulin in the Fight Against Forgetfulness (SNIFF) (NCT NCT01767909)

Last Updated: 2024-11-20

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2/PHASE3

Target enrollment

240 participants

Primary outcome timeframe

12 months (blinded phase) followed by 6 months (open label phase)

Results posted on

2024-11-20

Participant Flow

Participant milestones

Participant milestones
Measure	Insulin (Humulin® R U-100) 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.	Placebo 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).
Overall Study STARTED	121	119
Overall Study COMPLETED	108	107
Overall Study NOT COMPLETED	13	12

Reasons for withdrawal

Reasons for withdrawal
Measure	Insulin (Humulin® R U-100) 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.	Placebo 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).
Overall Study Withdrawal by Subject	4	7
Overall Study Adverse Event	3	1
Overall Study Withdrawal by Study Partner	3	1
Overall Study Non-Compliance	2	0
Overall Study Perceived Lack of Efficacy	1	0
Overall Study Investigator Recommendation	0	1
Overall Study Lost to Follow-up	0	1
Overall Study LP uncessessful	0	1

Baseline Characteristics

Number of participants analyzed is lower than the total number of baselined participants due to the primary analysis being a modified intent-to-treat (mITT) analysis using the mixed model repeated measures (MMRM) where only randomized participants with at least one post-baseline assessment are included.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Insulin (Humulin® R U-100) n=121 Participants 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.	Placebo n=119 Participants 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 n=240 Participants Total of all reporting groups
Race (NIH/OMB) More than one race	0 Participants n=121 Participants	1 Participants n=119 Participants	1 Participants n=240 Participants
Age, Continuous	70.46 years STANDARD_DEVIATION 7.38 • n=121 Participants	71.06 years STANDARD_DEVIATION 6.79 • n=119 Participants	70.76 years STANDARD_DEVIATION 7.09 • n=240 Participants
Sex: Female, Male Female	59 Participants n=121 Participants	58 Participants n=119 Participants	117 Participants n=240 Participants
Sex: Female, Male Male	62 Participants n=121 Participants	61 Participants n=119 Participants	123 Participants n=240 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants n=121 Participants	5 Participants n=119 Participants	10 Participants n=240 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	116 Participants n=121 Participants	113 Participants n=119 Participants	229 Participants n=240 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=121 Participants	1 Participants n=119 Participants	1 Participants n=240 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=121 Participants	0 Participants n=119 Participants	0 Participants n=240 Participants
Race (NIH/OMB) Asian	1 Participants n=121 Participants	4 Participants n=119 Participants	5 Participants n=240 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=121 Participants	0 Participants n=119 Participants	0 Participants n=240 Participants
Race (NIH/OMB) Black or African American	3 Participants n=121 Participants	6 Participants n=119 Participants	9 Participants n=240 Participants
Race (NIH/OMB) White	117 Participants n=121 Participants	108 Participants n=119 Participants	225 Participants n=240 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=121 Participants	0 Participants n=119 Participants	0 Participants n=240 Participants
Education	16.07 years STANDARD_DEVIATION 2.64 • n=121 Participants	16.31 years STANDARD_DEVIATION 2.92 • n=119 Participants	16.19 years STANDARD_DEVIATION 2.78 • n=240 Participants
ApoE-e4 carrier status (Positive vs Negative) Negative	42 Participants n=121 Participants	42 Participants n=119 Participants	84 Participants n=240 Participants
ApoE-e4 carrier status (Positive vs Negative) Positive	79 Participants n=121 Participants	77 Participants n=119 Participants	156 Participants n=240 Participants
Alzheimer's Disease Assessment Scale-Cognitive 12 (ADAS-Cog12)	25.91 units on a scale STANDARD_DEVIATION 8.28 • n=121 Participants • Number of participants analyzed is lower than the total number of baselined participants due to the primary analysis being a modified intent-to-treat (mITT) analysis using the mixed model repeated measures (MMRM) where only randomized participants with at least one post-baseline assessment are included.	24.73 units on a scale STANDARD_DEVIATION 7.56 • n=118 Participants • Number of participants analyzed is lower than the total number of baselined participants due to the primary analysis being a modified intent-to-treat (mITT) analysis using the mixed model repeated measures (MMRM) where only randomized participants with at least one post-baseline assessment are included.	25.33 units on a scale STANDARD_DEVIATION 7.94 • n=239 Participants • Number of participants analyzed is lower than the total number of baselined participants due to the primary analysis being a modified intent-to-treat (mITT) analysis using the mixed model repeated measures (MMRM) where only randomized participants with at least one post-baseline assessment are included.
Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB)	3.59 units on a scale STANDARD_DEVIATION 1.51 • n=121 Participants	3.35 units on a scale STANDARD_DEVIATION 1.51 • n=119 Participants	3.47 units on a scale STANDARD_DEVIATION 1.51 • n=240 Participants
Memory Composite (Story Recall and the Free and Cued Selective Reminding Test)	-0.16 units on a scale STANDARD_DEVIATION 2.47 • n=117 Participants • Number of participants analyzed is lower than the total number of baselined participants due to the primary analysis being a modified intent-to-treat (mITT) analysis using the mixed model repeated measures (MMRM) where only randomized participants with at least one post-baseline assessment are included.	0.25 units on a scale STANDARD_DEVIATION 2.59 • n=113 Participants • Number of participants analyzed is lower than the total number of baselined participants due to the primary analysis being a modified intent-to-treat (mITT) analysis using the mixed model repeated measures (MMRM) where only randomized participants with at least one post-baseline assessment are included.	0.04 units on a scale STANDARD_DEVIATION 2.53 • n=230 Participants • Number of participants analyzed is lower than the total number of baselined participants due to the primary analysis being a modified intent-to-treat (mITT) analysis using the mixed model repeated measures (MMRM) where only randomized participants with at least one post-baseline assessment are included.

PRIMARY outcome

Timeframe: 12 months (blinded phase) followed by 6 months (open label phase)

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

Outcome measures

Outcome measures
Measure	Insulin (Humulin® R U-100) n=121 Participants 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.	Placebo n=119 Participants 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).
Change in Global Measure of Cognition as Measured by the Alzheimer's Disease Assessment Scale-Cognitive 12 (ADAS-Cog12) Blinded Phase (M12 change from Baseline)	3.893 Modeled change score on a scale Standard Error 0.643	3.867 Modeled change score on a scale Standard Error 0.650
Change in Global Measure of Cognition as Measured by the Alzheimer's Disease Assessment Scale-Cognitive 12 (ADAS-Cog12) Open Label Phase (M18 change from Baseline)	7.091 Modeled change score on a scale Standard Error 0.937	6.164 Modeled change score on a scale Standard Error 0.942

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Insulin (Humulin® R U-100) n=121 Participants 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.	Placebo n=119 Participants 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).
Change in Memory Composite as Measured by Story Recall (Immediate Paragraph Recall and Delayed Paragraph Recall) and Free and Cued Selective Reminding Test (FCSRT) Blinded Phase (M12 change from Baseline)	-0.496 modeled change score on a scale Standard Error 0.163	-0.433 modeled change score on a scale Standard Error 0.162
Change in Memory Composite as Measured by Story Recall (Immediate Paragraph Recall and Delayed Paragraph Recall) and Free and Cued Selective Reminding Test (FCSRT) Open Label Phase (M18 change from Baseline)	-0.594 modeled change score on a scale Standard Error 0.183	-0.802 modeled change score on a scale Standard Error 0.184

SECONDARY outcome

Timeframe: 12 months (blinded phase) and 6 months (open label phase)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Insulin (Humulin® R U-100) n=121 Participants 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.	Placebo n=119 Participants 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).
Change in Daily Functioning as Measured by the ADCS-MCI Activities of Daily Living (ADCS-ADL-MCI) Blinded Phase (M12 change from Baseline)	-3.63 modeled change score on a scale Standard Error 0.769	-4.26 modeled change score on a scale Standard Error 0.779
Change in Daily Functioning as Measured by the ADCS-MCI Activities of Daily Living (ADCS-ADL-MCI) Open Label Phase (M18 change from baseline)	-7.35 modeled change score on a scale Standard Error 0.925	-6.56 modeled change score on a scale Standard Error 0.934

SECONDARY outcome

Timeframe: 12 months (blinded phase) followed by 6 months (open label phase)

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

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.

Outcome measures

Outcome measures
Measure	Insulin (Humulin® R U-100) n=121 Participants 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.	Placebo n=119 Participants 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).
Change in Cognitive Deficit as Measured by Clinical Dementia Rating - Sum of Boxes (CDR-SB) Open Label Phase (M18 change from Baseline)	2.361 Modeled change in test score Standard Error 0.247	2.122 Modeled change in test score Standard Error 0.249
Change in Cognitive Deficit as Measured by Clinical Dementia Rating - Sum of Boxes (CDR-SB) Blinded Phase (M12 change from Baseline)	1.682 Modeled change in test score Standard Error 0.195	1.402 Modeled change in test score Standard Error 0.196

SECONDARY outcome

Timeframe: Screen and Month 12

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Insulin (Humulin® R U-100) n=116 Participants 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.	Placebo n=116 Participants 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).
Change in Hippocampal and Entorhinal Atrophy as Measured by Magnetic Resonance Imaging (MRI) Normalized hippocampal volume change	-0.01 % change in volume Standard Deviation 0.02	-0.02 % change in volume Standard Deviation 0.02
Change in Hippocampal and Entorhinal Atrophy as Measured by Magnetic Resonance Imaging (MRI) Normalized whole brain volume change	-1.35 % change in volume Standard Deviation 1.09	-1.41 % change in volume Standard Deviation 1.18
Change in Hippocampal and Entorhinal Atrophy as Measured by Magnetic Resonance Imaging (MRI) Normalized entorhinal volume change	-0.01 % change in volume Standard Deviation 0.03	-0.01 % change in volume Standard Deviation 0.03

SECONDARY outcome

Timeframe: Baseline and Month 12

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

Quantify Abeta and Tau biomarkers in CSF

Outcome measures

Outcome measures
Measure	Insulin (Humulin® R U-100) n=72 Participants 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.	Placebo n=75 Participants 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).
Change in CSF Biomarkers of AD Abeta 40	-264.851 pg/ml Standard Deviation 1168.995	-127.539 pg/ml Standard Deviation 1600.604
Change in CSF Biomarkers of AD Abeta 42	-15.552 pg/ml Standard Deviation 61.884	-4.456 pg/ml Standard Deviation 82.156
Change in CSF Biomarkers of AD Total Tau	-4.717 pg/ml Standard Deviation 263.810	1.937 pg/ml Standard Deviation 291.160
Change in CSF Biomarkers of AD p-Tau	-2.764 pg/ml Standard Deviation 18.729	-0.567 pg/ml Standard Deviation 25.293

Adverse Events

Insulin (Humulin® R U-100)

Serious events: 18 serious events

Other events: 98 other events

Deaths: 1 deaths

Placebo

Serious events: 10 serious events

Other events: 91 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Insulin (Humulin® R U-100) n=121 participants at risk 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.	Placebo n=119 participants at risk 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).
Blood and lymphatic system disorders BLOOD AND LYMPHATIC SYSTEM DISORDERS	1.7% 2/121 • Number of events 2 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	0.00% 0/119 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.
Cardiac disorders CARDIAC DISORDERS	1.7% 2/121 • Number of events 2 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	2.5% 3/119 • Number of events 4 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.
Gastrointestinal disorders GASTROINTESTINAL DISORDERS	2.5% 3/121 • Number of events 3 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	0.84% 1/119 • Number of events 1 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.
General disorders GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS	0.83% 1/121 • Number of events 3 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	1.7% 2/119 • Number of events 2 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.
Hepatobiliary disorders HEPATOBILIARY DISORDERS	0.83% 1/121 • Number of events 1 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	0.00% 0/119 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.
Infections and infestations INFECTIONS AND INFESTATIONS	0.83% 1/121 • Number of events 1 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	1.7% 2/119 • Number of events 2 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.
Injury, poisoning and procedural complications INJURY, POISONING AND PROCEDURAL COMPLICATIONS	0.83% 1/121 • Number of events 1 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	0.00% 0/119 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS)	0.83% 1/121 • Number of events 1 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	0.84% 1/119 • Number of events 1 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.
Nervous system disorders NERVOUS SYSTEM DISORDERS	0.83% 1/121 • Number of events 1 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	1.7% 2/119 • Number of events 2 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.
Psychiatric disorders PSYCHIATRIC DISORDERS	0.83% 1/121 • Number of events 1 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	0.00% 0/119 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.
Renal and urinary disorders RENAL AND URINARY DISORDERS	1.7% 2/121 • Number of events 3 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	0.00% 0/119 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.
Vascular disorders VASCULAR DISORDERS	3.3% 4/121 • Number of events 7 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	0.84% 1/119 • Number of events 1 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.

Other adverse events

Additional Information

Suzanne Craft, PhD, Project Director for Clinical Trial

Wake Forest School of Medicine

Phone: (336) 713-8830

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER

Measure	Insulin (Humulin® R U-100) n=121 participants at risk 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.	Placebo n=119 participants at risk 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).
Blood and lymphatic system disorders BLOOD AND LYMPHATIC SYSTEM DISORDERS	3.3% 4/121 • Number of events 4 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	1.7% 2/119 • Number of events 2 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.
Cardiac disorders CARDIAC DISORDERS	6.6% 8/121 • Number of events 9 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	5.0% 6/119 • Number of events 8 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.
Nervous system disorders DEMENTIA AND AMNESTIC CONDITIONS	0.00% 0/121 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	0.84% 1/119 • Number of events 1 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.
Endocrine disorders ENDOCRINE DISORDERS	0.83% 1/121 • Number of events 1 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	0.00% 0/119 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.
Eye disorders EYE DISORDERS	4.1% 5/121 • Number of events 5 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	1.7% 2/119 • Number of events 2 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.
Gastrointestinal disorders GASTROINTESTINAL DISORDERS	17.4% 21/121 • Number of events 26 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	10.9% 13/119 • Number of events 17 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.
General disorders GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS	9.1% 11/121 • Number of events 11 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	5.9% 7/119 • Number of events 8 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.
Hepatobiliary disorders HEPATOBILIARY DISORDERS	0.83% 1/121 • Number of events 1 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	0.00% 0/119 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.
Immune system disorders IMMUNE SYSTEM DISORDERS	1.7% 2/121 • Number of events 2 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	0.84% 1/119 • Number of events 1 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.
Infections and infestations INFECTIONS AND INFESTATIONS	26.4% 32/121 • Number of events 36 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	22.7% 27/119 • Number of events 32 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.
Injury, poisoning and procedural complications INJURY, POISONING AND PROCEDURAL COMPLICATIONS	16.5% 20/121 • Number of events 31 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	25.2% 30/119 • Number of events 36 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.
Investigations INVESTIGATIONS	5.0% 6/121 • Number of events 9 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	3.4% 4/119 • Number of events 4 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.
Metabolism and nutrition disorders METABOLISM AND NUTRITION DISORDERS	3.3% 4/121 • Number of events 6 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	3.4% 4/119 • Number of events 5 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.
Musculoskeletal and connective tissue disorders MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS	14.0% 17/121 • Number of events 20 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	13.4% 16/119 • Number of events 19 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS)	7.4% 9/121 • Number of events 10 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	5.0% 6/119 • Number of events 6 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.
Nervous system disorders NERVOUS SYSTEM DISORDERS	15.7% 19/121 • Number of events 23 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	17.6% 21/119 • Number of events 25 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.
Psychiatric disorders PSYCHIATRIC DISORDERS	14.9% 18/121 • Number of events 20 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	16.8% 20/119 • Number of events 23 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.
Renal and urinary disorders RENAL AND URINARY DISORDERS	5.8% 7/121 • Number of events 8 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	2.5% 3/119 • Number of events 3 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.
Respiratory, thoracic and mediastinal disorders RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS	16.5% 20/121 • Number of events 23 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	20.2% 24/119 • Number of events 28 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.
Skin and subcutaneous tissue disorders SKIN AND SUBCUTANEOUS TISSUE DISORDERS	8.3% 10/121 • Number of events 11 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	5.0% 6/119 • Number of events 6 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.
Surgical and medical procedures SURGICAL AND MEDICAL PROCEDURES	1.7% 2/121 • Number of events 3 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	0.84% 1/119 • Number of events 1 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.
Vascular disorders VASCULAR DISORDERS	12.4% 15/121 • Number of events 20 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.	5.0% 6/119 • Number of events 7 • Adverse Event Table represents data collected over a period of 12 months (blinded phase). "Other (Not Including Serious) Adverse Events" reported include both Serious and Non Serious Adverse Events.